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Vademecum for VitaminFormulations

Wissenschaftliche Verlagsgesellschaft mbH Stuttgart 2001

by Volker Bühler

2nd revised edition

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Preface

Vitamin products began to be developedseveral decades ago. Nevertheless, thereis still much that is obscure in the phar-maceutical technology of vitamins. Thisderives from the specific problems asso-ciated with this class of substances. Themultivitamin products are unique in com-bining such a large number of active sub-stances with entirely different chemicalstructures and physical properties. Thisis compoundes by the fact that virtuallyall the vitamins are more or less unstablewhen formulated and some of them inter-act to result in decomposition.There has been a large number of publi-cations on the pharmaceutical technologyof vitamin formulations. The intention ofthis text is not merely to review the lite-rature. Although a wide selection of pu-blications has been quoted in order to

give an overview, our own work repre-sents a large proportion of the text andthis is reflected by the many formulationswhich are specified, almost all of whichwere developed in the food products/pharmaceuticals applications laboratoriesof BASF AG, Ludwigshafen, FRG. Ho-wever, not all of them have been exami-ned for chemical stability.On this basis, the present text aims tomake the process of development of vit-amin products intelligible and thus to aidpharmacists engaged in this work.The entries have been arranged alphabe-tically to provide rapid access to the in-formation, and this is facilitated by cross-references and the key words which areprinted in italics.

Spring 1988 Volker Bühler

In the second edition of this book some amendements and actualizations wereintroduced. This concerns e. g. the situation of the Pharmacopoeias and other legalconditions. Furthermore several new formulations of vitamin combinations (e. g.multivitamin syrup, vitamin C + E tablets, vitamin B complex injectable, multivitamineffervescent tablets, multivitamin tablets with minerals) and a great chapter of multi-vitamin solutions were added to impart an even better knowledge about the pharma-ceutical technology of vitamins.Since this book has the structure of a dictionary and many crosslinks between theindividual sections are included it was decided to offer it also in an electronic form ofthe attached CD-ROM.An alphabetical index of all formulations listed in the book was added.

September 2000 Volker Bühler

5

Index of Formulations

The following vitamin formulations are includes in this book as typical examples.Further formulae are available in the literature [279].

Formulation page Formulation page

Acetylsalicylic acid + Vitamin C tablets(400+ 200 mg) 8

Beta-carotene + Vitamin C + Vitamin Echewable tablets (10+ 500 + 250 mg) 9

Beta-carotene tablets (15 mg) 31Beta-carotene tablets (5 mg) 16Calcium D-pantothenate tablets (250 mg) 21Multivitamin + copper + zinc mixture

and tablets 134Multivitamin effervescent tablets

(1-2 RDA) 76Multivitamin instant granules 62Multivitamin syrup (1-2 RDA/20 ml) 120Multivitamin tablets with minerals

(2 RDA) 75Multivitamin tablets 76Multivitamin two chamber ampules 130Nicotinamide tablets (200 mg) 80Pyridoxal phoshate solution for

lyophilization 99Suspension for a water-soluble

film-coating of tablets 46Suspension for automatic sugar-

film-coating of tablets 119Suspension of ethylcellulose for

film-coating of tablets 43Tretinoin cream with dexpanthenol 35Vitamin A chewable tablets

(100,000 I.U.) 71Vitamin A chewable tablets

(50,000 I.U.) 102Vitamin A drops (50,000 I.U/ml) 93Vitamin A drops, unstabilized

(50,000 I.U./ml) 112Vitamin A tablet (75,000 I.U.) 35Vitamin A/D/E emulsion

(for veterinary use) 19Vitamin A/D/E emulsion for injection

(for veterinary use) 41Vitamin A + D concentrate for

processing (100,000 + 20,000 I.U./ml) 89Vitamin A + D drops

(25,000 + 2,500 I.U./ml) 103

Vitamin A + E chewable tablets(30,000 I.U.+ 30 mg) 114

Vitamin A + E drops(25,000 I.U.+ 50 mg/ml) 96

Vitamin A + E drops(825,000 I.U.+ 50 mg/ml) 89

Vitamin B complex + C effervescenttablets 123

Vitamin B complex + C syrup 15, 34Vitamin B complex injectable 32Vitamin B complex tablets 15, 125Vitamin B1 tablets (100 mg) 67, 125Vitamin B1 tablets (50 mg) 37Vitamin B2 tablets (100 mg) 105Vitamin B6 tablets (250 mg) 99Vitamin B6 tablets (160 mg) 57Vitamin B6 tablets (40 mg) 117Vitamin B6 tablets (30 mg) 28Vitamin C+ Rutin tablets 107Vitamin C capsules (100 mg) 53Vitamin C chewable tablets (100 mg) 30Vitamin C effervescent tablets

(1000 mg) 28Vitamin C effervescent tablets

(500 mg) 40Vitamin C sustained release tablets

(200 mg) 119Vitamin C tablets (100 mg) 12, 51Vitamin C tablets (500 mg) 36Vitamin C tablets (250 mg) 109Vitamin C tablets (500 mg) with trace

elements 129Vitamin C+ D + calcium effervescent

tablets 74Vitamin C+ E chewable tablets 7Vitamin C+ E chewable tablets

(500+ 20 mg) 12Vitamin E acetate solutions

(20 mg/ml) 113Vitamin E chewable tablets (200 mg) 24, 70Vitamin E chewable tablets (50 mg) 21Vitamin E tablets (100 mg) 128Vitamin K1 solution (10 mg/ml) 92

6

A

A, vitaminsee retinol, retinyl acetate, retinyl pal-mitate and retinyl propionate.

Acetiamine

Acetiamine (syn. thianeurone or diaceta-mine) is a thiamine derivative which israrely used in pharmaceuticals. It differsfrom other thiamine derivatives in beinglipid-soluble.

AdsorbateAn adsorbate is a dry powder consistingof a carrier (e. g. silica gel) onto which adefined percentage of a usually liquidvitamin has been bounded by adsorption.Examples are adsorbates of tocopherylacetate and dexpanthenol. Adsorbatesare produced to allow these vitamins tobe incorporated into solid drug forms.Adsorbates are usually unsuitable for di-rect tabletting if their particle size distri-bution includes excessively fine materialand/or the expressibility is too high. Theycan, nevertheless, be compressed directlyif the concentration of the adorbate in thetablet is not too high, as in the followingcomposition for a vitamin C+E chewabletablet.

Vitamin C+E chewable tablet

Tocopheryl acetate dry powderadsorbate 50 % [1] 550.0 mgAscorbic acid for directcompression 400.0 mgSorbitol 800.0 mgOrange flavo(u)r 10.0 mgSaccharin, sodium salt 0.3 mgCyclamate, sodium salt 3.0 mg

Aerosil�

Aerosil is a registered trademark [4] forhighly disperse silica. The type usuallyemployed in vitamin products is Aero-sil 200.

Alfacalcidol

Alfacalcidol (syn. 1-alpha-hydroxy-cho-lecalciferol) is a synthetic substance hor-monal form of cholecalciferol.The substance takes the form of whitecrystals which are insoluble in water butsoluble in oil and are encapsulated, forexample, as vitamin D3. Alfacalcidol hasthe same vitamin action as cholecalcife-rol.

7 Alfacalcidol

A

AnalgesicsIt is sometimes appropriate to combinesome analgesics, such as acetylsalicylicacid or paracetamol, with ascorbic acid.A typical example is the following com-position for a mixture for direct tablet-ting:

Acetylsalicylic acid + vitamin C tablet(400 mg/200 mg)

Acetylsalicic acid 400 mgAscorbic acid, for directcompression

220 mg

Sorbitol 150 mgCellulose, microcrystalline [2] 50 mgCopovidone 20 mgCrospovidone 35 mgMagnesium stearate 3 mgPolyethylene glycol 6000, powder 20 mg

AnalysisIn the analysis of vitamins a distinctionhas to be made between examination ofpure substances and that of products. Theanalysis of pure substances will complywith current pharmacopeias. This willoften also apply to single-vitamin pro-ducts.Determination of the contents of vitaminsin combination products is nowadaysmainly carried out by highpressure liquidchromatography (HPLC), which can fre-quently be used to determine several vit-amins at the same time.Analysis in products is of importance toformulating pharmacists since the stabili-ty of the vitamins is a major problem, andthis can be monitored only by analysis.

AneurineAneurine is a former name for thiamine.

AntagonistSome sustances act as vitamin antago-nists, i.e. they may reduce or abolish thevitamin activity. The table below listssome examples.

Vitamin antagonists (selection)

Vitamin Antagonist

Retinol Liquid paraffinThiamine Ethanol, sugars in

large amountsRiboflavin Ethanol, contracep-

tives, antibioticsNicotinamide Ethanol, antibiotics,

sugars in largeamounts

Pyridoxine Levodopa, isoniazid,hydralazine andothers [172]

Cyanocobalamin ContraceptivesFolic acid Ethanol, contracep-

tives, phenytoin,primidone

Ascorbic acid Nicotine, ethanol,acetylsalicylic acid,corticoids, indometh-acin

Cholecalciferol Liquid paraffinTocopherol Liquid paraffin,

contraceptives, ironBiotin Antibiotics, sulfon-

amides

Vitamin antagonists should not be com-bined or taken with vitamin products. Ifthis is unavoidable for more than a shortperiod, the daily requirement of the rele-vant vitamin will be increased.

AntioxidantsSince many vitamins are sensitive to oxi-dation, it is important to use antioxidantsin the relevant vitamin products [13, 14,209, 241]. Antioxidants for vitamins arelisted in the table below.

Analgesics 8

Antioxidants for vitamins

Vitamin Antioxidant

Retinol,cholecalciferoland ergocalciferol

Butylated hydroxya-nisole or butylatedhydroxytoluene, al-pha-tocopherol andpropyl gallate

B vitamins Propyl gallateAscorbic acid Sodium sulfite,

propyl gallateBeta-carotene Alpha-tocopherol,

ascorbyl palmitateFolic acid Butylated hydroxy-

anisole, nordihydro-guaiaretic acid

The modes of action of the individualantioxidants differ. Thus, for example,tocopherols, butylated hydroxytoluene,and propyl gallate trap free radicals, andsodium sulfite and ascorbyl palmitate arereducing agents or oxygen traps. The twogroups may complement each other's ac-tion, and their actions are potentiated bysynergists, such as lecithin, citric acid orethylenediaminetetraacetic acid.Ascorbic acid can also be used as a wa-ter-soluble antioxidant in other products.Beta carotene, vitamin C and vitamin Eare considered as physiological antioxi-dants. A typical formulation of such pre-paration is given in the table below.

Beta-carotene + vitamin C + vitamin Echewable tablet (10 mg/500 mg/250 mg)

Beta carotene dry powder 10% 100 mgAscorbic acid, crystalline 250 mgSodium ascorbate, crystalline 280 mgVitamin E acetate 50 % SD 500 mgSorbitol, crystalline 600 mgLudipress 500 mgFructose 350 mgPolyethylene glycol 6000,powder 50 mgManufacturing:Direct compression

Apocarotenal

Apocarotenal (syn. beta-apo-8'-carote-nal) is a carotenoid as found in natureand, when used to colo(u)r food products,has the E number E 160 e. It takes theform of brown crystals which are insolu-ble in water. Apocarotenal is soluble tothe extent of about 5 % in oils.In sugar-coating, apocarotenal has pro-ved to be the carotenoid colorant whichis most stable to light. It can be dissolvedin the coating suspension as a 5% copre-cipitate with polyvinylpyrrolidone. Thecoating is darker than that obtained withbeta-carotene.

Aquocobalaminsee hydroxocobalamin.

Ascorbic acid

Ascorbic acid (syn. L(+)-ascorbic acid)and its salts, e.g. sodium or calcium as-corbate, are vitamin C.Ascorbic acid is a white, odo(u)rless, ma-cro- or microcrystalline powder with astrongly acid taste. It dissolves to theextent of about 30% in water, is nothygroscopic and has a relatively high re-duction potential. This is why it under-goes many chemical interactions withother vitamins and has to be regarded as

9 Ascorbic acid

A

one of the unstable vitamins. Ascorbicacid decomposes in two ways, both ofwhich involve the reversible step to pro-duce dehydroascorbic acid:1. Anaerobic hydrolysis resulting in car-

bon dioxide and furfural (q.v. for reac-tion scheme), and brown resins produ-ced from the latter.

2. Aerobic degradation, in which oxida-tion produces oxalic acid (q.v. forreaction scheme).

The rates of these decomposition reacti-ons vary with the pH [15, 125, 253], asshown by the following figure.

Effect of the pH on the decomposition ofascorbic acid [15].

Liquid drug forms containing ascorbicacid have been examined for their stabi-lity by a number of authors. For oralsolution, particular attention must bepaid to the pH, the addition of chelatingagent to counter the catalytic action ofheavy metals on oxidation, the absence ofoxidizing agents including oxygen, thesolvent, and the possible stabilizing ac-tion of sugars [16]. It is possible to sta-bilize ascorbic acid solutions with, forexample, sucrose, glucose, fructose, ethy-

lenediaminetetraacetic acid (EDTA), ci-tric acid, propyl gallate, glycerol, andpropylene glycol.For examples of use in vitamin B com-plex + C syrup, see B complex and dex-panthenol. The table below shows thebest stabilizers for an aqueous ascorbicacid solution of pH 2.7 [20]:

The best stabilizers for ascorbic acid solu-tions in water

Storage Stabilizer Ratio ofascorbicacid tostabilizer

Under air Ethylenediaminete-traacetic acid 100 : 1Sodium sulfite 100 : 1Citric acid 10 : 1Glucose 10 : 1

Under Sodium sulfite 100 : 1nitrogen Maltose 10 : 1

Propyl gallate 100 : 1

A syrup containing no sucrose with asherry flavo(u)r, composed of glyceroland sorbitol, containing 25 mg or100 mg ascorbic acid per teaspoon(4 ml), with an excess of 20 %, can havethe following composition [22]:

Composition of auxiliaries for a vitamin Csyrup

Sherry essence 0.4 gCitric acid 10.0 gWater 10.0 gGlycerol 75.0 g70% sorbitol solution ad 1000.0 g

After storage for one year at room tem-perature, the loss of ascorbic acid wasabout 15%. The relative losses wereless at higher than at lower concentra-tions. The stability of the ascorbic acid

Ascorbic acid 10

was somewhat better in the glycerol/sor-bitol base than in a sucrose syrup.When the effects of glucose, sucrose andsorbitol on the stability of vitamin C inmultivitamin drops were compared, o dif-ference was found between sorbitol andsucrose at pH 4.5 and 7.0. The stabilitywas worse with glucose [152].Addition of carboxymethylcellulose and/or tragacanth reduced the stability of as-corbic acid in oral solutions [21].In the production of injectables it isabsolutely necessary to minimize thecontents of heavy metals, e.g. iron andcopper, and oxygen. Thus, only waterwhich has been freshly distilled overglass or silver, and from which the oxy-gen has been completely removed byboiling immediately before use, shouldbe used. The ascorbic acid solution mustbe processed under an inert gas atmo-sphere. All the vessels and the apparatuswhich come into contact with the solu-tion must be made of glass or stainlesssteel.The optimum pH for stability of ascorbicacid solutions is between 5.5 and 6.5.Sodium bicarbonate is best for adjustingto this pH.The solution is dispensed, under a streamof carbon dioxide, into brown ampules

which have been carefully cleaned andsterilized. The ampules are then imme-diately sealed and sterilized.Ascorbic acid is generally much morestable in solid drug forms than in liquidproducts. In uncolo(u)red or uncoated ta-blets, it is the hydrolysis and the associa-ted discoloration, which becomes evidentmuch sooner than the oxidation. Thereare contradictory reports in the literatureon the effect of auxiliaries on the stabilityof vitamin C tablets (see table below).The reason for these differences is pro-bably that these auxiliaries usually exertonly an indirect effect on the hydrolysisof ascorbic acid. This is evident from thefact that ascorbic acid granules of a par-ticular composition differ greatly in co-lo(u)r stability when produced using anaqueous solution of polyvinylpyrrolidoneon the one hand in a fluidized bed and onthe other hand in a traditional granulator.The granules from the fluidized bed showno change in colo(u)r for more than12 months while those from the traditio-nal process, which have been well dried,show a brownish colo(u)r after only6 months. This means that great caremust be taken with the contact betweenwater and ascorbic acid during and afterthe granulation of the product.

Effect of auxiliaries on the stability of ascorbic acid tablets

[16] [23] [21] [24] [129]

Very suitable MannitolCellulose,microcryst.

Polyvinyl-pyrrolidoneLactose

LactoseStarchDextrin

MannitolLactoseSucrose

SorbitolLactose

Suitable SucroseLactose

SucroseStarch

Less suitable GlucoseCalciumhydrogenphosphateStarch

Mannitol Polyvinyl-pyrrolidone

StarchGlucoseAluminiumoxide

11 Ascorbic acid

A

The ideal solution to this problem is di-rect tabletting or compaction [261]. Un-fortunately, the physical properties of as-corbic acid mean that it is unsuitable fordirect tabletting at concentrations above50% in the tabletting mixture.However, at lower concentrations there isno problem if the ascorbic acid has theparticle size distribution which is appro-priate for the particular formulation. Thisis shown by the following example of avitamin C composition for direct tablet-ting [176]:

Vitamin C tablets (100 mg)

Ascorbic acid(90 % below 150 �m) 40.0%Starch, mechanically treated,Type 1500

57.5%

Stearic acid 2.0 %Silica, highly dispers [4] 0.5 %

Slight modification of the tablet composi-tion may allow the ascorbic content to beincreased [257].An example of vitamin C + vitamin Echewable tablets is given in the followingtable.

Vitamin C + vitamin E chewable tablets(500 mg + 20 mg)

Ascorbic acid, powder 375 mgSodium ascorbate, crystalline 142 mgVitamin E acetate drypowder 50% 40 mgLudipress LCE 840 mgPolyethylene glycol, powder 40 mgOrange flavour 25 mgMango flavour 25 mgAspartame 20 mgManufacturing:Direct compression

For further examples of use in solid drugforms see compaction, effervescent ta-blets, copovidone, glucose, minerals,

multivitamin solid preparations, sodiumascorbate, tabletting pressure, instantgranules, tartaric acid, and vitamin mix-ture.If there is to be more than 50% ascorbicacid in the tablet, it is advisable to use atype meant for direct compression, com-mercially available with a vitamin C con-tent of 90 to 98%. However, the use ofthis type of ascorbic acid may be advan-tageous in other cases, too, as shown bythe examples given under adsorbate,analgesics, direct compressible vitamins,and trace elements.Also commercially available are coatedtypes of ascorbic acid. These are coatedwith, for example, 3 to 5% ethylcellulo-se, silicone oil or fat. The use of thesetypes of ascorbic acid may in some casesimprove the stability. However, this oftendoes not apply to tablets since the coatingis insufficient to withstand the mechani-cal stress of tabletting and maintain theprotection against chemical interactionswith other vitamins or moisture [25].Apart from its use as a vitamin, ascorbicacid is used in, for example, food pro-ducts as a reducing agent and water-so-luble antioxidant (E number E 300).

Ascorbyl palmitate

Ascorbyl palmitate (syn. palmitic acidester of L(+)-ascorbic acid) is a white,virtually odo(u)rless powder.Ascorbyl palmitate is used as a fatsolubleantioxidant with the E number E 304, ac-ting as an oxygen trap or reducing agent

Ascorbyl palmitate 12

to stabilize fats, oils, and beta-carotene.It can also act as a synergist with otherantioxidants by regenerating them andthus prolonging their action.The concentration range generally usedin fats and oils is 0.05 to 0.1%. Theconcentration can be higher in beta-caro-tene products, with use being made of thesynergism with lecithin and tocopherol.

Avicel�

Avicel is a registered trademark [2] formicrocrystalline cellulose.

The Avicel types used most often formsolid drug forms containing vitamins arePH 101, PH 102 and PH 200, the partic-les in the latter being somewhat morecoarse than those in the former.

Axerophthololder name for retinol or vitamin A alco-hol.

13 Axerophthol

A

B

B1, vitaminsee cocarboxylase, thiamine hydrochlori-de, thiamine mononitrate.

B2, vitaminsee riboflavin, riboflavin-phosphate so-dium.

B3, vitaminsee niacin, nicotinamide, nicotinic acid.

B5, vitaminsee calcium pantothenate, dexpanthenol,sodium pantothenate.

B6, vitaminsee pyridoxal phosphate, pyridoxine hy-drochloride.

B12, vitaminsee cyanocobalamin, hydroxocobalamin.

B13, vitaminsee orotic acid.

BC, vitaminsee folic acid.

B complex

The following vitamins are regarded asbelonging to the vitamin B complex:k thiamine,k riboflavin,k niacin,k pantothenic acid,k pyridoxine,k cobalamin,k folic acid.Not all the commercially available vitaminB complex products contain all these vit-amins. This particularly applies to folic acidand/or pantothenic acid, which considera-bly simplifies formulation.In the case of liquid drug forms, if possi-ble, cyanocobalamin should not be com-bined with the other vitamins in the samesolution. The main reason for stabilityproblems with folic acid and D-pantothe-nates is the pH, which should be about 4for the other B vitamins. The main ad-verse factor with cyanocobalamin is thechemical interactions with the other vit-amins. In general, pyridoxine hydrochlo-ride, riboflavin-phosphate, sodium, andnicotinamide can be regarded as invol-ving the fewest problems amongst thevitamins of the B complex. Thiamine hy-drochloride occupies an intermediate po-sition.Thought has to be given to the possibleuse of antioxidants, chelating agents, andsolvents, the protection from light, theminimization of chemical interactions,and the consequent overages [33]. Thefollowing formulation for a vitamin Bcomplex + C syrup attempts to take ac-count of all these (see also dexpanthenoland cyanocobalain).

B1, vitamin 14

Vitamin B complex + C syrup

I. Thiamine hydrochloride 27 mgRiboflavin-phosphatesodium 27 mgNicotinamide 125 mgDexpanthenol 55 mgPyridoxine hydrochloride 27 mgAscorbic acid 400 mgOrange flavo(u)r 50 mgEthylenediaminetetraaceticacid, disodium salt 10 mg

II. Propylene glycol + water(2 + 1) 30 ml

III. Parabens 250 mgSorbitol 15 mgSucrose 100 mgWater 70 ml

Dissolve I in II; prepare solution III byheating, allow to cool and mix with I/II.Adjust the pH to 4.2 or 4.3, Dispense undernitrogen.The syrup has been stored in the dark atroom temerpature for 1 year and analyzedby HPCL. The measured losses were asfollows:Thiamine hydrochloride 15%Riboflavin-phosphate sodium 13%Nicotinamide 0 %Dexpanthenol 14%Pyridoxine hydrochloride 4 %Ascorbic acid 12%

The stability is distinctly better in soliddrug forms. There are no problems withdirect tabletting of the B complex whensufficient amounts of auxiliaries are used[198], as is shown by the two variants ofa mixture for direct tabletting in the fol-lowing table.For another formulation of vitamin Bcomplex tablets, see thiamine mononitra-te. For an example of vitamin B complex+ C effervescent tablets, see tartaricacid.See vitamin derivatives for the forms ofvitamins which are best for solid andliquid products.

Vitamin B complex tablets

Variant 1 Variant 2

Thiaminemononitrate 24 mg 15 mgRiboflavin 24 mg 15 mgNicotinamide 80 mg 50 mgCalciumpantothenate 40 mg 25 mgPyridoxinehydrochloride 16 mg 10 mgCyanocobalamin,0.1 % gelatin-coated [3] 16 mg 10 mgCellulose,microcryst. [2] 280 mg 175 mgPolyvinyl-pyrrolidone K 30 16 mg 10 mgSilica,highly disperse[4] 3 mg 2 mg

Benfotiamine

Benfotiamine is a white, crystalline pow-der.It is occasionally used as vitamin B1. Thehighest stability is shown by aqueous so-lutions of pH 3.8 since hydrolysis increa-ses at higher and lower values [171].

Benzoylthiamine disulfideBenzoylthiamine disulfide is a fine whitepowder.This thiamine derivative is occasionallyused and is said to have a prolonged ac-tion. Its stability in tablets is better thanthat of thiamine hydrochloride or thia-mine mononitrate [21]. In aqueous solu-tion at pH 7.4, benzoylthiamine disulfide

15 Benzoylthiamine disulfide

B

is unstable compared with thiamine sul-fide [225].

Benzyl alcohol

Benzyl alcohol is a clear colo(u)rless li-quid with an aromatic odo(u)r, which issoluble to the extent of about 4% inwater and freely soluble in oils.It is used as a preservative in aqueousand oily vitamin injectables ± especiallyin veterinary products. The concentrationis normally below 2 %.For examples of use, see emulsion andtwo-chamber ampules.

Beta-carotene(see formula below)

Beta-carotene (syn. all-trans-beta-carotene,provitamin A) is a brownish-violet crystal-line powder with a characteristic odo(u)rand taste. It is insoluble in water, ethanoland cold oils. It is soluble to the extent ofabout 3% in chloroform. It can be dissolvedin hot oils or fats, because heat causespartial isomerization, which improves thesolubility. In nature, too, all-trans-beta-ca-rotene is mixed with isomers.The pure all-trans compound is normallystated to have a vitamin A activity of1.67 million I. U./g. However, accordingto the German Society for Nutrition, thevitamin A activity of 1 mg retinol corre-

sponds to 6 mg beta-carotene [27]. Beta-carotene is sensitive to heat, oxidationand light, although it can be more stablethan vitamin A.Beta-carotene is mainly used in soliddrug forms and soft gelatin capsules.For use as a colorant (E number E 160 a)in sugar-coating, it can be incorporatedin the coating suspension in the form of adry powder which is dispersible in coldwater, or of a 5 % coprecipitate with po-lyvinylpyrrolidone. It is less suitable forfilm-coatings containing no sucrose, be-cause it rapidly undergoes photolytic de-composition in this form.For tablets, hard gelatin capsules andgranules, beta-carotene is used as provit-amin A in the form of dry powders (e.g.10% beta-carotene) in order to avoid vit-amin A. The following example of abeta-carotene composition for direct ta-bletting illustrates this:

Beta-carotene tablet (5 mg)

Beta-carotene dry powder, 10% 50 mgLudipress� [1] 150 mgMagnesium stearate 1 mg

For further examples of use in tablets, seeantioxidants, crospovidone, minerals andmultivitamin solid preparations.For the production of soft gelatin capsu-les, it is best to use the oily suspensionsof beta-carotene which are comperciallyavailable.In solid drug forms, it is preferably sta-bilized with the antioxidant/synergistmixture of tocopherol, ascorbyl pal-mitate, and lecithin (e.g. 1+5+10).

Benzyl alcohol 16

The presence of ascorbic acid may havean adverse effect on the stability of beta-carotene dry powders.In liquid drug forms, beta-carotene canbe used as a colorant by addition of adry powder which is dispersible in coldwater to, for example, suspensions oremulsions. A 4 or 5% solution for injec-tion can be prepared using 25% of thesolubilizer PEG hydroxystearate [28].

BHAsee butylated hydroxyanisole.

BHTsee butylated hydroxytoluene.

BindersBinders are auxiliaries which are used ingranules and, especially, tablets in orderto increase tablet hardness. The bindersmost commonly used in vitamin tabletsare listed below.

Binders commonly used for vitamin pro-ducts

StarchPolyvinylpyrrolidone (povidone)Cellulose, microcrystallineCarboxymethylcelluloseCopovidoneGelatinHydroxypropyl(methyl)cellulosePolyethylene glycol(Sucrose)(Sorbitol)(Mannitol)

In direct tabletting the binders like copo-vidone are added dry, not all being suita-ble for this purpose (e.g. gelatin), while asolution of the binder is normally usedfor granulation.

Virtually the only ones suitable, becauseof the solubility in water, for effervescenttablets are polyvinylpyrrolidone, copovi-done, and possibly polyethylene glycol.

BioavailabilityInvestigations into the behavio(u)r of vit-amin products in the body are less com-mon in the literature than are those onsome other pharmaceuticals. This may beconnected with the fact that, in the past,the analysis of some vitamins in biologi-cal fluids was difficult. On the otherhand, a bioavailability study on a multi-vitamin product involves an effort whichcan scarcely be justified.The bioavailability of the hydrophilic vit-amins from normal products (without de-layed release) is usually good.Examination of the bioavailability of thelipophilic vitamins is more important. Itcan be greatly influenced by the auxiliaries± solubilizers, solvents, food additives, etc.[264]. The figure below shows the diffe-rence caused by auxiliaries in vitamin Asolutions injected into chickens.

Bioavailability of vitamin A in chickens 14days after parenteral administration.

In solid forms with beta-carotene, theparticle size of the latter may also affectthe bioavailability (see particle size dis-tribution).

17 Bioavailability

B

Sustained-release vitamin products arerelatively uncommon. This effect can beachieved as follows:1. Addition of more than 20% galacto-

mannan delays the release of ascorbicacid from 250 mg vitamin C tablets[30].

2. Mannitol and aminoacetic acid delaythe release of cyanocobalamin fromtablets [31].

3. Embedding of vitamin B2 in traga-canth, gum arabic, and ethylcellulosein a tablet core which is provided witha riboflavin-containing ethylcellulosecoating extends the period of release[32].

4. Mixing of vitamins with a spray driedcombination of polyvinylacetate andprovidone (8+2) and compression togive tablets may delay the releasemarkedly.

BioflavonoidsBioflavonoids (syn. flavonoids) are agroup of substances formerly called vit-amin P. The basic chemical structure ofthe bioflavonoids is that of flavone:

The most important bioflavonoids are ru-tin, quercetin, and hesperidin. Rutin isvirtually the only bioflavonoid which isused as active ingredient in pharmacyand it is said to have the highest vitaminP activity (synergistic action with ascor-bic acid).Bioflavonoids are also used as auxilia-ries, because they inhibit the oxidationof ascorbic acid catalyzed by heavy me-tals [29].

For examples of the use of rutin in ta-blets, see minerals.

Biotin

Biotin (syn. D(+)-biotin, vitamin H) is awhite powder which is very slightly so-luble in water (below 0.1%).Biotin is used almost exclusively in mul-tivitamin products. The optimum pH forthe stability of aqueous biotin solutions isbetween 5 and 8. Biotin is not sensitive toweak oxidizing agents (e.g. air) reducingagents and visible light. Strong oxidizingagents, UV light, and acids may adver-sely affect the stability of biotion.A stable 1 % dry powder is normally usedin solid drug forms, e.g. one based oncalcium hydrogen phosphate.

Butylated hydroxyanisole

Butylated hydroxyanisole (syn. tertbutyl-4-methoxyphenol, BHA) is a white orpale yellowish, wax-like powder with amild, typical odo(u)r. It is insoluble inwater but freely soluble in ethanol, pro-pylene glycol, and peanut oil.BHA is an antioxidant which is oftenused for vitamins A and D and has theE number E 320. It acts as a free radicaltrap. The concentrations normally usedare in the range 0.01 to 0.1%.

Bioflavonoids 18

It is also suitable in concentrations of0.02 to 0.05% for the stabilization offolic acid [35].BHA has on occasion been banned inJapan for toxicological reasons.

Butylated hydroxytoluene

Butylated hydroxytoluene (syn. 2,6-di-tert-butyl-p-cresol, BHT) is a white cry-stalline powder. It is insoluble in waterand propylene glycol but freely soluble inethanol and oils.BHT is the antioxidant which is usedmost often in pharmaceutical vitaminproducts containing vitamins A and D.Like BHA, it traps free radicals in thepresence of oxygen or oxidizing agents.The antioxidant action of BHT for vit-amin A is greater than that of BHA. Theeffect is even greater on combination ofBHA with BHT [36]. The concentrationsin vitamin solutions may be between 0.01and 0.5%.

The figure below compares the stabilityof vitamin A in a vitamin A/D/E emul-sion with and without addition of BHT.

Vitamin A/D/E emulsion (for veterinaryuse)

Composition

Retinyl propionate 23.0 gCholecalciferol 0.2 gTocopheryl acetate 5.5 gPEG-35 glyceryltriricinoleate [1]

10.0 g

Benzyl alcohol 1.0 gWater ad 100 ml

Stability

For further examples of use, see emulsi-on, PEG glyceryl trihydroxystearate andsyrup.

19 Butylated hydroxytoluene

B

C

C, vitaminsee ascorbic acid, calcium ascorbate, so-dium ascorbate.

Calcifediol

Calcifediol (syn. 25-hydroxycholecalcife-rol) is a metabolite of cholecalciferol andis thus an intermediate in the formationof 1-alpha-25-dihydroxy-cholecalciferolin the body (= calcitriol). It is possibleby solubilization to incorporate it intoaqueous vitamin D solutions, but this israrely employed.

Calciferolsee ergocalciferol.

Calcitriol

Calcitriol (syn. 1-alpha-25-dihydroxy-cholecalciferol) is the biologically activeform of vitamin D3. It is occasionallyused in vitamin D capsules.

Calcium ascorbate

Calcium ascorbate (syn. calcium salt ofvitamin C, calcium salt of L(+)-ascorbicacid) is a white, odo(u)rless powder witha very slightly bitter taste. It has the Enumber E 302.In terms of vitamin C activity, 1.0 g cal-cium ascorbate is equivalent to 0.826 gascorbic acid.The product is not suitable for liquid drugforms, because aqueous solutions are toounstable and calcium oxalate may preci-pitate out on storage.In solid drug forms, such as tablets, cal-cium ascorbate maintains its colo(u)rsomewhat better than ascorbic acid. Ho-wever, once again the humidity must bekept below 30% during production andthe water content of the tabletting mixtu-re must be minimized in order to sup-press hydrolysis.

Calcium hydrogen phosphateCalcium hydrogen phosphate (syn. diba-sic calcium phosphate, anhydrous or di-hydrate) is a fine white odo(u)rless pow-der which is insoluble in water.

C, vitamin 20

Calcium hydrogen phosphate is used as alowcost filler in tablets, coated tabletsand hard gelatin capsules. Since the par-ticles are very fine, the material is nor-mally granulated.Calcium hydrogen phosphate which hasbeen granulated with polyvinylpyrolidoneis very suitable for direct tabletting. Atypical example of this type of use isthe composition for vitamin E chewabletablets which follows.

Vitamin E chewable tablet (50 mg)

Tocopheryl acetate,dry powder 50 %spray-dried with gelatin [1] 100 mgCalcium hydrogen phosphyte,granulated with 5 % polyvinyl-pyrrolidone K 30 300 mgSilica, highly dispers [4] 3 mg

For further examples of the use of cal-cium hydrogen phosphate, see calciumpantothenate and crospovidone.For some vitamin tablets it is importantto know that the dihydrate slowly loseswater at elevated temperature.

Calcium oxalateOxalic acid is formed by the oxidation ofascorbic acid.If a liquid drug form contains a calciumsalt, e.g. calcium pantothenate, in addi-tion to ascorbic acid, the calcium oxalatemay crystallize out after storage for sometime.

Calcium pantothenate

Calcium pantothenate (syn. calcium D-pantothenate, calcium salt of D-pantothe-nic acid, formerly vitamin B5) is a white,virtually odo(u)rless powder with aslightly bitter taste.It is freely soluble in water.1.0 g calcium D-pantothenate is equiva-lent to 0.919 g D-pantothenic acid.Calcium pantothenate is used almost ex-clusively in solid drug forms. Particularattention must be paid to the fact that thehygroscopicity of the substance may af-fect the stability of such products. It de-composes rapidly in the presence of as-corbic acid if a certain amount of mois-ture is present. This is why the waterconent of multivitamin tablets containingcalcium pantothenate must be as low aspossible and the tablets must be packedin air-tight containers. However, it is of-ten better to use an adsorbate of dexpan-thenol in place of calcium pantothenatein multivitamin tablets. Another possibi-lity is to incorporate calcium pantothe-nate into the gelatin in soft gelatin capsu-les or into the coating of coated tablets inorder to prevent chemical interactionswith other vitamins.The following calcium pantothenate ta-blet composition is an example for directtabletting.

Calcium D-pantothenate tablet (250 mg)

Calcium pantothenate 275 mgCalcium hydrogen phosphate 150 mgCellulose, microcryst. [2] 50 mgCrospovidone 20 mgStearic acid 3 mgMagnesium stearate 3 mg

For further examples of the use of cal-cium pantothenate in solid drug forms,see B complex, multivitamin solid prepa-rations, thiamine mononitrate, and tarta-ric acid.

21 Calcium pantothenate

C

Calcium pantothenate is unsuitable forliquid forms, because it is reasonably sta-ble only at a pH of 5.7 to 6.2 [159, 220].Dexpanthenol or sodium pantothenate aresubstitutes. Multivitamin solutions whichcontain calcium pantothenate in additionto ascorbic acid may precipitate calciumoxalate on storage [37].

Capsulessee hard and soft gelatin capsules.

Carbon dioxideCarbon dioxide can be used as an inert gasfor some vitamin solutions. Its advantageover nitrogen is that its solubility in water isdistinctly higher than that of oxygen. Ho-wever, account has to be taken of the effecton the pH of the solution.

Formation of carbon dioxide and loss ofascorbic acid in vitamin C solutions (25 %in water, 93 h, 55�C).

Carbon dioxide can also occur as a pro-duct of the anaerobic hydrolysis of ascor-bic acid [72, 73, 124]. This may havevery undesirable results, with blister-packs or polyethylene bottles becomingdistended, and, in extreme cases, ampulesbursting. The maximum formation of car-bon dioxide takes place at pH 4.1 as doesthe maximum loss of ascorbic acid, asshown by the preceding figure [72].The use of carbon dioxide as an inert gasin vitamin C solutions has two effects:prevention of oxidation by oxygen andsuppression of hydrolysis (Law of massaction). For examples of its use, see inertgas.

CarboxymethylcelluloseIn pharmacy, carboxymethylcellulose isused in the form of the sodium salt,which dissolves in water and diluteethanol.For granulation for use as a binder, it ispossible to prepare a 5 or 6% aqueous oraqueous-ethanolic solution. For use as adry excipient in tablets binder, it is ne-cessary to incorporate about 5 to 10% ofthe weight of the tablet.Certain types of carboxymethylcellulose(e.g. Nymcel�) can be used as disinte-grants by drymixing about 2 to 6% intothe tablets. An even better disintegrant isthe crosslinked form croscarmelose.

CarboxymethylstarchCarboxymethylstarch can be used in theform of the sodium salt as a tablet dis-integrant. Examples of trade names areExplotab� or Primojel�.Sodium carboxymethylstarch is normallyadded in a concentration of 2 to 8% tothe dry mixture before tabletting.

Capsules 22

CaroteneNatural carotene is the chief representa-tive of the carotenoids and comprises amixture of three chemical substances (al-pha-, beta- and gamma-carotene), each ofwhich in turn comprises a number ofstereoisomers (see formulas above). Allhave provitamin A activity although thestrength varies.To date, only beta-carotene has been im-portant in vitamin formulations, becauseit has, in the all-trans form, the highestprovitamin A activity and the syntheticproduct is identical to the natural product.

CarotenoidsThe term carotenoids comprises a groupof substances including more than onehundred pigments of vegetable and ani-mal origin [145].The chief representatives are beta-caro-tene, apocarotenal, canthaxanthin, lyco-pene, astaxanthin, capsanthin, zeaxanthinand citranaxanthin. The E numbers areE 160 a to f.In pharmacy, beta-carotene, canthaxan-thin and apocarotenal have some import-ance as pigments, in particular for sugar-coating or for colo(u)ring soft gelatincapsules and suppositories.

In contrast to sugar-free film-coating, thecoating obtained by sugar-coating has areasonably stable colo(u)r if the thicknessand amount of carotenoid are adequate.The effect of light is the main problem.In sugar-coated tablets, apocarotenal hasproved to be the most stable to light ofthe three substances.Skin-tanning agents containing cantha-xanthin are no longer produced in Ger-many.

CaseinCasein (syn. milk protein) is used as anauxiliary in some dry powders of vit-amins A and E. In these formulations,casein acts as an emulsifier to assist inmaking the dry powders dispersible incold water.Account must be taken of the possibilityof incompatibility with ascorbic acid,which results in a pink coloration of ta-blets, for example, due to the formationof a complex with ascorbic acid [38].

CelluloseCellulose is a polysaccharide with beta-glycosidic linkages between the glucoseunits.

23 Cellulose

C

Microcrystalline or microfine cellulose isa white, odo(u)rless powder which is in-soluble in water, ethanol, and propyleneglycol.It is marketed in various forms and parti-cle sizes and with various names (e.g.Avicel� [2], Vivacel� and Elcema� [4]).These differences mean that the varioustypes of cellulose are not necessarily in-terchangeable. The E number is E 460.Microcrystalline and microfine celluloseare used in vitamin tablets as fillers, bin-ders and, to a certain extent, as disinte-grants. A typical example of use is thefollowing vitamin E composition for di-rect tabletting to chewable tablets:

Vitamin E chewable tablet (200 mg)

Tocopheryl acetate dry powder50%, spray-dried with gelatin [1]

400 mg

Cellulose, microcryst. [2] 130 mgSilica, highly dispers [4] 10 mg

Microcrystalline or microfine cellulose issuitable for direct tabletting, as in thisexample; it can also be incorporated bygranulation.Owing to its insolubility, cellulose isscarcely suitable for effervescent tablets.It is not known to have adverse effects onthe stability for vitamins.For further examples of use of microcry-stalline cellulose in tablets, see analge-sics, B complex, calcium pantothenate,copovidone, crospovidone, direct com-pressible vitamins, nicotinamide, pyrido-xine hydrochloride, thiamine hydrochlo-ride, and thiamine mononitrate.

Chelating agentsChelating agents (syn. complexingagents) form chelates for complexeswith metal ions.

Heavy metals may act as catalysts to havean adverse effect on the stability of manyvitamins (e.g. B1, B6 and C), which iswhy they are often inactivated by chelatingagents, especially in liquid products.The chelating agents which are mostcommonly used in vitamin solutions arecitric acid and ethylenediaminetetraace-tic acid.

Chemical interactionssee interactions.

ChloroflavinChloroflavin is a degradation product ofriboflavin, which may be produced inmultivitamin or B complex solutions,especially due to interactions with thia-mine hydrochloride. Nicotinamide andascorbic acid may increase the formationof chloroflavin, which may even result ina precipitate.

Cholecalciferol

Cholecalciferol (syn. colecalciferol, vit-amin D3) is a white crystalline powderwhich is insoluble in water but solublein ethanol and oils. It is one of the lipo-philic vitamins.1.0 g cholecalciferol is equivalent to40 million international units of vitamin D.Since vitamin D3 is of animal origin, it isnowadays more important then vitamin

Chelating agents 24

D2 (= ergocalciferol), whose vegetablesynthetic precursors are less easily obtai-nable.In solid drug forms containing vitamin D,the primary problem is homogeneous dis-tribution in the formulation and, which isan associated problem, the content uni-formity, since the daily requirement isonly about 5 �g. This problem may besolved by using a highly diluted dry pow-der, i.e. one embedded in gelatin. Theusual concentrations in these compositi-ons are between 100,000 and 850,000I. U./g. Compositions of this type toge-ther with vitamin A esters are also com-mercially available (e.g. vitamin A/D3dry powder 500,000/50,000 I. U./g). Inthis form, cholecalciferol can be satisfac-torily tabletted and is distinctly more sta-ble than vitamin A. Nevertheless, it hasto be remembered that it is sensitive tolight, oxygen, heat, and humidity.Vitamin D dry powders virtually alwayscontain an antioxidant (e.g. butylated hy-droxytoluene and/or butylated hydroxya-nisole).The main problem with liquid drug formsis the insolubility. A solubilizer may re-medy this. The amounts of the solubilizerPEG glyceryl trihydroxystearate requiredfor various vitamin D concentrations areshown in the figure below. The concen-trations are based on the finished solubi-lizate.

Solubilization of cholecalciferol using PEG-40 glyceryl trihydroxysterate [1].

The stability of vitamin D solubilizates issubstantially independent of the pH. Ho-wever, isomerization may occur in veryacid solutions [39]. Addition of an antio-xidant in the manufacture of an aqueousvitamin D syrup using polysorbate 80may be advantageous [40]. Solutions ofvitamin D in propylene glycol are reaso-nably stable [166], but they, too, have tobe protected from light, oxygen and heat.

Cholecalciferol-cholesterol

Cholecalciferol-cholesterol (syn. vitaminD3-cholesterol) is a molecular compoundof cholecalciferol with cholesterol produ-ced by crystallizing equimolar amountsof the two substances. The white crystalsare insoluble in water but dissolve in oils.The vitamin D activity of cholecalciferol-cholesterol is equivalent to about 20 mil-lion international units per gram.Vitamin D3 is more stable in this formthan as pure cholecalciferol or ergocalci-ferol [41].Low-concentration compositions whichare based on lactose, for example, areused for solid drug forms.

25 Cholecalciferol-cholesterol

C

Choline

Although choline was in the past regar-ded as a B vitamin, it is not a true vitaminsince it is synthesized in the human liver.The choline derivatives used in pharmacyinclude:k choline chloride,k choline bitartrate,k lecithin,k choline orotate,k choline stearate.Choline chloride and bitartrate are hy-groscopic white powders and are stablein solid drug forms only if humidity isexcluded. Likewise, aqueous solutionsare stable for only a limited time. Cholinebitartrate is often preferred to cholinechloride on the grounds of taste.Choline salts are used rarely in vitaminproducts.

Citric acid

Citric acid is a white, odo(u)rless sub-stance with an acidic taste; it is freelysoluble in water and ethanol, and insolu-ble in fats.Citric acid and its esters are among themost important synergists. They are fre-quently combined with antioxidants invitamin products. The essential actioncomprises inactivation of traces of metalsby the formation of stable chelate rings,e.g. with copper or iron.

This is why citric acid is an effective sta-bilizer for ascorbic acid solutions storedunder air, with a possible ratio of ascorbicacid to citric acid being 10 : 1 [20].Citric acid can also be used in oily solu-tions of the lipophilic vitamins or in softgelatin capsules.Citric acid is also used as the acid com-ponent in effervescent tablets. Its advan-tage over tartaric acid, and especiallyascorbic acid, is that smaller amountsare required. The liberation of carbondioxide takes place more rapidly thanwhen tartaric acid is used [259].

Coated tabletsee sugar-coating.

Coatingssee film-coating and sugar-coating.

CobalaminCobalamin is vitamin B12. The most im-portant derivatives are cyanocobalaminand hydroxocobalamin.

Cocarboxylase

Cocarboxylase (syn. thiamine pyrophos-phate, thiamine diphosphate) is the actualcoenzyme form of vitamin B1. Both thetetrahydrate and the hydrochloride of co-carboxylase are white, crystalline pow-ders resembling thiamine hydrochloride.Aqueous solutions of cocarboxylase aremarkedly less stable than those of thia-mine hydrochloride in the pH range 4 to7 since hydrolysis results in thiamine mo-

Choline 26

nophosphate, thiamine, and phosphate[42, 235].Thus, products for injection are best ma-nufactured by lyophilization.Addition of the following stabilizes lyophi-lizates: 4% nicotinamide [233], 30% argi-nine [234], adenosine [237], valine [238],mannitol and polyvinylpyrrolidone [239].The loss of vitamin from a 0.5% aqueouscocarboxylase solution of pH 4 or 5 afterstorage at 40 �C for 2 months was redu-ced by addition of 0.1% maleic acid and0.05% EDTA from 90% without thisaddition to 2 % [236]. Cocarboxylase israrely used in solid drug forms, because itis cleaved to thiamine monophosphate inthe gastrointestinal tract, and the directcoenzyme activity of this compound ismuch weaker than that of cocarboxylase.But advantages are the faint taste andodo(u)r.

CoenzymeMost of the hydrophilic vitamins act ascoenzymes.

Vitamins as coenzymes

Thiamine Coenzyme of the decar-boxylases and aldehydetransferases

Riboflavin Constituent of the flavincoenzymes

Niacin Constituent of codehydra-ses

D-pantothenicacid

Constituent of coenzy-me A

Pyridoxal Coenzyme of transamina-ses and amino acid de-carboxylases

Cobalamin Coenzyme for fatty acid,amino acid and nucleotidemetabolism

Folic acid Coenzyme for C1-meta-bolism

Biotin Coenzyme of carboxyl-tranferases

ColorantsColorants can be divided either into so-luble colo(u)ring agents, colo(u)r lakesand pigments or into synthetic substancesand natural substances (or those identicalto the natural substances).Examples of soluble colo(u)ring agentsused in pharmacy are the substances li-sted in the table below.

Colo(u)ring agents for aqueous solutions

Colo(u)ring agent E number

Amaranth E 123Azorubine E 122Beta-carotene dry powderCWD* E 160aCochineal red E 124Erythrosine E 127Indigotine E 132Orange yellow(= Sunset Yellow)

E 110

Patent blue V E 131Quinoline yellow E 104Riboflavin E 101Tartrazine E 102

* Cold-water dispersible

Colo(u)r lakes or pigments are more of-ten used in solid drug forms [249]. Theseare aluminium oxide lakes of the solublecolo(u)ring agents, or pigments in theform of iron oxides (E number E 172)and titanium dioxide (E number E 171).The main areas of use are sugar-coatingand film-coating (for examples of use,see these entries).For direct colo(u)ring of tablets, it is ad-visable to prepare a premix of the lubri-cant with the colo(u)r lake in the ratio1+1 to 1+4, and to process this mixture inthe same way as the lubricant. It is thuspossible to obtain a concentration of 0.5to 3.0% of colo(u)r lake in the tablet asshown by the following composition of ayellow vitamin B6 tablet.

27 Colorants

C

Vitamin B6 tablet (30 mg)

I. Pyridoxine hydrochloride 30.0 mgLudipress� [1] 180.0 mg

II. Magnesium stearate 1.2 mgSicovit tartrazine lake 2.8 mg

Mix mixture II with components I andcompress.

Colo(u)ring agents and colo(u)r lakesvary in their stability in tablet coatingscontaining vitamins. Thus, for example,of the customary synthetic colorants, onlyquinoline yellow, patent blue and tartra-zine have been found to be relativelystable in vitamin C coated tablets [67].Similar incompatibilities have beenfound in food products and solutions con-taining vitamin C [222±224].Iron oxide pigments are increasinglybeing preferred for sugar-coating and infilm-coating.Carotenoids (e.g. beta-carotene, apoca-rotenal) can be used as oily dispersionsfor colo(u)ring soft gelatin capsules. Ac-count must be taken of their sensitivity tolight [262].

Colo(u)r stabilityThe colo(u)r stability of vitamin productsis of particular importance with vitaminsB1, B12 and C.Thiamine hydrochloride may be oxidizedto thiochrome in aqueous solutions. Therate of this oxidation may be increased inthe presence of riboflavin and nicotina-mide. It results in darkening of the solu-tion.Cyanocobalamin solutions in water arepink. A breakdown of cyanocobalaminis evident from a drecrease in the colo(u)rintensity.The colo(u)r stability of ascorbic acid inuncolo(u)red tablets is limited. Traces ofthe furfural degradation products which

have been produced by hydrolysis causethe originally white tablets to becomeyellow or brown.When colorants are used in vitamin pro-ducts, account must be taken of theirpossible reactions with vitamins (e.g. as-corbic acid) and light, which may causethe colo(u)r to pale rapidly. The colorantsbeta-carotene and riboflavin, in particu-lar, readily undergo photolysis.

CompactionFor vitamins sensitive against hydrolisis(e.g. vitamin C) the compaction is anexcellent granulation technology for themanufacturing of tablets to avoid the useof solvents and the residues of water.Normally a roller compactor is used forthis purpose [270].A typical formulation of a tablet withcompacted vitamin C is given in the tablebelow [261].

Vitamin C effervescent tablet (1000 mg)

Ascorbic acid, compacted with4 % of povidone K 30

1000 mg

Tartaric acid 200 mgSorbitol 200 mgSodium bicarbonate 172 mgPolyethylene glycol 6000 60 mgManufacturing: Direct compression

Compartmented ampulessee two-chamber ampules.

ComplexesTwo types of complexes can be distin-guished in vitamin products:1. Metal complexesComplexing agents are used to bind and(heavy) metals which are present in order

Colo(u)r stability 28

to protect and improve the stability of thevitamins. For details, see chelatingagents.2. Vitamin complexesNicotinamide and ascorbic acid are com-plexing agents. Examples of typical vit-amin complexes are the yellow nicotina-mide ascorbate, ascorutin from ascorbicacid and rutin, the pink amino acid/as-corbic acid complex [38], and the thia-min/menadione adduct [256]. Nicotina-mide forms complexes with folic acid[109] and riboflavin [126] and thus in-creases their solubility in water. Othersubstances form complexes with thesetwo vitamins [127, 139, 140], as shownby the following figure for folic acid withand without the ethanolamide of gentisicacid [107, 127].

Solubility of folic acid in water.

Copovidone

Copovidone (syn. PVP/VA copolymer) isa copolymer of 60 parts by weight ofvinylpyrrolidone and 40 parts by weightof vinyl acetate.It is a white or yellowish powder which ismarketed under the name Kollidon�

VA 64 [1, 263b]. In contrast to polyvinyl-pyrrolidone, the hygroscopicity of copo-vidone is slight, as is evident from thegraph which follows next.Moreover, it is suitable as a binder forgranulation and direct tabletting. This isshown by the example of a vitamin Ccomposition for direct tabletting to che-wable tablets.

Uptake of water by copovidone after7 days (25�C).

29 Copovidone

C

Vitamin C chewable tablet (100 mg)

Ascorbic acid, powder 105 mgCellulose, microcryst. [2] 70 mgSucrose, ground 32 mgSucrose, crystalline 20 mgCyclamate, sodium salt 6 mgCopovidone 6 mgPolyethylene glycol 6000, powder 5 mgOrange flavo(u)r 2 mgStrawberry flav(u)r 1 mgSilica, highly disperse 0.5 mgSaccharin, sodium salt 0.3 mg

For further examples of its use, see anal-gesics, instant granules, mannitol, multi-vitamin solid preparations, nicotinamide,pyridoxine hydrochloride, retinyl acetate,riboflavin, tocopheryl succinate and vit-amin mixture. The second area of use ofcopovidone is for film-coating since it isan excellent film-forming agent. Thefilms have the advantage of low hygros-copicity and high elasticity. For examplesof this use, see ethylcellulose, film-coa-ting and sugar-coating.

Corn starchsee starch.

CreamsVitamins are also used in dermatologicalsand cosmetics [43±46]. These are prefe-rably in the form of creams. The vitaminswhich are commonly used in creams in-cludek retinol and retinyl palmitate [48±51],k dexpanthenol [52, 191],k tocopherol (or tocopheryl acetate) andk tretinoin.A typical panthenol cream for healingwounds may contain 5% dexpanthenol.It is also possible to combine tretinoin

with dexpanthenol in a cream (for anexample see dexpanthenol).

Cremophor�

Cremophor is a registered trademark for anumber of emulsifiers and solubilizersfor use in pharmaceuticals and cosmetics[1].The types which are particularly used assolubilizers for lipophilic vitamins areCremophor EL (PEG glyceryl triricino-leate) and Cremophor RH 40 (PEG gly-ceryl trihydroxystearate).

CroscarmeloseCroscarmelose is crosslinked carboxyme-thylcellulose, with is marketed under theregistered trademark. Ac-Di-Sol� [2], forexample. It is insoluble in water and is avery good disintegrant for tablets.The concentrations which are normallyused are between 1 and 5% based onthe weight of the tablet.

CrospovidoneCrospovidone (syn. insoluble polyvinyl-pyrrolidone) is a white hygroscopic pow-der. It does not dissolve in any solvent sothat its molecular weight cannot be deter-mined. It is sold under the registeredtrademarks Kollidon� CL [1, 263] andPolyplasdone� XL [5].The non-micronized form of crospovi-done is used in concentrations between1 and 5% as a disintegrant in vitamintablets (for european food E 1202), as isevident from the following example ofthe composition of a beta-carotene tabletwith a very short disintegration time.

Corn starch 30

Beta-carotene tablet (15 mg)

Beta-carotenedry powder 10 % [1]

150 mg

Calcium hydrogen phosphate,granulated with 5 % polyvinyl-pyrrolidone K 30 175 mgCellulose, microcryst. [2] 100 mgCrospovidone 25 mgTalc 20 mgSilica, highly disperse 5 mgCalcium arachinate 2 mg

Micronized crospovidone can also beused as a suspension-stabilizer and asdessicant to stabilize the vitamins by re-duction of the free water content. Thiscan be utilized for oral vitamin powders.For an example of use, see instant gra-nules.

Cyanocobalamin

Cyanocobalamin is the most importantvitamin B12 derivative in pharmaceuticaltechnology. Like hydroxocobalamin, it isa dark-red crystalline powder which, de-spite having a relatively poor solubility inwater (1 or 2%), is one of the hydrophilicvitamins. A saturated solution in 90 %ethanol contains about 0.5 %.

Vitamin B12 is one of the most sensitiveand thus least stable vitamins.In liquid drug forms, the solubility is noproblem, because the usual doses arevery low. The stability of vitamin B12solutions is influenced by a number offactors, as follows:1. LightCyanocobalamin undergoes rapid photo-lytic decomposition (for details, seelight). The adverse effects of light canbe eliminated or at least minimized byappropriate measures during productionand packaging.2. pHThe optimal pH is between 4.5 and 5.0 [18].3. HeatCyanocobalamin solutions are sensitiveto heat and thus there are large losseson heat-sterilization, which is thereforenot recommended.4. Oxidizing agentsVitamin B12 solutions must not contain oxi-dizing substances. The effects of oxygenmust be eliminated by use of an inert gas.5. Chemical interactions with vitaminsIn combined vitamin products, e.g. multi-vitamin solutions, it is not possible to avoidthe chemical interactions of cyanocobala-min with other vitamins. It reacts with thia-mine and its breakdown products. Nicotin-amide promotes this reaction. Iron (III)salts are said to have a stabilizing effect.Vitamin B12 is also broken down by dehy-droascorbic acid. However, the reaction ofcyanocobalamin is distinctly less than thatof hydroxocobalamin [53].All these factors may results in the sta-bility of cyanocobalamin being very poorin combination with vitamins in liquidproducts [33]. The best ways of stabili-zing cyanocobalamin solutions has pro-ved to be the addition of cyanide ions[118] or of low molecular weight povi-done [263a]. The latter is demonstratedin the following formulation.

31 Cyanocobalamin

C

Vitamin B complex injectable

I Thiamine hydrochloride 11.0 mgRiboflavin monophosphate Na 6.6 mgNicotinamide 44.0 mgPyridoxine hydrochloride 4.4 mgCyanocobalamin 8.8 �gEDTA sodium 0.2 mgPropylgallate 0.5 mgKollidon 17PF 99.0 mg

II Parabens 1.6 mgCitric acid 22.7 mgNaOH solution, 1 mol/l 0.216 mlHydrochloric acid, 0.1 mol/l 0.720 mlPropylene glycol 0.200 mlWater 0.864 ml

Stability (9 months, room temperature):Vitamin B1 92%Vitamin B2 94%Vitamin B6 91%Nicotinamide 100%Vitamin B12 (with Kollidon) 87%Vitamin B12 (without Kollidon) < 50%

It is advisable for oral products to takethe form of instant granules, effervescentgranules, etc. The solution for productsfor injection is to use two-chamber am-pules or compartmented ampules withseparated solutions, only one of whichcontains cyanocobalamin. Another possi-bility is to produce injectables by lyophi-lization.The forms used for solid products are, byreason of the stability and the low dosa-ge, dry dilutions with the substance em-bedded in starch or gelatin or trituratedwith mannitol or galactomannan, someof which are commercially available.The concentration of cyanocobalamin inthese formulations is normally 0.1 to1.0%. For the multivitamin tablets, thebest way of preventing the chemical in-teractions with vitamins B1 and C is toembed the substance in gelatin. This isshown by the figure below which compa-res the stability of the substance when

mixed with an excess of ascorbic acidand either triturated with mannitol or em-bedded in gelatin and then stored [3].

Comparison of the stability of cyanocoba-lamin dry powders (mixed with ascorbicacid, room temperature).

For examples of the use of cyanocobala-min in solid drug forms, see B complex,instant granules, multivitamin solid pre-parations, thiamine mononitrate, and tar-taric acid.

Cyclamate

Sodium cyclamate (syn. sodium salt ofcyclohexylsulfamic acid) is a white pow-der which is soluble in water. It is used asa sweetener, being 15±30 times strongerthan sucrose. The advantage of cycla-mate over saccharin is that it has virtua-lly not bitter taste.In some countries, sodium cyclamate isnot approved for use in food products.Apart from the sodium salt, in some casesthe acid or the calcium salt is used.For examples of use in formulations, seeadsorbate, copovidone, direct compressi-ble vitamins, polyvinylpyrrolidone, sor-bitol, trace elements, and tartaric acid.

Cyclamate 32

D

D2, vitaminsee ergocalciferol.

D3, vitaminsee alfacalcidol, calcifediol, calcitriol,and cholecalciferol.

Daily requirementthere are some considerable differencesin the opinions about the amounts of theindividual vitamins required each day byhumans.A number of countries have fixed RDAs.Care is needed when examining thesefigures, because some lists of RDAs are

minimum amounts, while some are ofoptimal amounts. In addition, there arequantitative differences between the figu-res given for the RDAs in countries usingthe same definition and this has resultedin a great lack of uniformity. As an ex-ample, the following table lists the RDAsof the American Food and Drug Admini-stration (FDA) for the optimal amountsfor adults, the recommendations of theNational Academy of Sciences (USA)and the recommendations of the FederalBoard of Health in Berlin (BGA).In the case of beta-carotene, 6 mg asprovitamin A is considered as equivalentto 1 mg retinol (= 3333 I. U.) [27]. Insome cases, one gram of beta-caroteneis regarded as having a vitamin A activityof 1.67 million I. U.

Daily requirements of vitamins by adults

Vitamin FDA, 1986[203]

National Academyof Sciences 1998(USA)

BGA recommenda-tions 1983 [204]

A 5000 I. U. 1000 I. U. 2000±6000 I. U.B1 1.5 mg 1.2 mg 0.75±2.25 mgB2 1.7 mg 1.3 mg 0.8±2.6 mgNicotinamide 20 mg 1.6 mg 9±27 mgD-pantothenic acid 10 mg 5 mg 4±12 mgB6 2 mg 1.3 mg 1±3 mgB12 6 �g 2.4 �g 3±9 �gFolic acid 0.4 mg 0.4 mg 0.2±0.8 mgC 60 mg 60 mg 30±90 mgD 400 I. U. 200 I. U. 100±600 I. U.E 30 mg 10 mg 6±24 mgH 0.3 mg ± 75±225 �gK ± 80 �g 50±150 �g

33 Daily requirement

D

These figures are of importance for phar-macists, because the formulations of mul-tivitamin products are often based onthem so that each dose contains exactlythe relevant daily requirement or a mul-tiple thereof. Thus, for example, it iscustomary in the FRG for vitamin pro-ducts with up to three times the dailyrequirement per dose to be declared asfood products (see also food productsand marketing).

Dexpanthenol

Dexpanthenol (syn. D-panthenol, D-pan-tothenyl alcohol, provitamin B5) is quan-titatively converted into D-pantothenicacid in the body. Thus 1.0 g dexpanthen-ol is equivalent to 1.068 g D-pantothenicacid.Dexpanthenol is a colo(u)rless liquidwhich is soluble in water but, due to itsvery high viscosity, is not easy to process.For this reason, dilutions in propyleneglycol or water are also commerciallyavailable.

Stability of dexpanthenol and calcium pan-tothenate in multivitamin drops (6 weeks,45�C).

Dexpanthenol is particularly used in li-quid and semisolid drug forms, because itis much more stable in them than is, forexample, calcium pantothenate [21, 220].This especially applies to combinationswith other vitamins where the pH-depen-dent hydrolysis and the chemical interac-tions with other vitamins are of great im-portance. The preceding figure shows thedifference in stability between dexpan-thenol and calcium pantothenate in mul-tivitamin drops [41].It is clear from this figure that, unlikecalcium pantothenate, dexpanthenol is re-latively stable in aqueous solutions whenthe pH is below 5. This is very importantfor use in vitamin B complex solutions.For comparison with sodium pantothe-nate, see under this entry.In the following example of a vitamin Bcomplex + C syrup, the loss of dexpan-thenol after storage at room temperaturefor 12 months was 10 % (see also B com-plex).

Vitamin B complex + C syrup

I. Thiamine hydrochloride 60 mgRiboflavin-phosphate sodium 55 mgNicotinamide 250 mgDexpanthenol 120 mgPyridoxine hydrochloride 55 mgAscorbic acid, crystalline 800 mgOrange flavo(u)r 25 mgEthylenediaminetetraaceticacid, sodium salt 5 mgPropyl gallate 50 mgSorbic acid 200 mgPolyvinylpyrrolidone K 25 5.0 gSorbitol 10.0 gGlycerol 9.0 gPropylene glycol 10.0 gWater 5.0 g

II. Sucrose 64 gWater 36 g

Mix solution I with syrup II, adjust the pHto 4.0±4.3, and store under nitrogen.

Dexpanthenol 34

Another possibility for the stabilizationof dexpanthenol in an aqueous mediumis to add D-pantolactone [158].This particularly applies to the extensiveuse of dexpanthenol in products for ex-ternal use, it being particularly used inointments and creams to promote woundhealing [191]. It can also be combinedwith tretinoin, as is shown by the follo-wing composition for a cream.

Tretinoin cream containing dexpanthenol

I. Tretinoin 0.05 gLuvitol� EHO [1] 8.0 g

II. Cremophor� A 6 [1] 3.0 gCremophor� A 25 [1] 1.5 gGlyceryl monostearate 3.0 gCetyl alcohol 3.0 gTegiloxan� 100 [7] 0.5 g

III. Butylated hydroxytoluene 0.04 gPropylene glycol 4.0 gDexpanthenol 2.5 gPreservative 0.5 gWater 73.8 g

Heat mixture II to 75�C, and stir in solutionI. Heat mixture III until a clear solution isobtained, add hot mixture I/II, and stir whilecooling.

In multivitamin soft gelatin capsules andcoated tablets, it is possible to incorpora-te dexpanthenol in the gelatin or sugar-coating in order to avoid chemical inter-actions with other vitamins.For use in tablets and hard gelatin capsu-les, dexpanthenol adsorbates on silica gelare commercially available.

DextrinDextrin is a product of the breakdown ofstarch and is used like gum arabic as aprotective colloid in the production ofvitamin dry powders. It can also act as afiller in the tabletting of ascorbic acid[21].

Dextrosesee glucose.

Direct compressible vitaminsSince their physical properties mean thatnot all vitamins are suitable for directtabletting, a number of modificationshave been worked out specifically forthis purpose and are commercially avai-lable. This is of particular interest forhigh-dose vitamins, because a direct ta-bletting auxiliary may solve the problemwhen the concentration of the relevantvitamin in the tablet is low.The most important commercially availa-ble vitamins for direct compression arevitamins A, C, D and E. CorrespondingB vitamin products are only of minor im-portance in Europe.In place of vitamin A, the usual dry pow-ders can be used for direct tabletting withvarying success. It is possible with somemodified products to manufacture small,high-dose tablets, e.g. having the follo-wing composition.

Vitamin A tablet (75,000 I. U.)

Retinyl acetate dry powder500,000 I. U./g [1]

163 mg

Cellulose, microcrystalline [2] 82 mgTalc 5 mg

For another example of its use, see sor-bitol.In the case of vitamin C, types containing2 to 10% auxiliaries are commerciallyavailable for direct compression. Theamount of auxiliaries which are neededfor direct tabletting depends on the as-corbic acid type [198, 261]. An exampleis the following composition for a tablet.

35 Direct compressible vitamins

D

Vitamin C tablet (500 mg)

Ascorbic acid for directcompression 530 mgSorbitol 50 mgPolyethylene glycol 6000,powder 37 mgCyclamate, sodium salt 10 mgOrange flavo(u)r 5 mg

For further examples of ascorbic acid fordirect tabletting, see adsorbate, compac-tion and trace elements. The brochures ofthe manufacturers of vitamin C productsfor direct compression also contain sug-gested formulations.In the case of vitamin E, spray-dried drypowders containing 25 to 50% tocophe-ryl acetate are most suitable for directtabletting. For examples of their use, seecalcium hydrogen phosphate, Ludipress�,multivitamin products, and sorbitol.

Direct tablettingDirect tabletting or direct compressionmeans the compression of a powder mix-ture without previous granulation. Theactive ingredients and auxiliaries are mi-xed and compressed. Many vitamins areunsuitable above a certain concentrationsin the tablet for this type of processing,because the particles are very fine, or theflow properties are poor, or the hardnessof the resulting tablets is inadequate, orthey are in the form of liquids or pastes.On the other hand, direct tabletting is thebest way of producing tablets for a varietyof vitamins, for reasons of stability, becausethis process avoids contact with solvents ±especially water ± and the possibility ofsolvent residues. Thus, direct tabletting au-xiliaries and direct compressible vitaminsare increasingly being used for the manu-facture of vitamin products [198].For examples of the use of direct tablet-ting, see adsorbate, ascorbic acid, B

complex, beta-carotene, calcium hydro-gen phosphate, calcium pantothenate,cellulose, compaction, copovidone, cros-povidone, direct compressible vitamins,direct tabletting auxiliaries, colorants,minerals, sodium ascorbate, nicotinami-de, tabletting pressure, pyridoxine hydro-chloride, retinyl actate, riboflavin, sorbitol,trace elements, and thiamine mononitrate.

Direct tabletting auxiliariesA number of auxiliaries or auxiliary for-mulations are marketed with the object offacilitating or making possible direct ta-bletting. Some of these products are li-sted in the table below.

Direct tabletting auxiliaries (selection)

Trade name Basis Manufac-turer

Avicel� types Cellulose FMC,USA

Di-Tab� Calciumphospate

Amstar,USA

Elcema� types Cellulose Degussa,FRG

Emcompress� Calciumphosphate

Mendell,USA

Emdex� Glucose Mendell,USA

Karion� Instant Sorbitol Merck,FRG

Ludipress� Lactose +povidone +crospovido-ne

BASFFRG

Ludipress LCE Lactose +povidone

BAS,FRG

STA-RX� 1500 Starch Staley,USA

Tablettose� Lactose Meggle,FRG

Zeparox� Lactose DairyCrest,USA

Direct tabletting 36

The following composition is an exampleof a vitamin B1 tablet.

Vitamin B1 tablet (50 mg)

Thiamine hydrochloride 55 mgLudipress� 290 mgMagnesium stearate 5 mgSilica, highly disperse 2 mg

Distinct differences in the disintegrationand dissolution times emerged when va-rious direct tabletting auxiliaries wereused in a vitamin B6 tablet by way ofexample. Avicel� had the best results[254].For some applications it is straightfor-ward to prepare direct tabletting auxilia-ries rather than buy them. This applies to,for example, calcium hydrogen phos-phate or corn starch if they are granula-ted with 3 to 10% polyvinylpyrrolidoneK 30. For examples of use, see crospovi-done and calcium hydrogen phosphate.

DiscolorationPossible changes in the colo(u)r of vitaminproducts

Vitamin Colo(u)r change/cause

B1 Darker colo(u)r due to for-mation of thiochrome

B2 Loss of colo(u)r due tophotolysis

B12 Decoloration due to oxida-tion or photolysis

C Yellow or brown colo(u)rdue to hydrolysis

E (alcohol) Darker colo(u)r due to oxi-dation

Beta-carotene Change to a more reddishcolo(u)r due to isomerizati-on, decoloration due tophotolysis

Discoloration of a vitamin product is evi-dence of decomposition or instability ofthe components. The possible causes arelisted in the preceding table. Many ofthese colo(u)r changes occur most com-monly in vitamin combination products[19].

DisintegrantsThe disintegrants which are most com-monly used in vitamin tablets are listedin the table which follows. Most of thesesubstances can be considered as dissolu-tion agents too.

Disintegrants* in vitamin tablets

Substance Concentration in the tablet

Carboxymethylcellulose 2± 6 %Carboxymethylstarch 2± 8 %Cellulose, microcrystalline 10±50%Croscarmelose 1± 5 %Crospovidone 1± 5 %Starch 5±40 %

* For details, see the individual disintegrants.

DissolutionThe dissolution test is used to determinethe release of active ingredient or to ex-amine the bioavailability in vitro. It maybe necessary to examine the solid formsof the individual vitamins in differentways, because they are absorbed at verydifferent points in the gastrointestinaltract.All in all, this test is not of importancefor all vitamins, specially the oil-solublevitamins.This is evident from the fact that, forexample USP XXIV does not requirethat the dissolution test be carried outon all of the preparations listed in thefollowing table.

37 Dissolution

D

Dissolution test in USP monographs of solidvitamin preparations (selection)

Preparation Dissolution required

Ascorbic acid tablets +Beta carotene capsules ±Calcium pantothenate tablets +Nicotinamide tablets +Oil-Soluble vitamin tablets ±Oil- and water-solublevitamin tablets +Pyridoxine HCl tablets +Riboflavin tablets +Thiamine HCl tablets +Vitamin A capsules ±Vitamin E capsules ±Water-soluble vitamin tablets +

Dosesee daily requirement.

D-panthenolsee dexpanthenol.

D-pantothenic acidsee pantothenic acid.

DropsVitamin drops have become relativelyrare, because the stability of the vitaminsis considerably greater in a syrup, forexample, and even more so in solidforms.

Dry powdersIn connection with vitamins, dry powdersare produced from vitamins and auxilia-ries by embedding, granulating, tritura-

ting or mixing, with the content of auxi-liary being at least 50%.The possible reasons for producing andusing vitamin dry powders in drug formsare as follows:1. The vitamin is a liquid and has to be

converted into a solid form for use intablets, hard gelatin capsules, etc. Ty-pical examples are adsorbates or gra-nules of tocopheryl acetate and dex-panthenol.

2. The stability of the vitamin in adsor-bates is inadequate, resulting from theincrease in direct contact with oxygendue to the large surface area, and theexpressibility is too great. In this case,microencapsulation is carried out, e.g.in a gelatin/carbohydrate matrix whichhas a relatively low permeability tooxygen . Typical examples are drypowders of vitamins A and D.

3. The stability of the vitamin in tritura-tions or adsorbates is inadequate, re-sulting from promotion of chemicalinteractions by contact with other vit-amins. This is countered by embe-dding the vitamin in a gelatin matrix,for example.One example is vitamin B12 whichdecomposes in direct contact with as-corbic acid [25].

4. The dose of the vitamin in the drugforms is normally so low that inhomo-geneities may be produced on mixingwith other vitamins and/or auxiliaries.This problem is solved by preparingdry dilutions in the form of triturations(e.g. vitamin B12) or embedding thevitamin in a gelatin/carbohydrate ma-trix (e.g. vitamins D and B12).

5. The odo(u)r or taste of the vitamine isoffensive in the drug form. Such un-desired organoleptic properties can begreatly reduced by embedding in amatrix. Typical examples are dry pow-ders of vitamin B1 or B2.

Dose 38

There has been a large number of publi-cations on the methods of producing drypowders [14, 41]. The principal processesare spray-drying, spray-cooling, the ad-sorbate technique and the double-emulsi-on process.Apart form these dry powders vitamins,which have been coated or granulated in

various ways to improve the stability orfor direct tabletting, are commerciallyavailable. The auxiliary content in theseproducts does not exceed 10%. Typicalexamples are vitamin B2 and, especially,vitamin C.

39 Dry powders

D

E

E, vitaminsee tocopherol, tocopheryl acetate, toco-pheryl nicotinate, tocopheryl PEG succi-nate, tocopheryl succinate, and tocophe-ryl succinate calcium.

EDTAsee ethylenediaminetetraacetic acid.

Effervescent tabletsEffervescent tablets are a popular formfor vitamins, especially for vitamin Cand multivitamin products. The efferve-scence is caused by the liberation of car-bon dioxide, which is brought about byuse of sodium bicarbonate (and sodiumcarbonate) together with citric, tartaricor ascorbic acid.The stoichiometric ratios of the amountsof sodium bicarbonate to these acids areas follows [259]:1 g sodium bicarbonate is equivalent to0.76 g anhydrous citric acid, 0.90 g tarta-ric acid or 2.09 g ascorbic acid.In practice, these components are oftengranulated, as in shown by the exampleof the composition of a vitamin C effer-vescent tablet to the right.Direct tabletting of effervescent tablets isalso possible, but strict care must be ta-ken about the relative humidity duringproduction and packaging.This particularly applies to vitamin Ceffervescent tablets, its being necessarynot to exceed 30% relative humidity inorder to avoid problems when tablettingand with discoloration [34]. To produceeffervescent tablets with a high vitamin C

content by direct tabletting, it is necessa-ry to use types of ascorbic acid designedfor this purpose [261].

Vitamin C effervescent tablet (500 mg)

I. Sodium bicarbonate 500 mgTartaric acid 400 mg

II. Polyvinylpyrrolidone K 25 8 mgIsopropanol q.s.

III. Ascorbic acid, crystalline 550 mgSucrose (0.5 mm) 661 mg

IV. Polyethylene glycol 6000,powder 67 mgOrange flavo(u)r 10 mgSaccharin, sodium salt 1 mg

Granulate mixture I with solution II, passthe granules through a 0.5 mm screen, anddry at 70�C. Also dry mixture III at 60 �C,and mix with I//II and IV. Compress toeffervescent tablets at a relative humiditynot exceeding 35%.

For further examples of effervescent ta-blets, see compaction, multivitamin solidpreparations and tartaric acid.

Elcema�

Registered trademark [4] for various ty-pes of microfine cellulose.

EmulsionThe emulsion is a drug form which isused for vitamins, too. This particularlyapplies to the solubilization of the lipo-philic vitamins, in which a transparentmicroemulsion is produced.Less fine emulsions (macroemulsions)are produced in the form of creams, lo-tions and high-concentration vitamin am-

E, vitamin 40

pules for veterinary use. This is shown bythe following example of a formulationfor a physically stable emulsion for injec-tion which contains 500,000 I. U. vitaminA, 75,000 I. U. vitamin D and 50 mgvitamin E acetate per ml.

Vitamin A/D/E emulsion for injection (forveterinary use)

Retinyl propionate 23.0 gCholecalciferol 0.2 gTocopheryl acetate 5.5 gPEG-15 hydroxysterate 15.0 gButylated hydroxytoluene 0.5 gBenzyl alcohol 1.0 gWater ad 100 ml

Heat all the components, apart from water, to60�C and slowly stir in the water, which is atthe same temperature. The pale yellow low-viscosity emulsion can be sterilized by filtra-tion or by heat. After heat-sterilization, theampules should be briefly shaken while hotin order to eliminate any phase separation.

On the chemical stability of this emulsi-on, see prediction of stability.

E numberAll substances which appear on the Eu-ropean Community List of ApprovedFood Additives have been given a num-ber, called the E number. Only vitaminswhich act as auxiliaries have an E num-ber [47].

E numbers of vitamins acting as auxiliaries

E 101 RiboflavinE 101a Riboflavin-Phosphate sodiumE 160a CaroteneE 300 Ascorbic acidE 301 Sodium ascorbateE 302 Calcium ascorbateE 304 Ascorbyl palmitateE 307 Tocopherol and tocopheryl

acetate

A number of other auxiliaries used invitamin products are included in the fol-lowing list of E numbers [47].

E numbers of food additives (selection)

Antioxidants

E 300±E 304 Ascorbic acid andascorbates

E 306±E 309 TocopherolsE 310±E 312 Gallates (e.g. propyl

gallate)E 320 Butylated hydroxyanisole

(BHA)E 321 Butylated hydroxytoluene

(BHT)

Thickening or gelling agents

E 400±E 405 Alginic acid and alginatesE 410 Locust bean gum

(galactomannan)E 412 Guar gum

(galactomannan)E 413 TragacanthE 414 Gum arabicE 415 XanthanE 440a + b PectinsE 461 MethylcelluloseE 466 Carboxymethylcellulose

Emulsifiers, stabilizers

E 322 LecithinsE 470 Salts of fatty acidsE 471 Mono- and diglycerides

of fatty acidsE 472a±f Mono- and diglycerides

of fatty acids esterifiedwith fruit acids

E 475 Polyglycerol esters offatty acids

Acidifying agents, acidity regulators

E 322 Carbon dioxideE 325±E 327 LactatesE 330±E 333 Citric acid and citratesE 334±E 337 Tartaric acid and tartrates

41 E number

E

E numbers of food additives (contd.)

Others

E 420 SorbitolE 421 MannitolE 422 GlycerolE 460 Microcrystalline or

powdered cellulose

Colorants

E 101 Lactoflavin (riboflavin)E 102 TartrazineE 104 Quinoline yellowE 110 Orange yellow SE 122 AzorubineE 123 AmaranthE 124 Cochineal red AE 127 ErythrosineE 131 Patent blue VE 132 Indigotine I

(indigo carmine)E 140 Chlorophylls a + bE 141 Copper complexes of

chlorophyll and chloro-phyllins

E 142 Acid brilliant greenE 150 CaramelE 151 Brilliant black BNE 160a±f Carotenes and carotenoidsE 161a±g XanthophyllsE 162 Beetroot red (betanin)E 163 AnthocyaninsE 170 Calcium carbonateE 171 Titanium dioxideE 172 Iron oxides and hydroxides

Preservatives

E 200±E 203 Sorbic acid and sorbatesE 210±E 213 Benzoic acid and benzoatesE 214±E 219 P-hydroxybenzoic esters

(parabens)E 220±E 227 Sulfur dioxide and sulfites.

Binders, disintegrants

E 1201 PovidoneE 1202 Crospovidone

Ergocalciferol

Ergocalciferol (syn. calciferol, vitaminD2) is a white crystalline powder whichis insoluble in water. it is soluble inethanol.Ergocalciferol is one of the lipophilicvitamins and has a biological vitamin Dactivity of 40 million international unitsper gram. The importance of D2 is muchless than that of cholecalciferol (= vit-amin D3), because the vegetable startingmaterials for the synthesis of vitamin D2are less readily obtainable.The problems associated with formula-ting ergocalciferol are the same as thosewith cholecalciferol (for details, see thatentry).

Solubilization of vitamin D2 using PEG-40glyceryl trihydroxystearate.

Ergocalciferol 42

The solubilization reveals a difference.The preceding graph shows the amountsof the solubilizer PEG glyceryl trihydro-xystearate required to prepare clear solu-tions of ergocalciferol. The figures arebased on the solubilisates.Also beta-cyclodextrin improves the so-lubility of ergocalciferol [266].The isomerization products, which mayoccur in ergocalciferol solutions, includeisotachysterol, precalciferol and isocalci-ferol [58].

EthanolEthanol is popular, especially in coun-tries with a low duty on alcohol, as asolvent for the granulation of vitaminsor for the production of vitamin solutionscontaining up to 25 %. At concentrationsabove 15 % ethanol can also act as apreservative.

EthylcelluloseEthylcellulose is a white, free-flowing,odo(u)rless powder. It is insoluble in wa-ter, glycerol and propylene glycol, andvirtually non-hygroscopic (for the graphof water adsorption, see hygroscopicity).Apart from its use as a binder, ethylcel-lulose is used for film-coatings of vitamintablets. The following example of a com-position of a coating suspension is for usein a fluidized bed.Ethylcellulose is also used for coatingcrystals, e.g. of ascorbic acid, to improvethe stability.

Suspension of ethylcellulose for film-coa-tings

Ethylcellulose 5 gCopovidone 5 gTitanium dioxide 20 gTalc 13 gColo(u)r lake 18 gIsopropanol 98 gWater 41 g

300 g of the suspension are passed through amill and then mixed with 210 g isopropanoland 90 g water before being used for coa-ting 2 kg of cores (200 mg, 9 mm).

Ethylenediaminetetraaceticacid

Ethylenediaminetetraacetic acid (syn.EDTA) is used in the form of the disodiumor the disodium calcium salt. Both arewhite powders which are soluble in water.EDTA salts are used as chelating agentsto bind heavy metals in aqueous solutionsof vitamins in order to eliminate or dimi-nish their catalytic action on the oxidati-ve breakdown of some vitamins. HenceEDTA may perform the function of asynergist.EDTA is only slightly soluble in oil andis thus scarcely suitable for oily systems.The vitamins which are listed in the tablebelow can be stabilized by addition of,for example, 0.01% or 3 mmol/l EDTAto the solution.Stabilization of vitamins in solution by EDTA

Ascorbic acid [59±60, 248]Thiamine hydrochloride [63±64]Pyridoxine hydrochloride [65]Nicotinamide [59]Tocopherol [66]

43 Ethylenediaminetetraacetic acid

E

Stabilization of ascorbic acid by EDTA in amultivitamin solution.

The preceding figure demonstrates thestabilizing effect using the example ofascorbic acid in a multivitamin solution[59].However, this stabilization of ascorbicacid by EDTA will often be effectiveonly if the solution has not been treatedand covered with an inert gas, or thesolution contains oxidizing agents, be-cause heavy metal ions only catalyze theoxidative breakdown of ascorbic acid[20].

For examples of the use of EDTA informulations, see B complex, dexpanthen-ol, polyvinylpyrrolidone, and sorbitol.

Expiration dateThe expiration date of a vitamin productdepends on its physical and chemical sta-bility. The chemical stability is usuallythe limiting factor, which can be dealtwith by a variety of measures, includingoverages if everything else fails. The ex-piration date is fixed on the basis of sta-bility tests and predictions of the stabili-ty, normally being the last date at whichit is certain that the vitamin content is notbelow 90% of the declared figure.

ExpressibilityThe expressibility or extrusion of oilyvitamins from dry powders is of import-ance in assessing the suitability of suchpowders for use in tablets [258]. If theextrusion is high, the tablets have aªgreasyº appearance (e.g. vitamin E)and/or reduced chemical stability (e.g.vitamin A). The expressibility is usuallydistinctly less with gelatin-based drypowders than with simple adsorbates.

Expiration date 44

F

F, vitaminsee fatty acids.

Fat-soluble vitaminssee lipophilic vitamins.

Fatty acids, polyunsaturatedThe polyunsaturated fatty acids are alsocalled omega fatty acids. The omega 3-fatty acids consist mainly of eicosapen-taenic acid (EPA) and docosahexaenicacid (DHA), and the omega 6-fatty acidsconsist mainly of linoleic acid, g-linole-nic acid and arachidonic acid. Togetherwith other unsaturated fatty acids it wasformerly called vitamin F.Polyunsaturated fatty acids are oxidizedby oxygen to resins, which can be retar-ded by the addition of antioxidants. Ome-ga fatty acids are frequently incorporatedin soft gelatin capsules for pharmaceuti-cal or nutraceutical use.

FØdØration InternationalePharmaceutiqueThe FØdØration Internationale Pharma-ceutique (abbreviated to F. I. P.) is an in-ternational association of pharmacists.Two recommendations of the industrialpharmacy section of the F. I. P. are ofsome importance for vitamin products:1. Overages for vitamins

The recommended overages of the in-dividual vitamins in various drugforms were published in 1965. Fordetails, see overage.

2. Microbiological statusA report in 1975 published a proposalabout the microbiological status ofpharmaceuticals. For details, see mi-crobiology.

FillersWhere the concentration of active ingre-dient in tablets and hard gelatin capsulesis low (e.g. vitamins A, B and D), a fillerin powder form is required. The fillersused most widely in vitamin productsare listed in the table below.

Important fillers for vitamin tablets andcapsules

Calcium hydrogen phosphateCorn starchGlucoseLactoseMannitolSorbitolSucrose

Direct tabletting auxiliaries also usuallyact as fillers.

Film-coatingWhereas sugar-coating was more oftenused in the past, nowadays film-coatingof tablets is increasingly preferred, be-cause it can be carried out more quicklyand with more automation. Film-coatingsare produced with film-forming agentswhich are virtually always synthetic.Coatings containing natural shellac arenow of minor importance and they canbe produced satisfactorily and reproduci-

45 Film-coating

F

bly only if a synthetic film-formingagents (e.g. copovidone) is also used.The coating agents which are most wide-ly used are cellulose derivatives, such ashydroxypropylmethylcellulose, celluloseacetate phthalate, methacrylic acid deri-vatives, copovidone, polyethylene glycolsand polyvinylpyrrolidone. A distinctionmust be made between coatings whichare soluble in and those which are resi-stant to gastric juice. The latter are oflittle importance for vitamin tablets. It ispossible, and often advantageous, tocombine various film-forming agents. Atypical composition for an aqueous sus-pension for a water-soluble film-coatingwith copovidone/hypromellose is as fol-lows:

Suspension for a water-soluble film-coatingfor tablets

I Copovidone 53 gPolyethylene glycol 6000 12 gHypromellose 6 mPa.s 79 gWater 732 g

II Pigments (white + red) 54 gTalc 54 gWater 216 g

Total: 1200 g

Mix solution I with suspension II to obtainthe final coating suspension

For a other examples, see ethylcelluloseand sugar-coating.The importance of organic solvents forfilm-coating continues to decrease.In the case of multivitamin tablets, sugar-coating is preferable to film-coatings, be-cause the latter are more permeable tooxygen and humidity and thus have adistinctly poorer stabilizing effect. Thisalso applies to colo(u)ring of the coatingswith carotenoids, which are stable tolight only in sugar-coatings. A satisfacto-ry compromise is a film-coating contai-ning a combination of sucrose and a syn-

thetic film-forming agent (see sugar-coa-ting).

Fish liver oilFish liver oil was formerly used as animportant source of vitamins A and D,especially for children. Nowadays in Eu-rope it is of only importance, in the formof soft gelatin capsules, it contains a re-latively high proportion of unsaturatedfatty acids (ªvitamin Fº).It is advisable, to stabilize the vitamins infish liver oil, to add a combination ofantioxidants, e.g. tocopherol or butylatedhydroxytoluene with ascorbyl palmitate,in order to prevent the oxidation of theunsaturated fatty acids, since the fattyacid peroxides decompose vitamins Aand D.

Flavonoidssee bioflavonoids.

Flavo(u)ringFlavo(u)ring is an important factor withmost oral vitamin products, because somevitamins have an unpleasant taste and/orodo(u)r. Fruit flavo(u)rings are oftenused, in solid or liquid form (orange,stawberry, lemon, maracuya etc.), aswell as sugars or sweeteners. For exam-ple, in order to mask the acid taste ofascorbic acid, it is possible to add fruc-tose, sucrose, saccharin and/or cycla-mate, or to replace part of the ascorbicacid by sodium ascorbate or calcium as-corbate.For examples of the flavo(u)ring of for-mulations, see adsorbate, ascorbic acid,B complex, copovidone, dexpanthenol,direct compressible vitamins, effervescenttablets, instant granules, multivitamin

Fish liver oil 46

products, sodium ascorbate, polyvinyl-pyrrolidone, sorbitol, tartaric acid andtrace elements.Polyvinylpyrrolidone can also be used toimprove the odo(u)r and flavo(u)r, e.g. ofvitamin B complex syrup.The B vitamins can also be embedded ingelatin for incorporation in tablets.

Flowability agentsSince many mixtures for tabletting havepoor flow properties, it is necessary toadd a flowability agent to them. Thecommonest flowability agents are highlydisperse silica, talc, and starch. Somelubricants may also improve the flowproperties of a powder mixture.

Fluidized bedThe technique of fluidized bed granula-tion is of considerable importance in theproduction of vitamin tablets or granules,because it is the least deleterious way ofgranulating vitamins with water or a sol-vent, and of drying them.This is most evident in the case of vit-amin C. Granules from a fluidized bedremain white for a long time on storagewhereas granules of the same composi-tion produced by wet granulation rapidlydiscolo(u)r.

FoamingUndesired foaming may occur during thesolubilization of lipohphilic vitamins.There is no generally applicable solutionto this problem. If it occurs, tests are tobe carried out to determine whether thetechnique of solubilization can be modi-fied, by reducing the stirring speed orsimilar measures, to reduce the foaming

sufficiently. If this is impossible, thecomposition of the solubilizate must bealtered:1. Addition of silicone oil in very low

concentration.2. Addition of polypropylene glycol

2000.3. Addition of Poloxamer 231.4. Modification of the solvent composi-

tion.5. Change of the solubilization technique

(vice-versa method, see solubilizati-on).

Folic acid

Folic acid (syn. pteroylglutamic acid, vit-amin Bc or vitamin M) is a yellowish ororange crystalline powder which has vir-tually no taste or odo(u)r. The solubilityof folic acid in 1 l of water is 1 or 2 mg at25�C and 100 mg at 100�C. There is agreat increase in solubility when the pHis increased above 6 (for diagram, seecomplexes, curve 1). Of the customaryorganic solvents, only methanol acts asa solvent to a limited extent.In liquid drug forms, folic acid is parti-cularly sensitive to reducing agents (e.g.ascorbic acid) and light. The strongeroxidizing agents and heavy metals mayalso adversely affect the stability of folicacid. Effective antioxidants are nordihy-droguaiaretic acid and butylated hydro-xyanisole [35]. The optimal pH for stabi-lity is between 6.0 and 9.8. It is verydifficult to combine it with most of theB vitamins because of the pH. In the case

47 Folic acid

F

of products for injection, this problemmay be solved by separate solutions (seetwo-chamber ampules).Hydrolysis of folic acid results in pterin-carbaldehyde and p-aminobenzoylgluta-mic acid [68].Nicotinamide distinctly increases the so-lubility of folic acid (see complexes). Ri-boflavin and ascorbic acid have adverseeffects on the stability.It was possible by use of microcrystallinecellulose in solid drug forms to achievesatisfactory stability with a decrease ofonly 1 % a year [69].In multivitamin tablets it is possible toavoid the chemical interactions with theother vitamins by producing multilayer orlaminated tablets or by incorporating thefolic acid in the coating.

Food productsNowadays a number of vitamin pro-ducts, especially multivitamin formula-tions, are marketed in pharmaceuticalforms as food products or dietetics inmany countries. In the FRG, this is nor-mally permitted with vitamin doses upto three times the daily requirement (fordetails, see marketing). It has to be re-membered when developing these formsthat not all auxiliaries and vitamin deri-vatives used in pharmaceuticals are per-mitted for use in food products. Legalrequirements must be observed in suchcases. In the FRG, for example, only thevitamin derivatives listed in the fore-going table are permitted in dieteticfood products.

Vitamin derivatives permitted in food pro-ducts (FRG)

Beta-caroteneAscorbic acidSodium ascorbatePotassium ascorbateCalcium ascorbateAscorbyl palmitateThiamine hydrochlorideThiamine mononitrateRiboflavinRiboflavin-phosphate sodiumNicotinamideNicotinic acidPyridoxine hydrochlorideSodium pantothenateCalcium pantothenateTocopherolTocopherol acetateTocopheryl succinateRetinyl acetate*Retinyl palmitate*Ergocalciferol*Cholecalciferol*Cholecalciferol-cholesterol*

* Only permitted in margarine, dietary productsand baby food.

In the FRG, some auxiliaries are not per-mitted in food products, examples beingmicrocrystalline cellulose, polyethyleneglycol, many solubilizers, etc.In the USA new labeling requirementsdeveloped by the Food and Drug Admi-nistration (FDA) are reported. Productscontaining ingredients such as vitaminsor minerals intended to supplement thediet will have to be labeled as dietarysupplements [273].

Freeze-dryingsee lyophilization.

Friabilitysee tablet friability.

Food products 48

Fructose

Fructose (syn. D(±)-fructose, levulose) isa white powder which is freely soluble inwater.Fructose is the sweetest sugar. Its swee-tening power is about 1.7 times that ofsucrose.Fructose is suitable as a filler and fla-vo(u)ring in some solid vitamin formula-tions. at high concentrations it improvesthe stability of ascorbic acid solutions[70]. however, it has to be rememberedthat fructose is a reducing agent. Fruc-tose granules containing, for example,3.5% polyvinylpyrrolidone are very sui-table for the direct tabletting of vitamintablets [71].Fructose stabilizes sodium ascorbate so-lutions when present in about 10 % of theamount of sodium ascorbate [20].

FurfuralFurfural occurs in vitamin C products,together with carbon dioxide, as a resultof the hydrolysis of dehydroascorbic acid[72, 73].The resins which are formed from furfu-ral and are very intensely colo(u)red haveserious effetcs on white vitamin C ta-blets, in particular, but solutions mayalso become perceptibly discolo(u)red.

Fursultiamine

Fursultiamine (syn. thiamine tetrahydro-furfuryl disulfide) is a vitamin B1 deriva-tive which is rarely used, is only sparing-ly soluble in water and thus is usuallyemployed only for solid drug forms.Lyophilisates are stabilized by sodiumdextran sulfate [247].

49 Fursultiamine

F

G

Galactomannan

Galactomannan is the main constituent oflocust bean gum (E number E 410) and ofguar gum (E 412). It is a polysaccaridecomposed of galactose and mannose. Thegalactomannan from locust bean gumcontains mannose and galactose in theratio of about 1 : 4 (see formula) whilein guar gum a galactose unit is bonded toevery second mannose molecule.Galactomannan does not form a clearsolution in cold water, and is thus usedonly in solid vitamin products as a filler.It is mainly used for producing cyanoco-balamin triturations.In 250 mg vitamin C tablets, contents ofgalactomannan exceeding 20% cause re-lease to be delayed [30].

GelatinGelatin is the water-soluble product ofthe breakdown of the scleroprotein colla-gen by boiling. It contains at least 95 %protein and is virtually odo(u)rless andtasteless. At 25�C, gelatin adsorbs up to10 times its weight of water but does notdissolve. It dissolves immediately at37�C.

See hygroscopicity for the water-adsorp-tion curve.The various types of gelatin can have thefollowing functions in vitamin products:1. Binder

In recent years, the use of 2 to 20 %gelatin solutions for granulation hasdecreased in favo(u)r of other poly-mers. The reasons include the difficul-ty of manipulating the gelatin soluti-ons, the greater risk of microbiologicalcontamination, and the variability inthe pharmaceutical properties. A gela-tin solution is best prepared by bra-king up the gelatin, leaving it to swellin cold water for 15 minutes, and thenheating the mixture until it has dissol-ved.

2. DisintegrantFormaldehyde-gelatin was formerlyused as a tablet disintegrant.

3. Matrix for vitamin dry powdersDry powders of lipophilic, and insome cases also hydrophilic, vitaminsare often produced using a gelatin ma-trix, because this stabilizes, both me-chanically and chemically, that vit-amins in them. A typical example is

Galactomannan 50

the following qualitative compositionof the matrix for a vitamin A drypowder.

Matrix for a vitamin A dry powder

GelatinSucroseStarchButylated hydroxytolueneSodium aluminium silicate

4. Soft gelatin capsulesIn this drug form, gelatin is used as aflexible encapsulating material whichenvelops the liquid, nonaqueous con-tents and stabilizes the vitamins con-tained therein.

5. Hard gelatin capsulesHardened gelatin, in form of two-pie-ce capsules, is used as a material forencapsulating powder mixtures and,more recently, solidified melts oreven non-aqueous liquids.

Glucose

Glucose (syn. dextrose, grape sugar, alpha-D-glucopyranose) is a white, odo(u)rlesspowder which is soluble in water and hasa slightly sweet taste. For the adsorption ofwater, see hygroscopicity.In solid drug forms containing vitamins,glucose monohydrate is used as a filler,especially in lozenges and chewable tab-les. In addition to this function, it acts asa binder to a certain extent, which mayreveal itself in an increase in the tablethardness. The following composition fora vitamin C tablet is an example of itsuse.

Vitamin C tablet (100 mg)

I. Ascorbic acid, crystalline 110 mgGlucose monohydrate 500 mg

II. Polyvinylpyrrolidone K 90 4 mgIsopropanol + water (1+1) q.s.

III. Polyethylene glycol 6000,powder

6 mg

Flavo(u)r q.s.

For another example of its use in tablets,see effervescent tablets.Glucose is useful in sugar-coating in theform of what is called a smoothing syrup.Glucose can act as a stabilizer in liquiddrug forms using vitamins. Thus, for ex-ample, ascorbic acid is much more stablein a glucose syrup than in pure water[17]. However, this does not apply tocyanocobalamin [74].

Glycerol

Glycerol (syn. glycerine) is a colo(u)r-less, syrupy liquid with a sweet taste. Itis highly hygroscopic and is misciblewith water, ethanol and propylene glycol.It has the E number E 422.In the production of solid drug forms,glycerol is used in tablet coatings andgelatin capsules as a wetting agent andplasticizer. For examples of use, see film-coating.In liquid vitamin products, glycerol in-creases the viscosity, reduces the rate ofdiffusion, and thus may improve the sta-bility of vitamin B1 [75], vitamin B12 [74,76] and vitamin C [17, 22, 75, 77]. Thesweet taste is usually regarded as advan-tageous. For examples of use, see ascor-

51 Glycerol

G

bic acid, dexpanthenol, sorbitol and sy-rup.Addition of glycerol may allow theamount of solubilizer in a multivitaminsolution to be reduced [246].At contents above about 30%, glycerolacts as a preservative.

GranulationThe types of granulation which are mostcommonly used for vitamin products areas follows:1. Wet granulation with binder solution

The vitamins, or only a part thereof,and a filler are granulated with thesolution of a binder in a granulator orin a fluidized bed.For examples, see effervescent tablets,glucose, instant granules, lactose,starch, thiamine hydrochloride, andtocopheryl succinate.

2. Wet granulation with pure solventThe procedure is identical to that insection 1, but a dry binder must beadded to the granulating mixture, orit must have sufficient intrinsic bin-ding capacity, such as with nicotina-mide.For examples, see hydroxypropyl(me-thyl)cellulose and tartaric acid.

3. Dry granulationDry granulation is also called briquet-ting or roller compaction and entailsthe dry material being compressed toform large pieces which are then re-duced to the desired particle size. Themixture must contain a binder in orderto give the granules the necessaryhardness.This process has the great advantagethat it operates without solvents, andthus their adverse effects on the stabi-lity of some vitamins can be avoided.This particularly applies to ascorbic

acid [261]. However, a possible disad-vantage is that the particle size distri-bution is wider than for granules pro-duced by wet granulation.

GranulesPossible reasons for preparing granules inconnection with vitamins are as follows:1. Granules containing vitamins and au-

xiliaries are used for producing tabletsand hard gelatin capsules.

2. Granules containing vitamins and au-xiliaries are themselves used as a drugform with instant granules being mostimportant.

3. Granules of one or more auxiliaries(e.g. calcium hydrogen phosphate orlactose) are used as direct tablettingauxiliaries.

The advantages of granules over a physi-cal mixture of the same composition arethe good flow properties, the greater bin-ding capacity in tablets, and the homoge-neous distribution of the components,which is not changed by mechanicalstress, such as shaking or compressing.A binder is almost always required forthe production of granules and is incor-porated by dry or wet granulation.

Gum arabicGum arabic (syn. arabic acid, gum aca-cia) is composed of linked units of arabi-nose, galactose, rhamnose and D-glucu-ronic acid. It has the E number E 414.For solid drug forms containing vitamins,it is possible to use gum arabic as amatrix for vitamin dry powders or insyrups used for sugar-coating.Gum arabic forms highly viscous solu-tions which are used in liquid forms.

Granulation 52

H

H, vitaminsee biotin.

Hard gelatin capsulesHard gelatin capsules (syn. two-piececapsules) consist of two halves whichcan be assembled together and sometimeshave different colo(u)rs. They are availa-ble in various sizes which are shownactual size in the figure below.Hard gelatin capsules are filled eitherwith a powder mixture, with granules,with a melt or with lipophilic, anhydrousliquids. In the latter case, it is necessaryto employ a process to seal the join be-tween the two halves of the capsule.A typical example is provided by theascorbic acid capsules described below[61].

Vitamin C capsules (100 mg)

Ascorbic acid 100 mgMannitol + silica,highly disperse(99.5 + 0.5)

q.s.

Size of hard gelatin capsules.

Hard gelatin capsules have the followingadvantages over tablets: the technologyof filling is simpler than that of tablet-ting, and the mechanical stress on thepowder mixture during the filling of thecapsules is less than that during compres-sion, which may have beneficial effectson the stability of some vitamins.The disadvantage of hard gelatin capsulesover tablets is the high surface of thefilled powder and therefore the higherrisk of oxidation by oxygen.

Hardnesssee tablet hardness.

HeatThermal decomposition (thermolysis) isof importance with virtually all the vit-amins. In addition, heat promotes all theother decomposition actions, such as hy-drolysis, interactions, oxidation, photoly-sis, reduction, etc. This is why unneces-sary increases in temperature should beavoided during manufacture of the pro-

53 Heat

H

ducts. The effects of heat sterilizationand drying processes on the stability ofthe vitamins must always be checked,and they may have to be replaced byless deleterious methods (e.g. sterilizati-on by filtration, fluidized bed drying, lyo-philization). There are many publicationson thermal decomposition.

Publications on the thermolysis of vitamins(selection)

Vitamin Reference

Vitamin A 215Beta-carotene 216Vitamin B1 42, 217±219, 250D-pantothenic acid 220Vitamin B12 193Folic acid 221Vitamin D 210

The increase in the rate of decompositionof vitamins is utilized in stress tests forchecking stability.For further information and references,see prediction of stability.

Heavy metalsIn connection with vitamins, the termheavy metals means, in particular, theelements lead, cadmium, iron, cobalt,copper, manganese and nickel. Eventiny amounts (ppb range) of ions of theseelements have a catalytic effect on theoxidative breakdown of many vitamins,those affected being listed in the tablewhich follows.

Vitamins sensitive to heavy metals

Retinol and its estersThiamineRiboflavinPantothenic acid and its saltsPyridoxine hydrochlorideAscorbic acid and its salts

Folic acidCholecal-ciferolErgocalci-ferolRutin

The catalytic effects of the heavy metalsvary in potency. This can be demonstra-ted by taking ascorbic acid as an exam-ple [16].

Catalytic effect of heavy metals on the oxi-dation of ascorbic acid

Cu2+ > Pb2+ > Zn2+ > Co2+ > Fe2+ >Mn2+ > Ni2+

In the case of thiamine, a potent catalyticeffect is shown by traces of copper, inparticular; the adverse effects of othermetals are only slight in comparison[250].The adverse effects of heavy metals onthe stability of vitamins are countered byadding a chelating agent, which formscomplexes with the metal ions, to theproducts.

High-pressure liquidchromatographyHigh-pressure liquid chromatography(syn. HPLC, high performance liquidchromatography) is nowadays the mostimportant method for quantitative deter-

HPLC of vitamin products

Vitamin Reference

Vitamin A 78, 80, 81, 82, 165Vitamin B1 87, 88, 90, 91, 94, 165Vitamin B2 87, 88, 90, 91, 94, 165Vitamin B6 87, 88, 90, 91, 94, 165Vitamin B12 89, 91, 94, 165, 276Nicotinamide 87, 88, 90, 91, 94, 165Pantothenate 89, 93, 165, 275Dexpanthenol 92, 165Folic acid 88, 91, 94, 96, 165Vitamin C 87, 88, 165Vitamin D 79, 80, 81, 83, 84, 85, 165Vitamin E 81, 165Vitamin H 89, 95, 165Vitamin K1 86, 165

Heavy metals 54

mination of vitamins in pharmaceuticalformulations [165]. The accuracy of theresults is distinctly better than that ofmethods previously used. This is an im-portant factor in the development of avitamin product, because this is impos-sible without a series of stability tests.The table above lists references descri-bing the HPLC methods for the determi-nation of each of the vitamins in theirproducts.HPLC is increasingly being used for de-termination of the pure vitamins, too[117, 164, 170].

HPLCsee high-pressure liquid chromatogra-phy.

HumidityThe humidity is of great importance inthe production of solid forms of vit-amins. In the case of ascorbic acid ta-blets, effervescent tablets, and multivit-amin tablets, the relative atmospherichumidity should, if possible, not exceed30%, otherwise high-concentration as-corbic acid compositions adhere to thepunches during tabletting, and the adsor-bed moisture always has adverse effectson the stability of many vitamins [34,141]. It is for this reason indispensablefor the rooms in which these vitaminproducts are tabletted to be air-conditio-ned. As an emergency measure, it ispossible to pass dry air through the clo-sed tabletting machine.(see also water content and stability)

HydrolysisHydrolysis is one of the important waysin which vitamins may be broken down.This particularly applies to preparationsof thiamine hydrochloride, calcium pan-tothenate, dexpanthenol, nicotinamide,pyridoxal phosphate, and ascorbic acid(for the chemical reaction of the lattersee below). The rate of hydrolysis almostalways depends on the pH, as is illustra-ted by the following example of thiaminehydrochloride [97].

Rate of thiamine hydrolysis at 96.4 �C.

The hydrolisis of ascorbic acid finallyforms carbon dioxide and a yellow tobrown colo(u)r caused by resins of fur-fural. Traces of water are sufficient tostart this reaction shown the figure be-low.The stability of dexpanthenol solutionsalso varies between the acid and alkalineranges, because the hydrolysis differs.This is shown by the figure below.

55 Hydrolysis

H

Hydrolysis of dehydroascorbic acid.

Stability of dexpanthenol solutions at 45�C.

Hydrophilic vitaminsThe hydrophilic vitamins (those whichare soluble in water) are distinguishedfrom the lipophilic vitamins and comprisethe following:k thiamine,k riboflavin,k nicotinamide,k pantothenic acid,k pyridoxine,k cobalamin,k folic acid,k ascorbic acid,k biotin.However, the solubility in water mayvary widely.

Hydroxocobalamin(see formula below)Hydroxocobalamin (syn. vitamin B12a)resembles cynaocobalamin in that it takesthe form of dark-red crystals which aresoluble in water and ethanol.Hydroxocobalamin is used in the form ofthe acetate virtually only in liquid drugforms, especially injectables. In these it isin equilibrium with the ionic isomeraquacobalamin [119]. The stability pro-blems are greater than with cyanocobala-min, because it cannot be stabilized bycyanide ions [118]. Hydroxocobalamin isless stable than cyanocobalamin in hepresence of ascorbic acid [53, 62]. Onthe other hand, in a multivitamin infusionsolution ascorbic acid is decomposed inthe presence of hydroxocobalamin, whichdoes not occur with cyanocobalamin[226].Stable solutions for injection which alsocontain vitamins B1 and B6 have beenproduced at a pH of 4.3 to 4.4 (acetatebuffer) with the addition of stabilizers(antioxidants, chelating agents) [193,

Hydrophilic vitamins 56

227]. Addition of 0.4% L-aspartic acidand 2.7 % sodium chloride distinctly im-proved the stability of a 0.1% hydroxo-cobalamin solution [228]. Maleic acid[197] and fumaric acid [230] also havestabilizing effects. Iron chloride and ci-tric acid, and iron (III) ammonium citratehave been described as photostabilizers[229].The action of hydroxocobalamin can beprolonged by preparing a complex withpolyvinylpyrrolidone [240].

Hydroxypropyl(methyl)cellu-loseHydroxypropylcellulose (syn. HPC) andhydroxypropylmethylcellulose (syn. Hy-promellose, HPMC) are marketed underthe registered trademarks L-HPC� [8]and Klucel� [12], and Pharmacoat� [8]and Viscontran� MHPC [11]. They areused as binders and disintegrants forboth granulation and direct tabletting.Hydroxypropyl(methyl)cellulose is alsoused as coating agent (see also film-coa-ting).Both substances are slightly hygroscopic(for the water adsorption curve, see hy-groscopicity).The following composition is recommen-ded for a vitamin B6 tablet [8]:

Vitamin B6 tablet (160 mg)

I. Pyridoxine hydrochloride 160 mgLactose 20±30 mgL-HPC 10±20 mgHPMC 0±4 mg

II. Water q.s.

III. Magnesium stearate 1 mgTalc 1 mg

Granulate mixtures I with II, add III, andcompress.

Direct tabletting of vitamin C tablets ispossible with hydroxypropylcellulose[98].

Hygroscopicity

Uptake of water by calcium D-pantothe-nate at 80 % relative humidity.

57 Hygroscopicity

H

With the exception of dexpanthenol andthe pantothenates, the hygroscopicity ofthe vitamins is low. The preceding graphshows the uptake of water by calciumpantothenate when stored at a relativehumidity of 80%, the substance havingencrusted after a few days.This contrasts with ascorbic acid whichhas absorbed less than 0.05% water afterstorage for 1 day at a relative humidity of80%.The hygroscopicity of auxiliaries is ofgreater importance. The figures whichfollow show the uptake of water after 7days at 25�C by some commonly usedadditives in vitamin products [116].

Hygroscopicity of auxiliaries.

Hygroscopicity 58

59 Hygroscopicity

H

Hygroscopicity 60

I

Incompatibilitiessee interactions, oxidation and reducingagents.

Inert gasAn inert gas (e.g. nitrogen or carbon dioxi-de) is often used to prevent oxidation ofvitamins by oxygen. This is advisable forall liquid drug forms containing vitaminswhich are sensitive to oxygen (vitamins A,B1, B12, C and D). The dissolved oxygenmust be driven out by passing the inert gasthrough the solution, and the solution isthen packaged under inert gas.The stabilizing effect of carbon dioxide asan inert gas is shown by the example of anascorbic acid solution which follows [99].

Stabilization of an ascorbic acid solution bycarbon dioxide.

InjectablesSome vitamin combinations (e.g. multi-vitamin or vitamin B complex) in liquiddrug forms entail very great or even in-

soluble problems of stability. This is whyit is advisable for injection solutions tocontain as few vitamins as possible. Sin-gle-vitamin injectables are preferable.If a combination product is indispensable,consideration should be given to com-partmented ampules, two-chamber ampu-les or freeze-dried injectables (lyophiliza-tion). This particularly applies if the pro-duct is to contain vitamin B12, for exam-ple.For examples of formulations, see cyano-cobalamin and two-chamber ampules.

Instant granulesSince the problems of stability with li-quid multivitamin products are verygreat, and some of them are insoluble,there is a continual search for alternati-ves. Possibilities are solid forms such asinstant granules, oral powders, efferve-scent granules or effervescent tablets, sin-ce these are likewise taken in the liquidform.The formulations of instant granules andoral powders may actually be the same,the difference being in the applicationform and the packaging (in a bottle whichis to be filled with water, or in individualenvelopes for dissolving).An example of this type of use is thefollowing composition of multivitamininstant granules. It may be sold as anoral powder, in which case the patientadds 100 ml water to 30 g and shakesvigorously to obtain a homogeneous sus-pension/emulsion. The suspension stabi-lizers are sucrose and micronized crospo-vidone [260].

61 Instant granules

I

Multivitamin instant granules

I. Vitamin A/D dry powder250,000/50,000 I. U./gCWD 19.0 mgThiamine mononitrate 2.6 mgRiboflavin 3.3 mgNicotinamide 11.0 mgPyridoxine hydrochloride 2.2 mgCyanocobalamin 0.1 %,gelatin-coated [3] 6.6 mgAscorbic acid, powder 115.0 mgTocopheryl acetate drypowder 50%, spray-dried 21.0 mgSucrose, finely ground 2000.0 mgCrospovidone, micronized(Kollidon� CL-M) 500.0 mgPreservative 20.0 mgOrange flavo(u)r 100.0 mgCalcium D-pantothenate 150.0 mg

II. Copovidone 200.0 mgEthanol approximately 0.7 ml

Pass mixture I through a 0.8 mm screen,granulate with solution II, and dry the gra-nules in an oven.

After storage of this formulation at roomtemperature for 12 months, no higherlosses than 5 % were detected (exceptionascorbic acid: 9 %).

Interactions (chemical)It is very important to take account of thechemical interactions between the indivi-dual vitamins in the formulation of pro-ducts containing several vitamins, but notall the details of them are known. Theyare much more pronounced in liquid thanin solid forms. The following chemicalinteractions are known:1. Thiamine hydrochloride is oxidized

by riboflavin to give thiochromewith the formation of chloroflavin[100]. Both may precipitate. Ascor-bic acid may to a certain extent pre-vent the precipitation of thiochrome

[100], but this may result in the for-mation of more chloroflavin [37].

2. The interaction between thiamineand riboflavin is intensified by nico-tinamide.

3. Cyanocobalamin is slowly decompo-sed by thiamine breakdown products[102±104].

4. Nicotinamide reduces the stability ofthiamine [268].

5. Nicotinamide greatly potentiates thereaction between cyanocobalaminand thiamine [105]. This interactionmay be substantially prevented byaddition of iron (III) chloride [55±57].

6. Folic acid is degraded by thiamineand riboflavin [107, 108]. However,this reaction takes place very slowlybelow pH 5 [107].-

7. Nicotinamide virtually triples the so-lubility of folic acid [109]. The solu-bility of riboflavin is also improvedby nicotinamide.

8. Ascorbic acid reduces folic acid[68].

9. Cyanocobalamin is degraded by de-hydroascorbic acid [18, 62, 110]. Toprevent this reaction, it is necessaryto stop the oxidation of ascorbic acidto dehydroascorbic acid [18]. Thepresence of copper ions plays an im-portant part in this [111].

10. Ascorbic acid reduces the stability ofcalcium pantothenate [112].

11. Ascorbic acid and nicotinamide to-gether form the yellow complex ni-cotinamide ascorbate which, fortu-nately, does not alter the chemicalstability of either vitamin.

12. Riboflavin catalyzes the aerobic de-gradadation of ascorbic acid. Thisinteraction can be prevented by ex-cluding light and oxygen [113].

13. Addition of nicotinamide to a solu-tion of ascorbic acid and riboflavin-

Interactions (chemical) 62

phosphate sodium increases the pho-tolysis of the latter. Tryptophan has astabilizing effect [101].

14. Ascorbic acid reduces the stability ofbeta-carotene dry powders in soliddrug forms.

15. Ergocalciferol is isomerized by as-corbic acid, folic acid, thiamine hy-drochloride, and pyridoxine hydro-chloride [114].

16. Ascorbic acid in solution reduces thehalflife of thiamine, as shown by thefigure below [115].

Chemical interaction between thiamine andascorbic acid at 80 �C.

It is easier than in liquid drug forms toavoid chemical interactions in solidforms by using some vitamins (e.g. cya-nocobalamin) embedded in gelatin, inplace of the pure substance. Reducingthe water content may also be very im-portant. Other possibilities are the use ofmultilayer or laminated tablets or the in-corporation of individual vitamins intothe coating or capsule shell instead ofthe interior of the drug form.There are few possibilities for preventinginteractions in liquid drug forms. In thecase of ampules, alternatives are com-partmented ampules, two-chamber ampu-les or lyophilization. For oral products,

the only possibility is to prepare an oralpowder or instant granules.

International unitsThe international units (I. U.) provide in-formation on the biological activity ofvitamins. Nowadays international unitsare officially used only for vitamins Aand D (see table below).

International units

Vitamin A

1 I.U. = 0.300 �g retinol1 I.U. = 0.344 �g retinyl actetate1 I.U. = 0.550 �g retinyl palmitate1 I.U. = 0.359 �g retinyl propionate

Vitamin D

1 I.U. = 0.025 �g cholecalciferol andergocalciverol

Provitamin A

Normally, 1 I.U. vitamin A is stated tobe equivalent to 0.6 �g beta-carotene.The German Society for Nutrition uses1.8 �g per 1 I.U. for calculation [27].

Vitamin E

Officially, the I. U. no longer exists.However, it is still used:1 I.U. = 1.00 mg DL-alpha-tocopheryl

acetate1 I.U. = 0.91 mg DL-alpha-tocopherol1 I.U. = 0.74 mg D-alpha-tocopheryl

acetate1 I.U. = 0.67 mg D-alpha-tocopherolThe USP units are identical to the I. U.

IronIron salts are, as are other trace elements,frequently combined with vitamins. Itshould be noted that the effect of iron

63 Iron

I

(III) ions on the stability of some vit-amins ± e.g. thiamine ± may differ fromthat of iron (II) ions, as is evident fromthe figure below [54].

Effect of iron salts on the stability of thia-mine solutions.

Moreover, the aerobic degradation of as-corbic acid is catalyzed by irons ions[16], and iron ascorbate has a dark violetcolour.On the other hand, addition of 0.05%iron (III) chloride to liquid drug formsmay prevent chemical interactions be-tween cyanocobalamin and thiamine hy-drochloride in the presence of nicotina-mide. This is explained by the oxidationof the thiamine degradation products sothat they are no longer available to de-compose cyanocobalamin [55±57].It is perfectly possible to add iron salts tovitamins in solid drug forms [56]. Forexamples of this use, see trace elements.For the use of iron oxides for coloration,see colorants.

IsomerizationIsomerization is observed with vitaminsA, D, K and beta-carotene.1. Vitamin A, beta-caroteneBoth with retinol and its esters and withbeta-carotene, isomerization takes placemainly in aqueous solubilizates with a pHbelow 6, and in oily solutions exposed toheat. All-trans-retinol is converted mai-nly into the 13-cis and 9-cis isomers (seeretinol palmitate).2. Vitamin DErgocalciferol and cholecalciferol mayundergo isomerization in solid forms[58] and in acid solutions [39, 120±122].In solid drug forms the rate of isomeriza-tion of ergocalciferol may be increasedby ascorbic acid [114], but it is reducedby polyethylene glycol 4000 [183].3. Vitamin KMenadione sodium bisulfite isomerizes inneutral solution to give methylnaphtho-quinone sulfonate [123].

IsopropanolIn countries where the duty on ethanol ishigh, isopropanol (syn. 2-propanol) is fre-quently used as a solvent for granulationor for film-coatings instead of ethanol.Even though there is a general trend toavoid, where possible, the use of organicsolvents in the production of pharmaceu-ticals, for many vitamins it is notstraightforward, for reasons of stability,to change to using water in the usual wetgranulation. Alternatives are aqueousgranulation in a fluidized bed, dry granu-lation or direct tabletting.For examples of the use of isopropanol,see effervescent tablets, glucose, lactose,ethylcellulose, starch, and tartaric acid.

Isomerization 64

IsotretinoinIsotretinoin (syn. 13-cis-vitamin A acid,13-Z-retinoic acid) is one of the reti-noids. It is employed not as vitamin A,but as an agent for the oral treatment ofacne in particular.

65 Isotretinoin

I

K

K, vitaminsee menadione, menadione sodium bisul-fite and phytomenadione.

Kollidon�

Kollidon is the registered trademark forsoluble polyvinylpyrrolidone (povidone)with K values between 12 and 90, cros-povidone and copovidone [1].

K, vitamin 66

L

Lactoflavinsee riboflavin.

Lactose

Lactose (syn. milk sugar) is a glucose-galactose disaccharide. It is a whiteodo(u)rless powder which is soluble inwater. Lactose with 1 molecule of waterof crystallization (monohydrate, loss ondrying = about 5%) is often used, butanhydrous lactose is also commerciallyavailable. Neither type is hygroscopic upto a relative humidity of 80% (for wateradsorption curve, see hygroscopicity).The main area of use of lactose withvitamins is in solid drug forms, in which

500 mg anhydrous lactose placebo tablets.

it acts primarily as a filler. However, italso functions as a binder to a certainextent, as is evident from the figure abo-ve, which shows the relation between thecompressive force and the tablet hard-ness [116].The following formulation of vitamin B1is a typical example of a vitamin tabletcontaining lactose.

Vitamin B1 tablet (100 mg)

I. Thiamine hydrochloride 100 mgLactose monohydrate 200 mg

II. Polyvinylpyrrolidone K 30 10 mgIsopropanol q.s.

III. Crospovidone 9 mgMagnesium stearate 2 mgSilica, highly disperse 1 mg

Granulate mixture I with solution II,mix with III, and press to tablets.

Lactose, or lactose-based preparations,are also used for direct tabletting (seedirect tabletting auxiliaries).In vitamin products, the incompatibilitywith primary and some secondary ami-nes, which is described in the literature,can be virtually neglected. On the contra-ry, ascorbic acid may be stabilized bylactose [21, 129], as may vitamin A andthiamine [105].

LecithinLecithin is one of the monophosphatidesand is mainly composed of a- and b-lecithin and cephalin. It is a wax-like,pale yellow or brown, odo(u)rless hy-groscopic material. It is soluble in ethan-ol and fixed oils. Lecithin swells in waterwith the formation of a colloidal solution.

67 Lecithin

L

Lecithin is used either as an emulsifier infood products or as a synergist to in-crease the effect of antioxidants (E num-ber E 322). The synergistic action of le-cithin derives predominantly from its me-tal-inactivating properties. It is assumedthat the cephalins have the main effect,and this is particularly attributed to theN-containing radical attached to thephosphoric acid moiety. The effect de-creases with increasing water content ofthe substrate. The best effects of lecithinas a synergist have been found in thestabilization of fats, oils, and beta-caro-tene. Thus the following mixture of an-tioxidants is very suitable for beta-caro-tene formulations.

Mixture of antioxidants for beta-carotenepreparations

Tocopherol 1 partAscorbyl palmitate 4±5 parsLecithin 5±15 parts

When lecitihin is used as an emulsifier, itis advisable to add 0.05% tocopherol asantioxidant to stabilize it.

LightBoth visible and ultraviolett light mayhave serious adverse effects on the che-mical stability due to photolysis of thevitamins listed in the following table.

Sensitivity of vitamins to light

Vitamin Reference

Retinol and esters 130Beta-caroteneThiamine (UV light) 41Riboflavin 133Riboflavin-phosphate sodium 101Pyridoxal phosphate 232Pyridoxine hydrochloride(concentration-dependent)

37, 172

Cynaocobalamin 134Folic acid (pH-dependent) 135, 136Ascorbic acid 113Cholecalciferol, ergocalciferol 251, 252Tocopherol (UV light) 41Biotin (UV light)Phytomenadione 41RutinTretinoin 255

The figure below shows the photolyticeffect of visible light on a cyanocobala-min solution [134].

Photolysis of a cyanocobalamin solution(11 �g/ml).

This is why it is worthwhile in general toprotect vitamin products from light. Insome cases, addition of auxiliaries (e.g.methionine for ascorbic acid, tryptophanfor pyridoxine hydrochloride or sucrosefor beta-carotene may stabilize the ef-fects of light.

Light 68

Lipophilic vitaminsThe lipophilic vitamins (syn. oil-solube vit-amins, fat-soluble vitamins) are distinguis-hed from the hydrophilic vitamins and com-prise those listed in the table below.

Lipophilic vitamins

Vitamin AProvitamin AVitamin DVitamin EVitamin K(Acetiamine)(Riboflavin tetrabutyrate)(Ascorbyl palmitate)

Solubilization is necessary to obtainaqueous solutions of these vitamins.

Liver extractLiver extracts are occasionally combinedwith vitamins in tonics or restoratives.They may have adverse effects on thestability of the vitamins.

LubricantsIt is almost always necessary to add alubricant to a mixture which contains vit-amins and is to be tabletted using thehigh-speed rotary machines customarynowadays. The lubricants most common-ly used in vitamin tablets are listed in thetable below.

Lubricants commonly used in vitamintablets

Magnesium stearateTalcPolyethylene glycol (PEG 6000,powder)Stearic acidCalcium arachinateCalcium stearateHydrogenated castor oil

The lubricants do not all belong to thesame class of substances and thus someof their effects differ. This is why diffe-rent concentrations may be used. Theamount of PEG 6000 usually required isa multiple of that of magnesium stearate.However, PEG 6000 has the advantagethat it is the only one of these lubricantswhich is soluble in water, which may beof great importance for effervescent ta-blets, for example.Lubricants are not normally added to vit-amin tablet compositions before granula-tion, otherwise they lose part of theiractivity. Lubricant concentrations whichare too high may adversely affect thetablet hardness ad tablet disintegration.Once again, polyethylene glycol is an ex-ception, as is evident from the figurewhich follows

Effect of the lubricant concentration on thehardness of placebo tablets containingLudipress�.

Mixing with magnesium stearate for toolong also reduces the tablet hardness.For notes on uses, see under the indivi-dual lubricants. For an example of cal-cium arachinate in tablets, see crospovi-done.

69 Lubricants

L

Ludipress�

Ludipress [1] is the registered trade markof a direct compression auxiliary.The Ludipress grade for normal tabletscombines the properties of a filler (lac-tose), binder (povidone) and disintegrant(crospovidone). The special grade for lo-zenges, chewable tablets and effervescenttablets without any disintegrant is calledLudipress LCE.An example of its use with vitamins isthe following composition of a vitamin Echewable tablet.

Vitamin E chewable tablet (200 mg)

Tocopheryl acetate dry powder50%, spray-dried with gelatin [1]

400 mg

Ludipress LCE 190 mgSilica, highly dispers 10 mg

For further examples of its use, see an-tioxidants, ascorbic acid, beta-carotene,direct tabletting, auxiliaries, colorants,multivitamin products, sodium ascorbate,tabletting pressure, and vitamin mixture.

Lumichromesee riboflavin.

Lumiflavinsee riboflavin.

LyophilizationThe technology of lyophilization (syn.freeze-drying) is used for the manufactu-re of vitamin products (especially injec-

tables). The aim is to improve the stabi-lity of the vitamins by ensuring that wateris absent during storage. For example,lyophilization ensures satisfactory stabi-lity of cyanocobalamin in the presence ofascorbic acid [142].The carriers which are commonly usedfor the lyophilisates are glucose, glycine,gum arabic, lactose, mannitol, low mole-cular-weight polyvinylpyrrolidone, andsucrose [143].

Lysine

Lysine (syn. L-lysine, 2,6-diaminohexa-noic acid) is an essential amino acid andthus is occasionally combined with Bvitamins or multivitamin products in theform of the hydrochloride.It reduces the colo(u)r stability of theseformulations.Stable vitamin B complex solutions orgranules containing lysine are reportedto be produced by using 5% polyvinyl-pyrrolidone K 17, 0.05% propylgallate,and 0.005% ethylenediaminetetraaceticacid [64, 144]. Stable solutions are alsopossible in multivitamin compartmentedampules [150]. The use of nitrogen asan inert gas increases the colo(u)r sta-bility.

Ludipress� 70

M

Macrogolsee polyethylene glycol.

Macrogol glyceryl hydroxy-stearatesee PEG glyceryl trihydroxystearate.

Macrogol hydroxystearatesee PEG hydroxystearate.

Magnesium stearate

Magnesium stearate is a fine white,odo(u)rless and tasteless powder whichfeels greasy. It is insoluble in water andethanol.Magnesium stearate is the most widelyused lubricant for tablets, in which theconcentration does not normally exceed1% by weight. Higher concentrationsmay have adverse effects on tablet hard-ness, tablet disintegration, and possiblybioavailability. Insufficient concentrati-ons may also be disadvantageous. It canbe combined with other lubricants (stea-ric acid, talc, etc.).It is not known to be incompatible withany vitamin.For examples of use in formulations, seeanalgesics, beta-carotene, calcium pan-tothenate, colorants, direct tabletting au-

xiliaries, hydroxypropyl(methyl)cellulose,lactose, mannitol, minerals, multivitaminsolid preparations, nicotinamide, tablet-ting pressure, pyridoxine hydrochlorid,retinyl acetate, riboflavin, and starch.

Mannitol

Mannitol (syn. mannite) is a white cry-stalline powder which is freely soluble inwater but slightly soluble in ethanol. It isnot hygroscopic, and it has the E numberE 421.Mannitol is mainly used in solid drugforms and as a carrier for lyophilization.In tablets, it acts not only as a filler, butalso as a binder, since it increases thetablet hardness. This is why it is prefer-red for use in chewable tablets and lozen-ges. The pleasantly sweet, somewhatcooling taste is an additional advantagein this drug form. An example of its useis the following vitamin A compositionfor direct tabletting to chewable tablets.

Vitamin A chewable tablet (100,000 I. U.)

Retinyl acetate or palmitate drypowder 325,000 I. U./gcold-water-dispersible [1] 355 mgMannitol 350 mgCopovidone 25 mgMagnesium stearate 5 mgSilica, highly disperse 3 mg

71 Mannitol

M

Mannitol is not known to be incompatiblewith any vitamin. The stability of vit-amins A, B1 and C in tablets is improvedby mannitol [24].For an example of its use in hard gelatincapsules, see this entry.

MarketingThe laws applying to the marketing ofvitamin products differ between coun-tries. Thus, for example, in the USA allnormal vitamin products are classified asªfoodº. In the FRG they can be categori-zed as food products, OTC products, pro-ducts available only in pharmacies, orprescription drugs. The table which fol-lows explains these categories, which arenot only based on the vitamin dose.

Classification of vitamin products (FRG)

Category Permissiblevitaminsincludingbeta-carotene

Dosage Form supplied Registration Marketingchannels

Foodstuffs All, apart fromA and D

Max. 3 timesthe dailyrequirement

Preferentiallyfood products(fruit juice,confectionery,etc.), but tabletsand capsulespossible

± Food stores,supermarkets,healthfoodstores,drugstores,pharmacies

OTC drugs All A: max.6000 I. U./dose.D: max.400 I. U./dose.Other vitamins:no limits

All drug formspossible. Forcough andthroat remediescontaining vit-amin C: lozen-ges

Approval of theFederal Boardof Health ne-cessary (analy-sis, toxicity,stability)

Supermarkets,drugstores orhealth food sto-res with specia-list staff; phar-macies

Drugsavailableonly inpharmacies*

All A: max. 50,000I. U./dose.D: max. 1000I. U./dose.Other vitamins:no limits

All drug formspossible

Approval of theFederal Boardof Health ne-cessary (analy-sis, toxicity,stability). Clini-cal trials alsonecessary formedical indica-tions defined bylaw

Pharmacies

Prescriptiondrugs**

All No limits All drug formspossible

As for drugsavailable onlyin pharmacies

Pharmacies

* The manufacturer can classify an OTC drug as a drug available only in pharmacies, with the dosageremaining the same, if there appear to be advantages in this.

** The manufacturer may decide to classify a drug which is available only in pharmacies as a prescriptiondrug.

Marketing 72

Menadiol

Menadiol (syn. vitamin K4) can be usedin the form of the diacetate, dibutyrate,tetrasodium diphosphate, or disodiumdisulfate.The diacetate and dibutyrate are insolublein water while the tetrasodium diphos-phate and the disodium disulfate are so-luble in water. Hence the two latter arepreferred for aqueous solutions (e.g. in-jectables).Menadiol and its esters are sensitive tolight and oxygen.

Menadione

Menadione (syn. vitamin K3) is a paleyellow powder, which is virtually insolu-ble in water (about 11 mg/100 ml). Solu-tions containing about 2% can be obtai-ned with vegetable oils.The solubility of menadione means that itis used virtually only in oily products. Injust the same way as the other vitamin Kderivatives, it is sensitive to light andoxygen. Since phytomenadione is evenmore soluble in oil than is menadione,the former is usually preferred.

Solubilizers can be used to improve thesolubility of menadione by as much as afactor of 10 [26] and to influence thephotostability [26, 106, 138].

Menadione sodium bisulfite

Menadione sodium bisulfite (syn. water-soluble vitamin K3) is a white powder,which is soluble in water.It is used for the preparation of aqueoussolutions (injectables). The product is notonly sensitive to light and oxygen butalso decomposes in alkaline solutions togive menadione which may precipitateout, and in neutral solutions it isomerizesto methyl naphthoquinone sulfonate[123].

Micellessee solubilization.

MicrobiologyThe recommendations of the FØdØrationInternationale Pharmaceutique on micro-biological purity were applied to vitaminproducts during many years [146]. Since1999 the requirements of the EuropeanPharmacopoeia are valid as listed in thetable which follows.

73 Microbiology

M

When synthetically prepared vitamins orauxiliaries are used, it is normally noproblem to comply with these recommen-dations. In the case of natural materials,such as starch, gelatin, or D-alpha-toco-pherol, more attention has to be paid tothe microbiological status (category 3 B).

MineralsA distinction is made between the mine-rals, on the basis of the physiologicallyessential amounts, into the ªmacroele-mentsº which are required in gramamounts (sodium, potassium, calcium,phosphorus, magnesium, and chlorine)and the trace elements, where the requi-rements are in the microgram to milli-gram range.An example of a combination of calciumwith vitamins C and D and rutin is the

following composition for direct tablet-ting to effervescent tablets.

Vitamins C + D + calcium effervescenttablet

Calcium carbonate 600 mgAscorbic acid 1000 mgCitric acid 1000 mgSodium bicarbonate 300 mgRutin 50 mgCholecalciferol dry powder100,000 I. U./g 4 mgPolyethylene glycol 6000,powder 300 mgPolyvinylpyrrolidone K 25 orcopovidone

100 mg

Saccharin, sodium salt 3 mgflavo(u)ring q.s.

For an example of the combination ofminerals with multivitamins in tabletform see in the table below.

Minerals 74

Grades of microbiological purity according to Ph.Eur. 1999, 5.1.4 (selection)

Category Products Requirements

1 Injectionsand other sterile preparations

Sterility as defined in the Pharmacopoeia

2 Preparations for topical useand for use in the respiratorytract

± Total viable aerobic count: Not morethan 102 micro-organisms (aerobicbacteria plus funghi) per gram or permillilitre.

± Absence of Pseudomonas aeroginosa,determined on 1 g, or 1 ml.

± Absence of Staphylococcus aureus,determined on 1 g, or 1 ml.

3 A Preparations for oraland rectal administration(synthetic origin)

± Total viable aerobic count:Not more than 103 bacteria and not morethan 102 funghi per gram or per millilitre.

± Absence of Escherichia coli(1 g or 1 ml).

Multivitamin tablets with minerals(2 RDA)

Beta-carotene dry powder 10 % 50 mgThiamine mononitrate 3 mgRiboflavin 3 mgPyridoxine hydrochloride 3 mgNicotinamide 22 mgCalcium D-pantothenate 12 mgAscorbic acid for directcompression 100 mgCalcium phosphate, dibasic 550 mgFerrous fumarate 80 mgMagnesium oxide 160 mgCupric sulfate 2 mgManganese sulfate 14 mgPotassium chloride 50 mgZinc sulfate 37 mgCellulose, microcrystalline 60 mgCrospovidone 50 mgStearic acid 6 mgMagnesium stearate 5 mgTotal tablet weight 12200 mg

M anufacturing: Direct compression

Chemical stability: After the storage atroom temperature the following vitamincontents were found:

6 months 12 monthsVitamin B1 98% 96 %Vitamin B2 98% 92 %Vitamin B5 100% 99 %Vitamin B6 97% 96 %Vitamin C 95% 94 %

Moisture content of granulesThe moisture content of granules meansnot only the absolute water content of thegranules but also, and more importantly,the relative humidity in the space abovethe granules in a closed system. The lat-ter parameter provides more informationthan does the absolute water content ab-out the absorbency and hygroscopicity ofthe relevant powder mixture. It is impor-tant to know the moisture content of gra-nules for tabletting, because it may affect

the mechanical properties, the beha-vio(u)r on compression, the accuracy ofdosing and the stability of vitamins.

Multivitamin productsOne of the greatest challenges to pharma-cists is the development of a multivit-amin product which is as stable as possi-ble and may be combined with trace ele-ments.The many factors which have adverseeffects on the stability of vitamins (seestability) make this much more difficultin aqueous forms than in solid or oilyproducts. This explains the preferencegiven to tablets, capsules, instant granu-les, two-chamber ampules, compartmen-ted ampules, and lyophilisates. The manypublications on multivitamin productshave never revealed a clear solution tothe multiplicity of problems; they havebeen able only to throw light on indivi-dual aspects [19, 24, 25, 56, 59, 75, 76,99, 105, 143, 144, 147±150, 152±156,198, 246, and many others].

Multivitamin solidpreparations(tablets, capsules, granules)The most stable multivitamin formula-tions are tablets and soft gelatin capsules.The tablets can be sugar-coated, film-coated or not coated. If the free watercontent is limited no difference of thestability will be found between coatedand not coated tablets. In such case themain function of the coating is the tastemasking effect.The vitamin derivatives given in the fol-lowing table can be recommended fortablets because they have a low contentof free water to avoid the hydrolisis and

75 Multivitamin solid preparations

M

the chemical interactions, or becausethey are the most stable derivativesagainst the mechanical stress of tablettingand because they have a good flowabili-ty.

Vitamin derivatives for multivitamintablets

± Vitamin A acetate dry powder (gelatinmatrix)

± Beta-carotene dry powder (gelatinmatrix)

± Thiamine mononitrate± Riboflavin powder 100% (not needles)± Calcium D-pantothenate± Nicotinamide± Pyridoxine hydrochloride± Cyanocobalamin dry powder 0.1 % or

1.0 % (gelatin matrix)± Ascorbic acid, crystalline or powder

(not fine powder)± Vitamin D dry powder (gelatin matrix)± Vitamin E acetate spray dried powder.

Many formulations showed that there isno significant influence of the auxiliaries(binders, fillers, disintegrants, lubricantsetc.) on the stability of the vitamins if thefree water content is limited.The most important technology for theproduction of multivitamin tablets is thedirect tabletting procedure because it isthe best method to obtain a low contentof free water in the tablet.The following two formulations of nor-mal multivitamin tablets and multivit-amin effervescent tablets are typical ex-amples for direct tabletting..

Multivitamin tablet

CompositionRetinyl acetate dry powder500,000 I. U./g 10.0 mgThiamine mononitrate 2.2 mgRiboflavin 2.2 mgNicotinamide 16.5 mgCalcium pantothenate 11.0 mgPyridoxine hydrochloride 2.2 mgCyanocobalamin 0.1 % coated [3] 6.0 mgAscorbic acid, powder 85.0 mgTocopheryl acetate dry powder50%, spray-dried 31.0 mgLudipress� [1]or Avicel� PH 101 [2] 300.0 mgCopovidone 21.0 mgMagnesium stearate 3.0 mgOrange flavo(u)r 7.2 mgSaccharin, sodium salt 5.2 mg

Stability

The losses of vitamins measured by HPLCafter storage at room temperature for 12months were as follows:Calcium pantothenate 8 %Vitamin B2 5 %Vitamin B6 6 %Vitamin B12 10%All other vitamins 0 %

Multivitamin effervescent tablet (1±2 RDA)

CompositionBeta-carotene dry powder10% CWD 23 mgVitamin E acetate 50 % dry powder 40 mgThiamine mononitrate 2 mgRiboflavin powder 2 mgNicotinamide 22 mgCalcium D-pantothenate 11 mgPyridoxine hydrochloride 2 mgCyanocobalomin 0.1 % dry powder 6 mgAscorbic acid, powder 85 mgLudipress� LCE 477 mgSodium bicarbonate 600 mgTartaric acid 400 mgPolyethylene glycol 6000 90 mgOrange flavour 60 mgAspartame 30 mg

Manufacturing: Direct compression

Multivitamin solid preparations 76

For further examples of multivitamin ta-blets with minerals/trace elements seeminerals and vitamin mixture.For an example of a multivitamin oralpowder, see instant granules.

Multivitamin solutionsBecause it is extremely difficult to get anacceptable chemical stability of multivit-amin solutions a summary of recommen-dations is given about the individual vit-amins in such preparations.

Vitamin A± The best derivative of vitamin A for

the solubilisation is retinyl palmitate.The acetate crystalizes to fast and thesolubilisates of propionate are sensiti-ve against light (formation of turbity).Only if a very high concentration ofvitamin A is required retinyl propio-nate should be used in combinationwith light protection.

± The selection of the best solubilizer(Cremophor� RH 40 for oral liquids,Solutol� HS 15 for injectables) is im-portant to obtain a good solubilizationand to avoid chemical interactions ofthe solubilizer with vitamin A. Infor-mations about the needed amounts ofsolubilizer see retinyl palmitate andretinyl propionate.

± The temperature of 65�C needed forthe solubilization procedure normallydoes not cause a stability problem.

± The best antioxidant is butylated hy-droxytoluene BHT (or/and butylatedanisole BHA). Tocopherol is less effi-cient and needs much higher concen-trations.

± A low pH causes isomerisation but thecompromise of pH 4 is needed for theother vitamins.

± The use of an inert gas (nitrogen, ar-gon etc.) reduces the oxidation of vit-amin A.

± A good protection agains light reducesthe isomerisation during storage.

Thiamine± Thiamine hydrochloride should be

used as vitamin derivative becausethe solubility of the mononitrate islow.

± A good protection against light redu-ces the degradation.

± The use of an inert gas (nitrogen, ar-gon etc.) reduces the oxidation.

± The chemical interactions between thevitamins B1, B2 and B3 forming brow-nish solutions (thiochrome etc.) andwith vitamin C can only partially beavoided by the use of solvents likepropylene glycol or glycerol.

± The optimal pH is 2.0±3.5. The com-promize of 4 is even acceptable.

± The addition of povidone K 25 or 30masks the bitter taste but flavo(u)ringis recommended.

± The presence of strong reducingagents as antioxidants like bisulfitemust be avoided.

Riboflavin± If the concentration of riboflavin is

low it is preferable to use normal ribo-flavin as vitamin derivative instead ofthe phosphate sodium salt because it ismore stable. But the solubility of nor-mal riboflavin is only max. 7 mg/100 ml.

± The chemical interactions with vit-amin B1 and nicotinamide cannot beavoided forming brownish solutions(see thiamine).

± The optimal pH is 3±4. Therefore thecompromize of pH 4 is good.

77 Multivitamin solutions

M

± The presence of strong reducingagents as antioxidants like bisulfitemust be avoided.

± The addition of povidone K 25 or 30masks the bitter taste but flavo(u)ringis recommended.

Nicotinamide± The use of nicotinic acid as vitamin

derivative is not very common due tothe strong increase of the perifericblood circulation (ªflash effectº). Nor-mally nicotinamide is preferred.

± The intensification of the chemical in-teractions between vitamin B1 and B2by nicotinamide cannot be avoided.

± The yellow colour formation with vit-amin C is not visible in presence ofthe vitamins A and B2.

± Antioxidants don't stabilize nicotina-mide.

Pantothenic acid, dexpanthenol± The best vitamin derivative for multi-

vitamin liquids is the provitamin dex-panthenol because calcium and so-dium pantothenate require a neutralpH.

± The optimal pH of dexpanthenol isabout 5. The compromise of pH 4 iseven acceptable.

± Antioxidants don't stabilize dexpan-thenol.

Pyridoxine± The best vitamin derivative is pyrido-

xine hydrochloride.± The optimal pH is 3±5. Therefore the

compromize of 4 is good.± Antioxidants don't stabilize vitamin

B6.

Cyanocobalamin± The addition of low molecular weight

povidone (Kollidon� 17 PF) increases

the chemical stability in paternal solu-tions of cyanocobalamin. It should betested if povidone K 25 or povidoneK 30 shows the same effect in oralsolutions.

± The chemical interactions with vit-amin C cannot be avoided.

± The optimal pH is 4±5. Therefore thecompromize of pH 4 is good.

± A good protection agains light reducesthe degradation.

± The use of an inert gas reduces theoxidation.

± The chemical interaction with nicoti-namide cannot be avoided.

Folic acid± The solubility if folic acid in water at

room temperature depends strongly onthe pH. At pH 4 the solubility is lessthan 0.5 mg/100 ml. At pH 6.0 about400 mg and at pH 6.4 more than1500 mg are soluble in 100 ml of wa-ter.

± A good protection against light redu-ces the degradation.

± The best antioxidants is BHT or/andBHA.

Vitamin C± The hydrolisis as main degradation of

vitamin C can be delayed by additionof propylene glycol, glycerol, sugar,fructose, sorbitol or glucose.

± The best vitamin derivative is ascorbicacid.

± The pH 4 as compromize would beacceptable.

± The chemical interactions with vit-amin B1, B3 and B12 cannot be avoidedforming coloured solutions.

± The use of an inert gas reduces theoxidation.

Multivitamin solutions 78

± If there is any risk of contaminationwith traces of heavy metals EDTA andcitric acid stabilize vitamin C.

± Strong reducing agents like sodiumbisulfite are excellent stabiliziers ofvitamin C but they cannot be used inmultivitamin preparations becausemost of the other vitamins are degra-daded by these substances.

Vitamin D± The most common vitamin derivative

is cholecalciferol because it is cheaperdue to its availability in the market.

± An excellent solubilizer for oral pre-parations is PEG glycerol trihydroxy-stearate. Informations about the nee-ded amounts of solubilizers, see cho-lecalciferol.

± According to our experience the stabi-lity of vitamin D is no major problemif the stability of vitamin A was opti-mized in the formulation.

± The pH 4 as compromize is accepta-ble.

± The best antioxidant is BHT or/andBHA.

± The use of an inert gas (nitrogen, ar-gon etc.) reduces the oxidation.

Vitamin E± Only the derivative tocopheryl acetate

is suitable for multivitamin liquids.Tocopherol is not stable enough.

± An excellent solubilizer for oral pre-parations is PEG glycerol trihydroxy-stearate. Informations about the nee-ded amounts of solubilizer, see toco-pheryl acetate.

± The pH 4 as compromize is accepta-ble.

For examples of multivitamin liquid for-mulations see B complex, cyanocobala-min, syrup, and two-chamber ampules.

79 Multivitamin solutions

M

N

Natural vitaminsIn terms of their structure, virtually allthe vitamins, and very many of the vit-amin derivatives which are used, can bedesignated naturally occuring. Based onthe mode of production, the vast majorityof vitamins are synthetic. This results inthe designation ªidentical to the naturalproductº.A few of the vitamins which are marke-ted are of natural origin. These include,for example, vitamin C extracted fromplants, provitamin A extracted from al-gae, vitamins A and D3 in fish liver oil,and a mixture of alpha-, beta-, gamma-and delta-tocopherol from soybeans.Vitamins produced by microbiologicalmethods or semi-synthetically occupy anintermediate position. An example of thelatter is D-alpha-tocopheryl acetate,which is obtained by methylation of thevarious D-tocopherols obtained from soy-bean oil to give D-alpha-tocopherol, fol-lowed by acetylation.In terms of pharmacy, the synthetic vit-amins scarcely differ from those of natu-ral origin.

NDGAsee nordihydroguaiaretic acid.

NiacinThe name niacin is used either for nico-tinic acid alone (USA) or as a term whichcovers the vitamin formerly called vit-amin PP or B3 and which includes nico-tinamide and nicotinic acid.

Nicotinamide

Nicotinamide (syn. niacinamide, former-ly vitamin PP or B3) is a white crystallinepowder with a faint odo(u)r. It is freelysoluble in water and glycerol.Nicotinamide is one of the most stablevitamins and gives rise to the fewest pro-blems in pharmaceutical technology. It isnot sensitive to light, oxidizing agents orreducing agents.In liquid drug forms, account has to betaken of the fact that nicotinamide maypotentiate the chemical interactions be-tween vitamins B1/B12 and B2. However,this has little effect on the stability ofnicotinamide itself. The pH can be be-tween 4 and 8. Hydrolysis to nicotinicacid takes place below pH 4 and abovepH 8. For examples of its use, see Bcomplex, dexpanthenol, and two-chamberampules.The advantages of nicotinamide in soliddrug forms are that direct tabletting ispossible and that it has a certain bindingaction. The latter may also result in un-desired agglomeration of the pure sub-stance. The following nicotinamide tablet

Nicotinamide tablet (200 mg)

Nicotinamide 200 mgCellulose, microcrystalline [2] 100 mgCopovidone 10 mgMagnesium stearate 2 mgSilica, highly disperse 2 mg

Natural vitamins 80

composition for direct tabletting is anexample of its use.When nicotinamide is combined with ge-latin-coated dry powders of, for example,vitamin A, it may destroy the structure ofthe gelatin and thus release the entrappedvitamin and reduce its stability [162].For examples of solid combinations withother vitamins, see B complex, instantgranules, multivitamin solid preparations,thiamine mononitrate, and tartaric acid.

Nicotinamide ascorbateNicotinamide ascorbate is a complex ofnicotinamide and ascorbic acid. Accor-ding to the Food Chemicals Codex III,the molecular ratio is 1+2 and the weightratio is 1+3. The complex has also beenreported to have a molecular ratio of 1+1[160].It is a lemon-yellow, odo(u)rless powderwhich is freely soluble in water.Nicotinamide ascorbate is used only insolid drug forms. It is very suitable formultivitamin tablets since direct tablet-ting is possible and it has a high bulkdensity.

Nicotinic acid

Nicotinic acid (syn. niacin, formerly vit-amin PP or B3) is a white crystallinepowder which is slightly soluble in coldwater.Unlike nicotinamide, nicotinic acid is notused widely in vitamin products for hu-man consumption, because it strongly sti-mulates peripheral blood flow (and cau-ses flushing).

NitrogenNitrogen is the most commonly used in-ert gas for preventing the adverse effectsof oxygen on vitamin stability. The nitro-gen must be passed through the solutionin order to displace the dissolved oxygen,and the solution must be blanketed withnitrogen before the container is closed.Since the solubility of oxygen is morethan twice that of nitrogen, the displace-ment of the former is time-consuming.Carbon dioxide is more advantageous inthe regard.The use of an inert gas is important forthe vitamins A, B12, C, and D which aresensitive to oxidation by atmosphericoxygen.

Nordihydroguaiaretic acid

Nordihydroguaiaretic acid (syn. NDGA)comprises white crystals which are freelysoluble in ethanol, glycerol and propy-lene glycol and less soluble in hot water.Up to 1% solutions in oils can be obtai-ned.Nordihydroguaiaretic acid is a natural an-tioxidant of vegetable origin. It is mainlyused for stabilizing fats and oils. It mayalso indirectly protect vitamins A and Dfrom oxidation in oily solutions by pre-venting the formation of lipid peroxides,which are able to oxidize the vitamins[51]. Folic acid is likewise stabilized byaddition of 0.02 to 0.05% NDGA [35].The concentrations normally used are inthe range 0.01 to 0.1%.For an example of its use in a multivit-amin syrup, see sorbitol.

81 Nordihydroguaiaretic acid

N

O

Octotiamine

Octotiamine comprises, as does benfotia-mine, colo(u)rless crystals.This vitamin B1 derivative is rarely usedbut is said to have a certain prolongationof action.

Odo(u)rsee flavo(u)ring.

OilsThe oils used as auxiliaries in vitaminproducts are usually vegetable oils (fattyacid glycerides). The oil which is mostcommonly used for this purpose is peanutoil, because it has no adverse effects onthe stability of vitamins, and is one of themost stable vegetable oils. Castor oil andsesame oil are very occasionally used forparenteral products.Pharmaceuticals containing oils togetherwith vitamins which are sensitive to oxi-dation (e.g. vitamins A or D) must bestabilized with an antioxidant combina-tion, because the lipid peroxides whichare initially formed by autoxidation willcause secondary decomposition of thevitamins [51]. Decreases in the vitaminA content in oils and emulsions essential-ly derive from reactions of this type. Thebreakdowns of vitamin A can be consi-derably delayed by addition of ascorbyl

palmitate together with an antioxidant,e.g. tocopherol.Oily dilutions of vitamins A and D andprovitamin A in peanut oil are commer-cially available for processing. They fa-cilitate the incorporation of these (other-wise crystalline) substances into oil pro-ducts (e.g. soft gelatin capsules, oily so-lutions or emulsions).Other oily components which are com-monly used in vitamin products areshort-chain saturated triglycerides (Mi-glyol� [9]).

Oil-soluble vitaminssee lipophilic vitamins.

OintmentsOintments based on fats and containingvitamins are uncommon. For bioavailabi-lity reasons, creams (oil-in-water emulsi-ons) are almost always used.

Omega fatty acidssee fatty acids, polyunsaturated.

Orotic acid

Orotic acid (syn. formerly vitamin B13) isno longer regarded as a vitamin. Never-theless, it ± or choline orotate or nicoti-

Octotiamine 82

namide orotate ± is still present in somemultivitamin products and geriatric pre-parations.The solubility of orotic acid in water isabout 1.7 mg/ml. Aqueous solutions canbe stabilized by amines [242]. Monoetha-nolamine improves solubility and stabili-zes 1.0 to 2.5% solutions when added toorotic acid in the ratio 0.8 : 1.0. The sta-bility of this solution was still satisfactoryafter the pH had been adjusted to be-tween 4 and 5 with citric acid [243].

OTC vitamin productssee marketing.

OverageThe adverse effects on the stability of al-most all the vitamins when they are con-verted into preparations explain why inmany countries relatively high overagesare applied. The industrial pharmacy sec-tion of the FØdØration Internationale Phar-maceutique (F. I. P.) many years ago re-commended the overages [212], as shownin the first of the two tables, and the actualUS Pharmacopeia permits the overages formultivitamin preparations, as given in thesecond of the tables which follow.However, the registration authorities inmany countries have recently started toinsist that the expiration periods are to beshortened rather than accepting highoverages in pharmaceuticals. This ap-pears sensible in some respects, becausethe accurate specification of the vitamincontent is one of the most important cri-teria distinguishing a pharmaceutical vit-amin product from a food product. Ho-wever, it is likely that the general upperlimit of 10 % for overages, which hasbeen laid down by the Federal Board ofHealth in Berlin, is impracticable for

many multivitamin products. The over-ages permitted in the USA for single-vitamin products are listed in the thirdtable which follows.

Overages of vitamins in single-vitamin pro-ducts (F. I. P. recommendations 1966)

Overage (%)Vitamin Liquid

formsSolidforms

Vitamin A (low-dose) 50 50Vitamin A (high-dose) 30 30Vitamin D (low-dose) 50 50Vitamin D (high-dose) 10 10Vitamin E 10 10Vitamin K 30 30Vitamin B1 10 10Vitamin B2 10 10Vitamin B6 10 10Vitamin B12 30 10Folic acid 30 10Calcium D-pantothenate 10 10Vitamin C (oral) 50 10Vitamin C (parenteral) 10 ±

Overages of vitamins in combinationproducts, e.g. multivitamin products (USPXXIV)

Overage (%)Vitamin Liquid

formsSolidforms

Vitamin A 150 65Vitamin D 150 65Vitamin E 150 65Vitamin B1 150 50Vitamin B2 50 50Vitamin B6 50 50Vitamin B12 350 50Folic acid ± 50Calcium D-pantothenate 50 50Nicotinamide 50 50Vitamin C 150 30Vitamin K1 ± 65

83 Overage

O

Overages in single-vitamin products per-mitted by US Pharmacopeia XXIV

Product Maximum overage

Vitamin A capsules 20%Vitamin E capsules 20%Thiamine mononitrate elixir 15%Thiamine hydrochloride elixir 35%Thiamine hydrochloride tablets 10%Thiamine hydrochloride injection 10%Riboflavin injection 20%Riboflavin tablets 15%Pyridoxine hydrochloride tablets 15%Pyridoxine hydrochloride injection 15%Calcium D-pantothenate tablets 15%Cyanocobalamin injection 15%Folic acid tablets 15%Folic acid injection 10%Vitamin C tablets 10%Vitamin C injection 10%Beta-carotene capsules 25%

Oxalic acidOxalic acid is the final product of theaerobic (= oxidative) decomposition ofascorbic acid. Therefore it is limited tomax. 0.2 % in ascorbic acid according toPh.Eur. 1997.Calcium oxalate may crystallize out ofvitamin C solutions containing calciumon prolonged storage [37].Stabilization is possible by addition ofoxalic acid to ascorbic acid solutions[70, 161].

Aerobic breakdown of ascorbic acid.

OxidationMany of the vitamins are sensitive tooxidation in their formulations, a distinc-tion being made between the action ofoxygen and that of oxidizing agents.

Oxalic acid 84

Sensitivity of vitamins to oxidation

Vitamin Oxygen Oxidizingagents

Vitamin A + +

Provitamin A + +

Vitamin B1 (±) +

Vitamin B6 ± +

Vitamin B12 + +

Vitamin C + +

Folic acid ± +

Vitamin D + +

Tocopherol + +

In aqueous solution the rate of oxidationmay depend on the pH. The figure whichfollows shows that vitamin B1 is virtuallyinsensitive to atmospheric oxygen at thepH of about 4 which is normally em-ployed. However, when the pH increasesto 5, the effect of oxygen is evident whenit is excluded by use of an inert gas [54].The ways of minimizing the oxidation ofvitamins and thus improving their stabi-lity in the products are as follows:1. Addition of an antioxidant.2. Exclusion of oxidizing agents.

3. Use of nitrogen or carbon dioxide asinert gas.

4. Addition of a chelating agent, whichbinds any traces of heavy metalswhich are present and thus preventstheir catalytic effect on oxidation.

Effect of nitrogen on the stability of thia-mine in vitamin B complex solution (stor-age at 22�C for 1 year).

OxygenAtmospheric oxygen is detrimental to thestability of some vitamins, and this mustalways be remembered during develop-ment, production and packaging. For de-tails, see inert gas and oxidation.

85 Oxygen

O

P

P, vitaminsee bioflavonoids.

PackagingCareful attention to packaging is impor-tant with many vitamin products, becauseit may affect the stability and the expira-tion date. The greatest care during deve-lopment and manufacture of a product isuseless if inappropriate packaging can-cels out all these efforts. This applies toall vitamins which are sensitive to light,humidity and oxidation by atmosphericoxygen. Gastight and opaque packagingis thus generally advisable to improvevitamin stability. For vitamin tablets thenormal blister pack material cannot berecommended [265, 269]. The new bli-ster pack material Topas� having an ex-cellent water vapour impermeabilitycould be an acceptable choice for vitamintablets [278].For liquid preparations only glass flasksshould be used as packaging [272].In some cases it is a further advantage touse an inert gas while the containers arebeing filled.It is advisable with effervescent tablets todesign packaging containing a desiccant[267].In certain circumstances, account has tobe taken of chemical or physical reac-tions with plastic materials (e.g. poly-ethylene) or their additives [151]. Vit-amin A may be adsorbed onto polyvinylchloride containers [213, 214].

Pangamic acid

Pangamic acid (syn. formerly vitaminB15) is only rarely used in multivitaminproducts or geriatric agents since there isdoubt about its effect [137].

Panthenolsee dexpanthenol.

Pantothenic acid

Pantothenic acid (syn. D-pantothenicacid, formerly vitamin B5) is a viscousand extremely hygroscopic liquid whichis miscible with water.Pantothenic acid is very unstable both asthe pure substance and in drug forms.Hence it is not used as such in pharmacy.

P, vitamin 86

Calcium pantothenate is mostly used insolid forms, and the provitamin dexpan-thenol or sodium pantothenate is used inliquid and semisolid products.1.0 g D-pantothenic acid is equivalent to:k 0.936 g dexpanthenol,k 1.088 g calcium D-pantothenate,k 1.099 g sodium D-pantothenate.

Parabens

The most important parabens (syn. para-hydroxybenzoic esters, PHB esters) aremethylparaben and propylparaben, whichare marketed under the names Nipagin�

M and Nipasol� M [10].Methylparaben consists of white needles,of which about 0.1 g dissolve in 100 mlwater at 20�C. It is more soluble in oils,and is freely soluble in ethanol.Propylparaben consists of white crystals,of which only 1 part dissolves in 2,500parts of water at 20�C. It is more solublein hot water, and is freely soluble inethanol.Both substances are used as preservatives(E number E 218 and 216). They areoften used together in the ratio 7+3, be-cause their preservative effects are com-plementary. The normal concentrationsof the combination are 0.1 to 0.2% inaqueous solutions and 0.2 to 1.0% inoily formulations. For an example oftheir use in syrups, see B complex andsorbitol.With parabens, as with all preservatives,account has to be taken of the fact thatsolubilizers and emulsifiers may reducetheir efficacy. Thus, for example, addi-

tion of 0.3% methylparaben + propylpa-raben (7+3) is insufficient to kill in 10days all the microorganisms added to anaqueous solution which contains 4 %PEG glyceryl trihydroxystearate.

Particle size distributionThe particle size distribution of the vit-amins and auxiliaries is of importance inthe production of solid drug forms. It isnecessary to take account of the fact thatthe particle size of a particular productoften differ between manufacturers andthe product may be marketed in severalvariants (e.g. vitamin A dry powder, py-ridoxine hydrochloride, ascorbic acid,sodium ascorbate, etc.).The particle size distribution is not al-ways stated in the same manner. Thescreens are usually defined in �m orªmeshº.

Screen definitions

Screen openings Mesh [128]

2000 �m 10850 �m 20600 �m 30425 �m 40300 �m 50250 �m 60212 �m 70180 �m 80150 �m 100125 �m 12075 �m 20063 �m 23053 �m 27045 �m 32538 �m 400

The optimal particle size distribution of avitamin for direct tabletting depends onthat of the other components. The upperlimit for soft gelatin capsules is 180 �m

87 Particle size distribution

P

(= 80 mesh) if the vitamins are to besuspended, not dissolved.With some lipophilic vitamins (e.g. beta-carotene) the particle size may also havean effect on absorption in the body. Thebioavailability increases with the finen-ess of the crystals, as is evident from theexperiment on chickens described below.A low vitamin A content in the liver wasincreased only slightly, compared with acontrol group, after administration of anoily beta-carotene dispersion with cry-stals between 1 and 5 �m in size. Admi-nistration of a dry powder containing 0.1to 0.4 �m beta-carotene crystals greatlyincreased the bioavailability.

Bioavailability of beta-carotene of variouscrystal sizes in chickens (24 h after oraladministration).

Peanut oilPeanut oil is a yellow oil which is widelyused as a diluent or solvent for oral solu-

tions and emulsions of lipophilic vit-amins, as well as for soft gelatin capsu-les. The use of peanut oil as a solvent ineyedrops containing tretinoin as activeingredient results in a stable product[255].Vitamin A, vitamin D and beta-caroteneare already commercially available as di-lutions or dispersions in peanut oil forprocessing. These products usually con-tain an antioxidant to stabilize both thepeanut oil and the vitamins.

PEGsee polyethylene glycol.

PEG glyceryl trihydroxystea-ratePEG-40 glyceryl trihydroxystearate (syn.macrogol glycerol hydroxystearate, poly-ethylene glycol 40 glyceryl trihydroxy-stearate, polyoxyl-40 hydrogenated castoroil) is composed of a hydrophilic andhydrophobic portion. The structure ofthe nominal main constituent can beseen below.The substance takes the form of a whitepaste or semiliquid which is virtuallyodo(u)rless and tasteless in aqueous solu-tion. It is miscible in any ratio with bothwater and lipophilic vitamins. This makesit one of the best non-ionic solubilizersfor oral and topical vitamin products(HLB value 14±16).PEG-40 glyceryl trihydroxystearate ismarketed for pharmaceutical purposes

Peanut oil 88

under the registered trade names Cremo-phor� RH 40 [1] or Arlatone� 975 [6],for example.A typical example of its use is the fol-lowing composition of vitamin A+Edrops.

Vitamin A+E drops 825,000 I. U. + 50 mgper ml)

Retinyl palmitate 1.5 gTocopheryl acetate 5.0 gPEG-40 glyceryl trihydroxy-stearate [1] 20.0 gAntoxidant q.s.Preservative q.s.Flavo(u)ring q.s.Water ad 100 ml

In order to obtain a clear solubilizate, it isnecessary to mix the vitamins with thesolubilizer at elevated temperature andto stir the hot solution of the preservati-ves and flavo(u)rings slowly into themixture.A concentrate containing 100,000 I. U.vitamin A and 20,000 I. U. vitamin Dper ml which is commonly used in phar-macy for the production of liquid drugforms has the following composition, forexample:

Vitamin A+D concentrate for processing(100,000 + 20,000 I. U. per ml)

Retinyl palmitate 6.5 gCholecalciferol 55 mgButylated hydroxytoluene 0.3 gPEG-40 glyceryl trihydroxy-stearate [1] 26.0 gWater ad 100 ml

For further examples of its use, see cho-lecalciferol, ergocalciferol, solubilizers,syrup, tocopheryl acetate, and vitaminderivatives.

PEG glyceryl triricinoleatePEG glyceryl triricinoleate (syn. macrog-ol glycerol ricinoleate, polyethylene glyc-ol-35 glyceryl triricinoleate, polyoxyl-35castor oil) is a viscous yellow liquidwhich is miscible in any ratio with waterand the lipophilic vitamins. The substan-ce is composed of a hydrophilic and ahydrophobic portion. The main compo-nent has a chemical structure analogousto that of PEG glyceryl trihydroxysteara-te.It is a non-ionic solubilizer which has aHLB value of 12 to 14 and is marketedfor pharmaceutical purposes under thetrade name Cremophor� EL, for exam-ple.The amounts required for the solubiliza-tion of tocopheryl acetate are evidentfrom the figure which follows, in whichall the data are based on the solubilizate.

Solubilization of vitamin E acetate.

The amounts needed for the solubiliza-tion of retinyl palmitate are about thesame as for PEG glyceryl trihydroxystea-rate (for graph, see vitamin derivatives).An example of its use for the solubiliza-tion of vitamin K1 is described underphytomenadione.

89 PEG glyceryl triricinoleate

P

PEG hydroxystearate

PEG hydroxystearate (syn. macrogol hy-droxystearate, PEG-15 hydroxystearate,polyethylene glycol 660 hydroxystearate)is a white paste which is miscible in anyratio with water and the lipophilic vit-amins. The substance is marketed as asolubilizer for parenteral products underthe trade name Solutol� HS 15 [1]. Oneof the great advantages of the substancefor pharmacy is its low viscosity ± below20 mPa.s (30% in water). The amountsof solubilizer, based on the solution, re-quired to prepare clear aqueous solutionsof retinyl palmitate and retinyl propio-nate are evident from the figure whichfollows.

Solubilization of vitamin A with PEG hy-droxystearate.

An analogous plot for vitamin K1 is to befound under phytomenadione. An injec-tion solution containing 4 or 5% beta-carotene in water can be prepared usingabout 25% PEG hydroxystearate [28].For an example of its use in a high-dosevitamin A+D+E veterinary ampule, seeemulsion.

PEG sorbitan oleatesee polysorbate.

pHThe pH is one of the most importantfactors for the stability of vitamins, be-cause in most cases their decomposition(hydrolysis, oxidation, chemical interac-tions, etc.) depends on the pH. This par-ticularly applies to vitamin products con-taining water. Unfortunately, the pH op-tima for the individual vitamins differ somuch that a compromise is always neces-sary in a multivitamin solution and insome cases relatively large losses haveto be accepted.

pH optima for the vitamins

Vitamin A above 6Vitamin B1 2±4Vitamin B2 3±5Nicotinamide 4±8D-pantothenates 6±8D-panthenol 5±6Vitamin B6 3±5Vitamin B12 4±5Folic acid 6±9Vitamin C 5±7Vitamin D 4±8Vitamin E 4±8Biotin 6±8

Only vitamins D and E and nicotinamidecan be regarded as being free of pro-blems.Vitamin A (e.g. retinyl palmitate) startsto undergo isomerization below pH 6,which reduces the vitamin A activity.

PEG hydroxystearate 90

With thiamine hydrochloride the pHshould not exceed 4.5 and is preferablybelow 4.0 (see hydrolysis and oxidation).Dexpanthenol is much more suitable forcombination with other B vitamins thanare the D-pantothenates, which requiretoo high a pH [159].In the case of ascorbic acid, there are tworanges in which the stability is satisfacto-ry or good (for graph, see ascorbic acid).The recommended compromise for amultivitamin solution is a pH between4.0 and 4.5. A vitamin B complex solu-tion containing only vitamins B1, B2, B6,nicotinamide, and dexpanthenol has grea-

Stability of vitamin B1, C, and dexpanthen-ol in vitamin B complex + C ampules (6weeks, 45 �C).

Stability of vitamin A in a multivit-amin solution (6 weeks, 45�C).

ter stability at a somewhat lower figure(e.g. 4.0).The preceding figures show clearly thedifferences in the dependence of the sta-bility on the pH for thiamine hydrochlo-ride, dexpanthenol, and ascorbic acid onthe one hand, and of vitamin A on theother hand [41].The measured pH values of aqueous solu-tions of the hydrophilic vitamins aresometimes outside the optimal pH ranges.

pH of vitamins in water

Vitamin Concen-tration

pH

Thiaminehydrochloride 2.5% 2.7±3.3Thiaminemononitrate 2.0% 6.0±6.7Riboflavin saturated

(4 mg +10 ml water)

5.5±7.2

Riboflavin-phosphatesodium 2.0% 4.0±6.0Pyridoxinehydrochloride 5.0% 2.3±3.5Dexpanthenol 5.0% 9.5±11.0Calciumpantothenate 5.0% 6.8±8.0Sodiumpantothenate 10.0% 9.0±10.5Nicotinic acid 1.0% 3.0±3.5Nicotinamide 5.0% 6.0±8.0Ascorbic acid 5.0% 2.2±2.5Sodium ascorbate 10.0% 6.0±8.0

PharmacopeiasThe common vitamins and their impor-tant derivatives are all to be found in thecurrent pharmacopoeias in the form ofmonographs on the pure substances and,in some cases, on preparations. The USPXXIV also contains monographs of vit-amin combination products, e.g. ªOil-

91 Pharmacopeias

P

and Water-soluble Vitamins tabletsº andªOil-soluble Vitamins Capsulesº.The requirements for the pure vitamins andthe methods of determination in the Euro-pean Pharmacopoeia (e.g. Ph.Eur. 3nd edi-tion) are not always identical with thoseoutside Europe (USA, Japan, etc.).

Phase separationPhase separation may occur with normalemulsions and with solubilizates (= mi-croemulsions) of the lipophilic vitamins.This phenomenon is observed after prolon-ged storage if the solubilizer content is toolow or the temperatures were very low orextremely high. Separation of solubilizatesof vitamin A propionate may also be indu-ced by prolonged exposure to light.Phase separation occurs during the headsterilization of solubilizates in ampules.This can be dealt with by briefly and vigo-rously shaking the solution which is stillwarm from sterilization, which returns itto the original homogeneous distribution.In addition, phase separation may be ob-served if the solubilizate is prepared inthe incorrect sequence, too rapidly, orusing cold water (see also emulsion andsolubilization).

PHB esterssee parabens.

PhotolysisDegradation by light (see this entry).

Phytomenadione

Phytomenadione (syn. phylloquinone,phyllomenadione, phytonadione, vitaminK1) is one of the lipophilic vitamins. Onlythe trans form occurs in nature. USP XXIVspecifies that synthetic products must notcontain more than 20% cis isomer, thelatter having no vitamin K activity.Phytomenadione is a clear viscous yellowliquid which is virtually odo(u)rless. It isinsoluble in water but disolves in abso-lute ethanol and oils.Phytomenadione is preferentially used inliquid pharmaceuticals in the form of oilsolutions for solubilizates. Both types offormulation are sensitive to heat andlight. The pH of aqueous solutions shouldbe weakly acid and reducing agents mustbe excluded. An example of a suitablesolubilizer is PEG glyceryl triricinoleate,which can be used to prepare a clearsolution of the following composition:

Vitamin K1 solution (10 mg/ml)

Phytomenadione 1.0 gPEG-35 glyceryl triricinoleate 6.5 gWater ad 100 ml

The recommended solubilizer for the pre-paration of solutions for injection is PEGhydroxystearate [1]. The figure belowshows the concentrations of solubilizerrequired in the solution.

Solubilization of phytomenadione withPEG hydroxystearate.

Phase separation 92

A phytomenadione dry powder must beused to prepare solid drug forms (e.g.adsorbate on silica gel or spray-driedmaterial).

Plasdone�

Plasdone is a registered trademark for asoluble polyvinylpyrrolidone which mayhave various K values [5].

Polyethylene glycol

Polyethylene glycols (syn. PEG, macrog-ol, polyoxyethylene) are available withmolecular weights between 200 and20,000. Both the properties and the usesvary with the molecular weight. PEG ab-sorbs hardly any water up to a relativehumidity of 80% (for plot of the wateradsorption, see hygroscopicity). The ty-pes of PEG used most commonly in vit-amin products are as follows:1. PEG-400 is a colo(u)rless liquid used

as a solvent. It may improve the sta-bility of some vitamins (see solubili-zer).

2. PEG-1500 and -4000 are white pow-ders or microbeads which are chieflyused in semisolid drug forms.

3. PEG-6000 is a powder which is mai-nly used in solid forms. Its solubilityin water makes it suitable as a glidantand lubricant, especially in efferve-scent tablets, but it also has a goodlubricant action in other tablets. Theamounts required are distinctly higherthan those of fatty acids and theirsalts, such as magnesium stearate.This is evident from the examples ofits use, which can be found under theheadings analgesic, ascorbic acid, ef-

fervescent tablets, copovidone, directcompressible vitamins, minerals, mul-tivitamin solid preparations, sorbitol,trace elements, and tartaric acid.

As a film-forming agent, PEG-6000 iscommonly combined with other poly-mers. For examples of its use, see film-coating.PEG may stabilize ergocalciferol in solidforms by reducing its contact with acidicsubstances and thus diminishing isomeri-zation [58].

Polyplasdone�

Polyplasdone XL is a registered trade-mark for crospovidone [5].

PolysorbateVarious types of polysorbate may be usedin vitamin products. By far the most use-ful is polysorbate 80 (syn. PEG-20 sorbi-tan oleate), which is marketed under thename Tween� 80 [6].Polysorbate 80 consists of a hydrophobicand a hydrophilic part, and the maincomponent of the hydrophobic part ispolyethylene glycol-20 sorbitan oleate.It is a yellow viscous liquid which has abitter fatty taste and is miscible in anyratio with water and the lipophilic vit-amins.Polysorbate 80 is one of the most com-monly used non-ionic solubilizers fororal and topical pharmaceuticals. TheHLB value is about 15. The followingcomposition of a clear aqueous solutionis an example of its use for the solubiliza-tion of vitamin A.

Vitamin A drops (50,000 I. U./ml)

Retinyl palmitate 3.0 gPolysorbate 80 12.0 gWater ad 100 ml

93 Polysorbate

P

The amounts of polysorbate 80 requiredto solubilize tocopheryl acetate areshown in the graph below.

Solubilization of vitamin E acetate withpolsorbate 80.

For further examples of its use, see solu-bilizer and sorbitol.It proved possible to reduce the amountof polysorbate in a multivitamin solutionby addition of glycerol [246].Because of the somewhat unpleasant ta-ste, particular care has to be taken withflavo(u)ring when polysorbates are used.Polysorbates may, as may all non-ionicsurfactants, reduce the effectiveness ofpreservatives.

Polyvinylpyrrolidone(Povidone)

Soluble polyvinylpyrrolidone (syn. Povi-done, PVP, polyvidone) is a white pow-der which is freely soluble in water,ethanol, glycerol, and propylene glycol.It is hygroscopic (for graph of the wateradsorption, see hygroscopicity). For inso-luble polyvinylpyrrolidone, see crospovi-done.

Povidone of various molecular weightsand of pharmaceutical quality is commer-cially available under the name Kolli-don� [1, 263d] and Plasdone� [5]. Theaverage molecular weight is normallycharacterized by use of the K value[175]. The functions of the individualtypes in vitamin products vary:1. Povidone with a K value between 11

and 18 is used as a carrier for lyophi-lization and for improving vitamin sta-bility and taste in aqueous solution[64]. The following mixture of auxi-liaries for a vitamin B complex solu-tion has been reported to be very sui-table for this purpose [144, 263a].

Auxiliaries for the preparation of a vitaminB complex solution in water

Povidone, K value 17 5.0 %Propyl gallate 0.05%Ethylenediaminetetraacetic acid,disodium salt 0.005%Benzyl alcohol 0.02%Ethanol 0.3 %Propylene glycol 2.0 %Cyclamate, sodium salt 1.0 %Saccharin, sodium salt 0.5 %Strawberry flavo(u)r 0.1 %

2. Povidone with a K value between 23and 33 can be used as a water-solublebinder in all types of vitamin tablets,including effervescent tablets. The ap-plies both to granulation and to directtabletting. 2 to 5% Povidone K 23±33,based on the weight of the tablet, isnormally used for this purpose. Forexamples of its use in formulations,see B complex, effervescent tablets,calcium hydrogen phosphate, compac-tion, crospovidone, lactose, minerals,starch, thiamine mononitrate, thia-mine hydrochloride, and tartaric acid.

Polyvinylpyrrolidone(Povidone) 94

In addition Povidone with K valuesbetween 23 and 33 is used as a granu-lation auxiliary for mixed powders forhard gelatin capsules and for instantgranules.Both low molecular-weight Povidonewith a K value of 17 and Povidone K25 improve the flavo(u)r and stabilityof vitamin B solutions [64].For examples of its use in the formula-tion of a B complex syrup, see dex-panthenol.Povidone with a K value between 23and 33 can also be used as a film-forming agent, and possibly as a pla-sticizer, in combination with cellulosederivatives in film-coating or in su-gar-coating. However, the hygrosco-picity of Povidone is a limitation onthis use.

3. Povidone with a K value between 85and 95 is an even more effective bin-der than the types of lower molecularweight. Hence the amounts required intablets or granules usually do not ex-ceed 2%. Wet granulation is mainlyused for this purpose in order to dis-tribute the binder uniformly. For ex-amples of its use, see glucose.

Povidone K 25±K 90 can be used asbinder in european food e.g. in vitamintablets. For this purpose it got the E num-ber E 1201.

PP, vitaminsee niacin, nicotinamide, and nicotinicacid.

PrecipitatePrecipitates in solution of vitamin combi-nations may have a variety of causes.

Examples of precipitates in vitamin solu-tions

1. Crystallization of the preservative (e.g.parabens).

2. Crystallization of calcium oxalate whereascorbic acid and calcium ions arecombined (e.g. calcium pantothenate)[37].

3. Precipitation of cholecalciferol from asolubilizate due to inadequate amountsof solubilizer.

4. Crystallization of colo(u)rless decompo-sition products when cyanocobalamin iscombined with other B vitamins.

5. Precipitation of yellow chloroflavin fromcombinations of thiamine hydrochloride,riboflavin, nicotinamide, and ascorbicacid [100].

6. Precipitation of thiochrome form combi-nations of thiamine hydrochloride andriboflavin and, possibly, nicotinamide[100].

Prediction of stabilitySince the stability is the main problem inmanufacturing vitamin products, there isvery great interest in shortening the pro-cess of examination of this factor, e.g. bystress tests, in order to gain rapid infor-mation on the effect of various factors onthe long-term stability.Since the kinetics of thermal decomposi-tion (thermolysis) of most of the vitaminsin their products are first order (or zeroorder), it is very often possible to use theprinciple of the stress test for predictionof stability.A very simple example is the stability ofvitamin A in the formulation of a vitaminA+D+E injection emulsion which is de-tailed under the heading emulsion, thefigure which follows showing what hap-pened over a period of 24 months.

95 Prediction of stability

P

Stability of vitamin A in vitamin A+D+Eemulsion.

The plot of the vitamin A content in theemulsion on storage for 24 months waslinear, with losses of 6% at the recom-mended temperature of 6�C in a refrige-rator and of 16% at 23 �C. Even withoutmathematical analysis, these two plotsshow that it will be possible to estimatethe stability at 6 �C from short-term stor-age at 23�C. This may be of interest fortesting the stability of future batches ofthe emulsion. However, it would beworthwhile also to test one or two highertemperatures to shorten the duration ofthe tests.A number of publications deals with de-tailed investigations of the prediction ofstability of vitamin products. The follo-wing results are derived from these:1. Vitamin A

In multivitamin drops the decomposi-tion follows zero order kinetics [185]or a prediction of stability can bemade using the Arrhenius equation[186]. First order kinetics were foundin multivitamin tablets [187, 188], ap-parently other mechanisms of break-down applying in this case. The latteris sometimes observed in vitamin Aproducts such that the kinetics of de-composition in the first one or twomonths differ from those thereafter. Atypical example of a non-stabilized vit-amin A+E solution demonstrates this.

Vitamin A+E drops, non-stabilized (25,000I. U. + 50 mg/ml).

Composition

Retinyl palmitate 1.5 gTocopheryl acetate 5.0 gPEG-40 glyceryl trihydroxy-stearate [1] 20.0 gWater ad 100 ml

Stability

2. Vitamin B1The kinetics of breakdown of thiaminein a vitamin B complex syrup contai-ning trace relements were found to befirst order [186, 189]. The same ap-plies to 2.5 and 5% solutions of thia-mine hydrochloride in water [205].

Stability of thiamine in a vitamin B com-plex syrup [189].

Prediction of stability 96

The results with multivitamin tablets[187, 190] and multivitamin drops[152] were analogous.

3. DexpanthenolThe Arrhenius equation was found toapply to dexpanthenol in a vitamin Bcomplex syrup containing trace ele-ments, a multivitamin syrup and mul-tivitamin drops [185, 186, 189].

4. Cyanocobalamin and folic acidThe kinetics of breakdown of bothvitamins in a multivitamin syrup arefirst order [185]. The same applies tocyanocobalamin tablets but not to a Bcomplex syrup containing iron [186].The kinetics of breakdown of folicacid mixed with microcrystalline cel-lulose were found to be zero order[69].

5. HydroxocobalaminFirst order kinetics of decompositionwere found for solutions of pure hy-droxocobalamin in various buffer sy-stems [193].

6. Vitamin CThe kinetics of breakdown of ascorbicacid in multivitamin tablets werefound to be zero order [190] or firstorder [187]. This also applied to amultivitamin syrup [185], ampulescontaining 10% ascorbic acid [194]and multivitamin drops containingsucrose, sorbitol or glucose [152].

Small changes in the concentrations ofthe substances used in the formulationmay be expected to have no significanteffect on the prediction of stability. Ho-wever, it must be remembered that eachprediction of stability or each stress testapplies only to the tested formulation andnot necessarily to any other. The kineticsof decomposition may vary both qualita-tively and quantitatively in products ofdifferent composition, as shown by theexamples of vitamin A and B12 above.Moreover, in a stress test it is not possi-

ble to raise the temperature indefinitely,because further reactions may start abovea particular temperature (e.g. in the pre-sence of sucrose) and alter the kinetics ofbreakdown.

Prescription vitamin productssee marketing.

PreservativesIt is usually necessary to protect water-containing vitamin products from thegrowth of microorganisms (fungi, yeasts,bacteria). This is normally achieved byaddition of a preservative (see table be-low).Other substances are used as preservati-ves in products for injection, such as ben-zyl alcohol, chlorobutanol, phenylmercu-ry compounds, and thiomersal.

Preservatives commonly used in oral vit-amin products

Preservative E number Concen-tration

Parabens E 214±E 219

0.03±0.2 %

Sorbic acid andsalts

E 200±E 203

0.1 %

Benzoic acid adsalts

E 210±E 213

0.1±0.2%

Propylene glycol ± above 15%Ethanol ± above 15%Glycerol E 422 above 30%Ascorbic acid E 300 min. 3%

The following two points must always betaken into account when preservatives areused.1. Their effectiveness depends on the

pH.2. Addition of emulsifiers or solubilizers

may markedly reduce the preservative

97 Preservatives

P

effect. A possible reason is that part ofthe preservative is trapped in the mi-celles.

Propylene glycol

Propylene glycol (syn. 1,2-dihydroxypro-pane, 1,2-propanediol) is a colo(u)rlessliquid which is miscible in any ratiowith water and ethanol and has a sweettaste.Propylene glycol is one of the most com-monly used organic solvents in liquidvitamin products, because it improvesthe stability of some vitamins. This parti-cularly applies to thiamine hydrochlori-de, ascorbic acid, cholecalciferol, ergo-calciferol and phytomenadione [17±19,59, 75, 144, 147, 163, 166],The concentrations of propylene glycol inthe products may vary widely. The bene-ficial effect on vitamin stability appearsto increase with increasing content ofpropylene glycol.For examples of its use, see B complex,cyanocobalamin, dexpanthenol, polyvi-nylpyrrolidone, sorbitol, syrup, and two-chamber ampules.

Propyl gallate

Propyl gallate is a white powder, about0.35 g of which dissolves in 100 ml wa-ter. It is freely soluble in ethanol and

approximately 1% solutions in oils canbe prepared.Propyl gallate is an antioxidant, acting asa free radical trap (E number E 310). Itsuse is not confined to lipophilic vitamins.Addition of 0.005% stabilizes a vitaminB complex solution, especially the thia-mine [64, 144].Ascorbic acid is also stabilized by addi-tion of propyl gallate [20]. The effect ofthe addition of propyl gallate on the sta-bility of retinyl palmitate in various lipo-philic solvents is shown in the tablewhich follows [167].

Stabilization of vitamin A in lipophilic sol-vents by propyl gallate

Solvent Vitamin loss af-ter170 h under airwithoutantioxi-dant

with0.05 %propylgallate

Peanut oil 76.2 % 31.3 %Ethyl oleate 74.3 % 31.3 %Ethyl stearate 46.9 % 31.3 %Liquid paraffin 79.8 % 44.6 %

In aqueous solutions, too, propyl gallatecombined with other antioxidants impro-ves the stability of vitamin A. Addition oftocopherol, butylated hydroxyanisole andpropyl gallate to a syrup containing vit-amins A, B1 and C reduced the loss ofvitamin A on storage at room temperatu-re for 180 days from 20 % to 6% [168].For examples of the use of propyl gallatein formulations, see dexpanthenol andpolyvinylpyrrolidone.

Provitamin Asee beta-carotene and carotene.

Propylene glycol 98

Provitamin B5

see dexpanthenol.

PVPsee polyvinylpyrrolidone (povidone).

Pyridoxal phosphate

Pyridoxal phosphate (syn. pyridoxal 5'-phosphate, PLP, vitamin B6) is the formof vitamin B6 which acts as coenzyme. Itis a pale yellow crystalline powder whichhas virtually no odo(u)r and is onlyslightly soluble in water. It is soluble inalkaline solutions, e.g. 1% sodium bicar-bonate. It is virtually insoluble in propy-lene glycol. It is also commercially avai-lable as the sodium salt.Pyridoxal phosphate is hydrolyzed in thestomach, and thus is used almost exclusi-vely in injectables. The stability in solu-tions for injection is distinctly less thanthat of pyridoxine hydrochloride or othervitamin B6 derivatives [169]. Dilute solu-tions of pyridoxal phosphate are verysensitive to light [232] and it is relativelyrapidly hydrolyzed under both acidic andalkaline conditions, with heat increasingthe rate. For this reason, lyophilization isrecommended. An example of a solutionfor freeze-drying is as follows.

Solution of pyridoxal phosphate for lyophi-lization

Pyridoxal phosphate 500 mgSodium hydroxide 75 mgCarrier q.s.Water min. 5 ml

Pyridoxine hydrochloride

Pyridoxine hydrochloride (syn. pyridoxolhydrochloride, vitamin B6 hydrochloride)is a fine white powder which is freelysoluble in water, is virtually odo(u)rlessand has a slightly salty and acidic taste. Italso dissolves in ethanol and propyleneglycol.Pyridoxine hydrochloride poses few pro-blems in pharmacy, because it undergoesno chemical interactions with other vit-amins and is insensitive to oxygen andreducing agents.The stability of pyridoxine hydrochlorideis good in virtually all solid drug forms.It can be granulated without problemsand tablets containing up to 70 % can beproduced by direct tabletting, as shownby the following composition of a vit-amin B6 tablet.

Vitamin B6 tablet (250 mg)

Pyridoxine hydrochloride 250 mgCellulose, microcrystalline [2] 100 mgCopovidone 13 mgMagnesium stearate 5 mg

Even higher concentrations of pyridoxinehydrochloride in tablets can be achievedby using it in a coarsely crystalline form[198].A tablet formulation containing 40 mgpyridoxine hydrochloride is an approvedstandard in the FRG [176].For examples of further uses in solid drugforms, see B complex, colorants, hydro-xypropyl(methyl)cellulose, instant granu-

99 Pyridoxine hydrochloride

P

les, minerals, multivitamin solid prepara-tions, starch, thiamine mononitrate, andtartaric acid.Pyridoxine hydrochloride is also quitestable in liquid drug forms [172] if nooxidizing agents are present and it is notexposed to light. Since (heavy) metalsmay reduce the stability of vitamin B6somewhat [172], it is advisable to add

a chelating agent. In a vitamin B com-plex + C syrup (for formulation, see Bcomplex) the loss of vitamin B6 wasfound to be 4% after storage at 23 to25�C for 12 months. In a similar formu-lation (see dexpanthenol) there was foundto be no decrease in the pyridoxinecontent after 9 months at room tempera-ture.

Pyridoxine hydrochloride 100

R

RDAThe RDA (recommended daily allowan-ce) indicates the vitamin requirementeach day. Various institutions in a num-ber of countries have drawn up listswhich differ at some points. The RDAlist of most importance worldwide wasdrawn up by the Food and Drug Admini-stration (FDA) in the USA. For details,see daily requirement.

Reducing agentsSome vitamins are sensitive to reducingagents. These include, for example, thia-mine, riboflavin, cyanocobalamin, folicacid, phytomenadione, and rutin.Although the reducing agent sodium sul-fite stabilizes ascorbic acid, it immedia-tely decomposes vitamin B1. Ascorbicacid itself reduces folic acid and ribofla-vin.

Releasesee dissolution.

Retinoic acidsee isotretinoin, retinoids, and tretinoin.

RetinoidsRetinoic acid (= vitamin A acid) and itsderivatives are called retinoids. The mostimportant retinoids are tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), and etretinate. The reti-

noids are not used as vitamin A, all ofthem being used for the topical or oraltherapy of acne and psoriasis.

Retinol

Retinol (syn. all-trans-retinol, vitamin A,vitamin A alcohol, axerophthol) is a vis-cous yellow liquid which has a typicalodo(u)r and slowly crystallizes as yellowneedles. It is insoluble in water but isfreely soluble in oils, ethanol, and paraf-fin. Retinol and its esters are lipophilicvitamins.1.0 g all-trans-retinol is equivalent to3.33 million I. U., or 1 I. U. vitamin A isequivalent to 0.300 �g retinol.Since retinol is even less stable than itsesters, virtually only retinyl acetate, reti-nyl palmitate, and retinyl propionate areused in pharmaceuticals.

Retinyl acetate

Retinyl acetate (syn. vitamin A acetate,all-trans-retinyl acetate, axerophthyl ace-tate) consists of yellow crystals which aregreasy or sticky and have a mild, charac-teristic odo(u)r. They dissolve in oils andethanol. They are insoluble in water.

101 Retinyl acetate

R

In theory, 1.0 g all-trans-retinyl acetate isequivalent to 2.907 million I. U. vitaminA. Commercial products containing atleast 2.8 million I. U./g are available. Inaddition, oily and dry dilutions can beobtained.Retinyl acetate is rarely incorporated asthe pure substance in pharmaceuticals.Normally, a commercially available drypowder containing 250,000 to 500,000I. U./g is used in solid forms. The flowproperties of these dry powders makethem suitable for tabletting or for fillinghard gelatin capsules. the vitamin A inthe dry powders is usually embedded ingelatin/carbohydrate, with the addition ofan antioxidant, this process protecting thevitamin much better form light, oxygen,humidity, and mechanical stress thanwould be the case with an adsorbate.Nevertheless, in tablets a loss in activityof 10 to 20% per year must be expected.Since nicotinamide has been reported todamage the structure of gelatin, vitaminA dry powders should, if possible, notcome into direct contact with nicotinami-de [162].The following composition of a vitaminA chewable tablet is an example of theuse of a retinyl acetate dry powder fordirect tabletting.

Vitamin A chewable tablet (50,000 I. U.)

Retinyl acetate dry powder500,000 I. U./g [1]

170 mg

Mannitol 170 mgCopovidone 25 mgMagnesium stearate 5 mgSilica, highly disperse 3 mgFlavo(u)ring q.s.

For further examples of use in solid drugforms, see direct compressible vitamins,multivitamin solid preparations, and sor-bitol.Retinyl acetate is hardly ever used inliquid drug forms, because it may crystal-lize out of oily solutions and is moredifficult to solubilize than are retinyl pal-mitate and retinyl propionate.

Retinyl palmitate(see formula below)Retinyl palmitate (syn. vitamin A pal-mitate, all-trans-retinyl palmitate, axero-phthyl palmitate) is a brillant yellow,partly crystalline oily mass with a charac-teristic odo(u)r. The crystals melt at bodytemperature. They are freely soluble inoils and ethanol but insoluble in water.In theory, 1.0 g all-trans-retinyl palmitateis equivalent to 1.82 million I. U. Thecommercial product has a minimum con-tent of 1.7 million I. U./g. Oily and drydilutions are also obtainable.One of the main problems with vitamin Ais its chemical stability. It is sensitive tohumidity, oxygen, heat, light, and heavymetals. This is why all formulations andsome of the commercial types of vitaminA contain an antioxidant. However, if adry inert gas is used to prevent all contactwith oxygen and moisture, the stability ofpure retinyl palmitate is found to be thesame whether an antioxidant is present ornot. Only thermal decomposition is thenresponsible for the measured losses, asshown by the figure on the next page[173].

Retinyl palmitate 102

Stability of pure retinyl palmitate with andwithout butylated hydroxytoluene (storageunder nitrogen at 23�C in the dark).

Liquid drug forms containing vitamin Apalmitate may be oily solutions (e.g. forsoft gelatin capsules) or aqueous systems.The latter are necessarily micro- or ma-croemulsions containing a solubilizer oremulsifier. In the following figure theamounts of three different solubilizersneeded for vitamin A palmitate are pre-sented.

Solubilization of retinyl palmitate withPEG hydroxystearate (1), PEG glycerol tri-hydroxystearate (2) or PEG glycerol triri-cinoleate (3).

A typical example of a clear aqueousformulation is the following compositionfor vitamin A+D drops.

Vitamin A+D drops (25,000 + 2,500 I. U./ml)

Retinyl palmitate 1.8 gCholecalciferol 7.5 mgButylated hydroxytoluene 0.5 gPEG-40 glyceryl trihydroxy-stearate [1] 11.0 gParabens 0.2 gSorbic acid 0.2 gPolyethylene glycol 400 10.0 gWater ad 100 ml

The stability of vitamin A in this formu-lation on storage at 22 to 25�C for 12months is shown in the graph which fol-lows.

Stability of vitamin A in vitamin A+Ddrops (25,000 + 2,500 I. U./ml).

The pH of aqueous solubilizates of vit-amin A should not be lower than 6.0,otherwise isomerization occurs until anequilibrium has been reached betweentwo-thirds all-trans-retinyl palmitate andone-third cis isomers. The main isomer isthe 13-cis form, which has only 75% ofthe vitamin A activity of the all-transform. Other cis isomers which are formed(e.g. 9-cis and 9,13-dicis) have even lo-wer vitamin A acitvity (15 o 24%). Thisis a particular problem in multivitaminsolutions, where the pH must always bebetween 4 and 5.The most effective antioxidant for vit-amin A solutions has proved to be buty-lated hydroxytoluene.

103 Retinyl palmitate

R

Losses of vitamin A in a syrup on storageat room temperature for 180 days werereduced from 20% to 6 % by addition of16.8% tocopherol, 1 % butylated hydro-xytoluene and 1 % propyl gallate (all per-centages based on retinyl palmitate)[168]. The purity of the auxiliaries (e.g.sucrose) may also affect the stability ofvitamin A. Purification of a sucrose syrupwith an ion exchanger distinctly impro-ved the stability of vitamin A [174]. Inaddition, aqueous vitamin A solubilizatesshould be (produced and) packaged underan inert gas.For further examples of its use and noteson retinyl palmitate in liquid forms, seePEG glyceryl trihydroxystearate, PEGhydroxystearate, polysorbate, solubilizer,vitamin derivatives, and two-chamberampules.For solid drug forms, retinyl palmitate isused in the form of dry powders.Those which are dispersible in cold waterand contain 250,000 to 325,000 I. U. vit-amin A per gram are particularly used formultivitamin products in the form of ef-fervescent tablets, effervescent granules,instant granules, and lozenges. For ex-amples of use, see instant granules andmannitol.

Retinyl propionate

Retinyl propionate (syn. vitamin A pro-pionate, all-trans-retinyl propionate, axe-rophthyl propionate) is a yellow, oily li-quid, which does not crystallize at roomtemperature and is readily miscible withoils. It also dissolves in ethanol.In theory, 1.0 g all-trans retinyl propio-nate is equivalent to 2.78 million I. U.

vitamin A. Commercial products containat least 2.5 million I. U./g.As it is readily solubilized, has a highvitamin content and is of an oily consis-tency, retinyl propionate is mainly usedfor highly concentrated veterinary injec-table solutions or emulsions. An exampleof a worldwide commercialized formula-tion see emulsion.Using PEG glycerol triricinoleate orPEG hydroxystearate, it is possible toobtain very high concentrations in clearaqueous solubilizates.

Solubilization of retinyl propionate withPEG hydroxystearate (1), PEG glycerol tri-hydroxystearate (2) and PEG glycerol tri-ricinoleate (3).

A disadvantage of the retinyl propionatesolubilizates compared with similar prepa-rations containing retinyl palmitate is thegreater sensitivity to light, which affects thephysical stability. This problem is dealtwith by effective protection form light.Otherwise, the factors affecting the stabi-lity of liquid formulations of vitamin Apropionate are the same as those for reti-nyl palmitate (q.v.).It is perfectly possible to produce relati-vely stable aqueous forms containing re-tinyl propionate. This is evident from theA+D+E veterinary ampule, whose formu-lation is to be found under the headingemulsion. The losses of vitamin A fromthis product on storage for 2 years were16% at room temperature and only 6% at6�C.

Retinyl propionate 104

Riboflavin

Riboflavin (syn. vitamin B2, lactoflavin)is a fine orange-yellow, strongly stainingpowder which has virtually no odo(u)rand a bitter taste. It is sparingly solublein water (7 mg/100 ml); it is somewhatmore soluble in ethanol.When used in solid drug forms, the formand size of the riboflavin crystals exert acertain effect. Usually it consists of fineneedles with a maximum length of20 �m, but also a granular type of pureriboflavin can be found in the market [1].If it is in the form of needles it can beelectrostatically charged and will agglo-merate. This makes it difficult to screenand mix. Applying the granular type ofriboflavin these problems do not exist.

Riboflavin crystals (magnification 1900 �).

Nevertheless, direct tabletting of theneedles is possible up to a content ofabout 25%, e.g. if the following compo-sition is used for the tablets.

Vitamin B2 tablet (100 mg)

Riboflavin 100 mgSorbitol 250 mgCopovidone 19 mgSilica, highly disperse [4] 10 mgMagnesium stearate 5 mg

However, granulation is normally em-ployed in the production of riboflavintablets. In solid forms vitamin B2 is rea-sonably stable, but they should be packedand stored with the exclusion of light. Tominimize the chemical interactions withascorbic acid, the water content in multi-vitamin tablets should be as low as pos-sible. For further examples of use in soliddrug forms, see B complex, instant gra-nules, multivitamin solid preparations,thiamine mononitrate, and tartaric acid.A 10 mg riboflavin tablet is an approvedstandard in the FRG [176].The low solubility of riboflavin in watermeans that it is used less in liquid pro-ducts. Riboflavin solutions are sensitiveto reducing agents, heavy metals andlight. the action of light on acidic andneutral solutions produces lumichrome,and on alkaline solutions produces lumi-flavin [133]. Heat promotes these reac-tions.The recommended way of increasing thevitamin B2 concentrations in liquid drugforms is to use riboflavin-phosphate so-dium which is much more soluble.Apart from its use as a vitamin, riboflavinis frequently used as a yellow colorant,identical to the natural product, in solidand liquid products, and foods (E numberE 101).

105 Riboflavin

R

Riboflavin-phosphate sodium

Riboflavin-phosphate sodium (syn. vit-amin B2 sodium phosphate, sodium ribo-flavin-5'-phosphate, sodium lactoflavin-5'-phosphate) is, like riboflavin, an oran-ge-yellow, strongly staining, microcry-stalline powder with a slight odo(u)r anda bitter taste. The solubility in water de-pends on the pH as shown by the figurebelow.It is also freely soluble in ethanol.1.0 g sodium riboflavin-5'-phosphate isequivalent to about 0.73 g riboflavin.

Riboflavin-phosphate sodium is used vir-tually only in vitamin solutions or in drugforms which are to be dissolved in water(e.g. effervescent tablets, instant granu-les) as a substitute for the sparingly solu-ble riboflavin. Particular account has to

be taken of the sensitivity to light sincethis is even more pronounced than in thecase of riboflavin and is increased byheat and increasing pH. Reducing agentsand heavy metals are also detrimental tosolutions of riboflavin-phosphate sodium.For examples of its use in formulations,see B complex, dexpanthenol, and two-chamber ampules.The vitamin B complex + C syrups men-tioned under the headings dexpanthenoland B complex lost 9% and 13%, respec-tively, of vitamin B2 after storage at roomtemperature in the dark for 12 months.

Riboflavin tetrabutyrate

Riboflavin tetratbutyrate (syn. vitamin B2tetrabutyrate, riboflavin 2', 2', 4', 5'-te-trabutyrate) is a fat-soluble riboflavin de-rivative which is used, especially in Ja-pan, as a therapeutic antioxidant.

RutinRutin (syn. vitamin P, rutoside) is a bio-flavonoid. It is a pale yellow, microcry-stalline powder which has no odo(u)r ortaste. It is very slightly soluble in water,and slightly soluble in ethanol. It dissol-ves in alkaline media with the formationof salts.The preferred use of rutin is in solid drugforms, in which it is usually combined

Riboflavin-phosphate sodium 106

with other vitamins. Reducing agents,heavy metals and light should be avoided.On the other hand, rutin is able to stabi-lize vitamin C by preventing the oxida-tion of ascorbic acid which is catalyzedby heavy metals [29, 177]. The combina-

tion of a vitamin C + rutin tablet below istaken from the literature [244].For an example of the combination withother vitamins and minerals in efferve-scent tablets, see minerals.Aqueous solutions of rutin are very sen-sitive to oxygen. On the other hand, alco-holic solutions with a minimal water con-tent are relatively stable at pH 9 [245].

Vitamin C + rutin tablet

I. Rutin 20 mgAscorbic acid 200 mgCorn starch 70 mg

II. 10% starch paste q.s.III. Talc 5 mg

Magnesium stearate 5 mg

107 Rutin

R

S

SaccharinSince pure saccharin is sparingly solublein water, it is the sodium salt which ischiefly used in pharmacy.

This salt takes the form of colo(u)rlesscrystals with an intensely sweet taste. It isfreely soluble in water, and also dissolvesin 90% ethanol.Saccharin and the sodium salt are used assweeteners. Their sweetness is 300 to 500times that of sucrose. One possible dis-advantage is the bitter aftertaste which isdetectable above a certain concentration.Saccharin is used in solid and liquid vit-amin products, principally in tablets. Theother sweeteners used in solutions arethose which improve the stability of thevitamins (sucrose, glucose, sorbitol, fruc-tose, glycerol, propylene glycol, etc.).For examples of its use, see adsorbate,copovidone, effervescent tablets, mine-rals, multivitamin solid preparations, so-dium ascorbate, polyvinylpyrrolidone,trace elements, and tartaric acid.

SeleniumSelenium is a trace element, and is som-etimes combined with vitamin E. Thereason for combining these two substan-ces is the synergistic action of tocopheroland selenium as biological antioxidants.

Suitable selenium compounds are sodiumselenite and selenium yeast. In a typicalproduct, 200 mg DL-alpha-tocopherylacetate and 20 �g sodium selenite mightbe incorporated in soft gelatin capsules.

SicovitSicovit is the registered trademark for anumber of synthetic colorants and ironoxide pigments [1].

SilicaIn connection with vitamins, silica (syn.silica gel, silicon dioxide) is used eitheras a carrier for the production of drypowders (e.g. adsorbates) or in the highlydisperse form (e.g. Aerosil� 200) as aflowability agent in tablets or hard gela-tin capsules. For examples of the use ofhighly disperse silica, see ascorbic acid,B complex, calcium hydrogen phosphate,copovidone, crospovidone, direct tablet-ting auxiliaries, hard gelatin capsules,lactose, Ludipress�, mannitol, sodium as-corbate, nicotinamid, retinyl acetate, ri-boflavin, starch, and thiamine mononitra-te.

Sodium ascorbate

Saccharin 108

Sodium ascorbate (syn. sodium L-ascor-bate, sodium salt of L(+)-ascorbic acid) isa white crystalline powder with a slightlysalty taste. It is freely soluble in water(about 90 g in 100 ml). When used as anauxiliary in food products, it has the Enumber E 301.In terms of vitamin activity, 1.12 g so-dium ascorbate is equivalent to 1.0 g as-corbic acid.Sodium ascorbate is used in pharmaceu-ticals much less than is ascorbic acid,because it is less stable. However, thetwo are often combined in tablets in or-der to diminish the acid taste. An exam-ple of a vitamin C composition for directtabletting is as follows:

Vitamin C tablet (250 mg)

Sodium ascorbate granular 210 mgAscorbic acid, powder 70 mgLudipress� 195 mgStearic acid 14 mgOrange flavo(u)r 5 mgSaccharin, sodium salt 3 mgSilica, highly dispers [4] 3 mg

Sodium ascorbate is used somewhat morein liquid drug forms than in tablets, espe-cially in injectables when the pH of the

Best stabilizers for use in sodium ascorbatesolutions in water (pH 5.4)

Storage Stabilizer Ratiosodiumascor-bate:stabilizer

Under air Ethylenediamine-tetraacetic acid

100 : 1

Glycerol 10 : 1Sodium chloride 10 : 1Fructose 10 : 1

Under Glycerol 10 : 1nitrogen Sodium chloride 10 : 1

Fructose 10 : 1

solution is above 6. For an example of itsuse in multivitamin ampules, see two-chamber ampules.The best stabilizers for aqueous sodiumascorbate solutions are listed in the tableabove [20].

Sodium pantothenate

Sodium pantothenate (syn. sodium D-pantothenate) is a fine white powderwhich is virtually odo(u)rless, and is free-ly soluble in water.In terms of vitamin activity, 1.0 g sodiumD-pantothenate is equivalent to 0.909 gD-pantothenic acid.

Stability of sodium pantothenate and dex-panthenol in solution.

109 Sodium pantothenate

S

Since its hygroscopicity is even greaterthan that of calcium pantothenate, andbecause its stability is reduced belowpH 6, sodium pantothenate is used onlyin liquid and semisolid forms, in whichthe pH can be adjusted appropriately. Ifthis is impossible (e.g. combinations withother B vitamins) sodium pantothenateshould be replaced by dexpanthenol.The preceding figures show the depen-dence of the stability of the two substan-ces on the pH in aqueous solutions,which backs up this recommendation[157].

Sodium sulfiteSodium sulfite has been used as a stabi-lizer for ascorbic acid solutions at 1 % ofthe amount of ascorbic acid [20].However, it is rarely suitable for combi-nations of vitamins, because many ofthem, e.g. thiamine, are decomposed byreducing agents.

Soft gelatin capsulesThe importance of soft gelatin capsulesin connection with vitamins appears toexceed that applying to other active sub-stances. This is most true in the case ofmultivitamin products and of lipohpilicvitamins. The reason is the high stabilityof the vitamins in soft gelatin capsules,which is not usually reached in otherdrug forms.The anhydrous vitamins are dissolved orsuspended in an oil, and are protectedfrom oxygen by the gelatin shell and thehigh viscosity of its contents.The gelatin contains glycerol or sorbitolas plasticizer, which also have beneficaleffects on the stability of some vitamins.Protection from light is achieved by co-lo(u)ring the capsules.

It is quite possible for the stability of thecritical vitamins A and B1 in soft gelatincapsules to reach levels which allow,with an overage of 15% in a multivit-amin capsules, an expiration date 2 yearsafter manufacture to be guaranteed.Calcium pantothenate poses a problemdue to its interaction with acidic vitaminC. This can be solved by incorporatingdexpanthenol into the gelatin casing. Insoft gelatin capsules, too, the low watercontent of thiamine mononitrate meansthat it is more stable than the hydrochlo-ride.In general, the particle size of hydrophilicvitamins which are to be suspended mustnot exceed 180 �m.

SolubilityThe lipophilic vitamins dissolve in oilsand are insoluble in water, and vice versafor the hydrophilic vitamins. However,the solubility of the latter in water varieswidely.

Solubility of the hydrophilic vitamins inwater

Vitamin Solubility(g/100 mg)

Thiamine hydrochloride 100Thiamine mononitrate 2±3Riboflavin 0.007±0.01Riboflavin-phosphatesodium 5±10Nicotinamide 100Calcium pantothenate 40Sodium pantothenate 100Dexpanthenol 100Pyridoxine hydrochloride 20Cyanocobalamin 1±2Ascorbic acid 30Sodium ascorbate 70±90Folic acid 0.0002±1.5Biotin 0.04

Sodium sulfite 110

The solubility of the hydrophilic vitaminsis rarely a problem in formulation, be-cause the very slightly soluble riboflavincan be replaced by its freely soluble de-rivative riboflavin-phosphate sodium.The solubility of folic acid dependsgreatly on the pH (for graph, see comple-xes). The solubility of biotin also increa-ses with increasing pH so that the sodiumsalt forms a 20% solution in water.Lipophilic vitamins can be dissolved inwater only by solubilization.

SolubilizationThere are various principles of solubiliza-tion. In the case of the vitamins, the onlyprinciple employed is that of producing amicroemulsion by formation of micellesusing non-ionic surfactants (solubilizers).All these compounds have a lipophiliccomponent, in the form of a fatty acid,and a hydrophilic portion, in the form ofpolyethylene glycol and/or glycerol orsorbitan. When the solubilizer is disso-lved in water, there is formation, abovethe critical micelle concentration (e.g.0.02% for PEG hydroxystearate), ofspherical micelles, which become ellip-soidal at somewhat higher concentrati-ons. In the micelles the lipophilic partsof the molecule are directed inwards andthe hydrophilic parts are directed out-

wards towards the surrounding liquid.The diameter of a micelle, for examplein a 1 % aqueous solution of PEG hydro-xystearate, is 12 nm. At and above a tem-perature of 60 �C there is a rapid increase,reaching 30 nm at 70 �C.When vitamin A, for example, is solubi-lized, the molecules of the vitamin aretrapped in the interior of the micelles.As long as they are not too heavily loa-ded with vitamin A, the micelles remainsmall enough to be invisible to the nakedeye. Above a certain size the solutionappears opalescent.It has to be remembered that in a solubi-lizate the surface area of the inner lipo-philic phase is very large. This meansthat oxygen, inter alia, has a larger areato attack, which results in vitamins A, Dand K1 being less stable in solubilizatesthan in oily solutions.In practice, the method of solubilizationis crucial. The heating of the vitaminwith the solubilizer and, where appro-priate, an antioxidant must always bein the absence of water, and only whenthe mixture has reached 60 to 70�C(usually), can the water be added (orvice versa), slowly and with vigorousstirring, to form the outer phase. If thisprocedure is not followed, the micellesare very often too large, and thus thesolutions are turbid, or at least opale-scent. Addition of polyethylene glycol

111 Solubilization

Micelle formation on solubilization.

S

to the solubilizer permits the temperatu-re to be reduced.Not all derivatives of the lipophilic vit-amins are equally suited for solubiliza-tion. The most suitable are the undilutedvitamin derivatives listed in the tablewhich follows.

Vitamin derivatives suitable for solubiliza-tion

Retinyl palmitateRetinyl propionateErgocalciferolCholecalciferolTocopheryl acetatePhytomenadione

Retinyl acetate is less suitable, becauseits solubilizates are physically and che-mically less stable [174]. Solubilizationof tocopherol is likewise inadvisable be-cause of its low chemical stability. For acomparison between retinyl palmitateand retinyl propionate, see PEG hydro-xystearate and vitamin derivatives.For examples of solubilization in formu-lations, see the individual lipophilic vit-amins and solubilizers.

SolubilizerIt is necessary to use a solubilizer toproduce aqueous solutions of the lipophi-

lic vitamins A, D, E, and K1. The mostsuitable solubilizers have proved to bethose listed in the table below.

Solubilizers commonly used for vitamins

Polysorbate 80PEG glyceryl trihydroxystearatePEG glyceryl triricinoleatePEG hydroxystearate

These solubilizers form micelles (see so-lubilization).The following three formulations are sui-table for preparing a clear solution con-taining 50,000 I. U. vitamin A per ml.

Vitamin A drops, unstabilized(50,000 I. U./ml)

1. Retinyl palmitate 3.0 gPEG 40 glyceryl trihydroxy-stearate [1] 11.0 gWater ad 100 ml

2. Retinyl palmitate 3.0 gPEG 40 glyceryl trihydroxy-stearate [1] 10.0 gPolyethylene glycol 400 5.0 gWater ad 100 ml

3. Retinyl palmitate 3.0 gPolysorbate 80 [6] 12.0 gWater ad 100 ml

After storage in the dark at about 23 �Cfor 12 months, all three solutions were

Solubilizer 112

Stability of vitamin A drops with various solubilizers (50,000 I. U./ml).

still clear and the losses were as shown inthe preceding figure [173].It is obvious that the chemical stability ofvitamin A depends on the solubilizer sy-stem.The amounts of solubilizer required forthe solubilization of vitamin E acetatemay differ widely from those for vitaminA. The following three formulations, forexample, can be used to prepare a clearsolution containing 20 mg tocopherylacetate per ml.

Vitamin E acetate solutions (20 mg/ml)

1. Tocopheryl acetate 2 gPolysorbate 80 [6] 8 gWater ad 100 ml

2. Tocopheryl acetate 2 gPEG 35 glyceryltriricinoleate [1] 12 gWater ad 100 ml

3. Tocopheryl acetate 2 gPEG 40 glyceryl trihydroxy-stearate [1] 13 gWater ad 100 ml

Increasing the vitamin E concentrationreduces the differences in the amountsof solubilizer required, until they becomeapproximately identical. For further de-tails of the solubilizer concentrations re-quired, see cholecalciferol, ergocalcife-rol, PEG glyceryl triricinoleate, PEG hy-droxystearate, phytomenadione, polysor-bate, tocopheryl acetate, and vitaminderivatives.The addition of a solubilizer may alsoreduce the rate of breakdown of ascorbicacid in aqueous solution [179].When a solubilizer is used, it is alwaysnecessary to check the effectiveness ofthe preservatives since these are adverse-ly affected by all solubilizers.

Solutol� HS 15Solutol HS 15 is a registered trademarkfor PEG 15 hydroxystearate [1].

SolventsThe most important solvent is water. Or-ganic solvents are becoming increasinglyless important in the manufacture of vit-amin products. However, it is necessaryto distinguish between solid drug forms,in which the hydrophilic solvent which isused should be absent from, or presentonly in traces in the final product, andliquid drug forms, including soft gelatincapsules, which are meant to contain ahydrophilic or hydrophobic solvent as aningredient.In the case of solid forms, the organicsolvents ethanol or isopropanol are fre-quently preferred for granulation or film-coatings in order to avoid the adverseeffects of water. Other organic solventsincluding methylene chloride are onlyrarely used nowadays, for toxicologicalreasons.The hydrophilic organic solvents used inliquid vitamin forms are mainly propy-lene glycol, ethanol, glycerol or low mo-lecular-weight polyethylene glycol. Suita-ble hydrophobic solvents for oily solu-tions are oils (e.g. peanut oil), short-chainsaturated triglycerides (e.g. Miglyol�

[9]), ethyl stearate or liquid paraffin.Solvents do affect the stability of vit-amins. The most pronounced changes instability brought about by solvents occurwith ascorbic acid: the greatest improve-ment in the stability compared with wa-ter, which is apparently the worst solventfor this vitamin, is obtained with propy-lene glycol or glycerol [17±19].The solvent may also affect the chemicalstability of B vitamins [19, 75]. Vitamin

113 Solvents

S

A behaves similarly, the stability inaqueous solutions being worse than inoily formulations.

Sorbic acid

Sorbic acid is a white crystalline powderwith a characteristic odo(u)r. It is slightlysoluble in water, and dissolves in ethanol.Sorbic acid and its salts are used as pre-servatives in pharmaceuticals and foodproducts, the relevant E numbers beingas follows.

E numbers of sorbic acid and its salts

Sorbic acid E 200Sodium sorbate E 201Potassium sorbate E 202Calcium sorbate E 203

In oral vitamin solutions without an ad-ded solubilizer, an adequate preservativeeffect is normally ensured with 0.1 or0.2% sorbic acid. The pH of the solutionshould be in the acidic range, becausesorbic acid and its salts lose their preser-vative effect in alkaline media. In thepresence of a solubilizer the concentra-tion which is needed must be determinedby experiment. The effect may be inten-sified by combination with other preser-vatives.For an example of use in a syrup, seedexpanthenol and syrup.

Sorbitol(see formula to the right)

Sorbitol (syn. D-glucitol) is a white cry-stalline or spray-dried powder which is

odo(u)rless and has a slightly sweet taste.It is freely soluble in water (sorbitol sy-rup) and less soluble in ethanol. Above arelative humidity of 65% sorbitol is hy-groscopic (for water adsorption plot, seehygroscopicity). Sorbitol is an importantauxiliary for vitamin products, because itstabilizes some vitamins.Sorbitol is used in solid drug forms as afiller, also having a certain binding ef-fect, which increases the tablet hardness.Hence it is commonly used in lozengesand chewable tablets.Sorbitol is able to adsorb thiamine mono-nitrate, riboflavin, and pyridoxine hydro-chloride up to certain concentrations.These adsorbates are more suitable fordirect tabletting than are the physicalmixtures [181]. In some tablet formula-tions it is advisable to compare crystal-line and spray-dried sorbitol, because it isperfectly possible for them to result intablets with different properties.The following composition for direct ta-bletting to vitamin A+E chewable tabletsmay be regarded as a typical example ofthe use of crystalline sorbitol.

Vitamin A+E chewable tablet (30,000 I. U.+ 30 mg)

Retinyl acetate dry powder500,000 I. U./g

66 mg

Tocopheryl acetate dry powder50%, spray-dried with gelatin [1] 65 mgSorbitol, crystalline 425 mgPolyethylene glycol 6000, powder 15 mgOrange flavo(u)r 15 mgCyclamate, sodium salt 9 mg

Sorbic acid 114

For further examples of use in solid drugforms, see adsorbate, analgesics, directcompressible vitamins, riboflavin, traceelements, and tartaric acid.Sorbitol is used in liquid drug forms mai-nly to stabilize vitamins. Thiamine hydro-chloride and riboflavin [153], cyanoco-balamin [74, 76], and ascorbic acid [17,77, 153, 184] are stabilized in syrups orsolutions containing sorbitol.In a multivitamin syrup containing vit-amin concentrations corresponding tothe RDAs, the following composition ofauxiliaries was found to be the most be-neficial for the stability of vitamins B1and C [75].

Composition of auxiliaries for a multivit-amin syrup

Butylated hydroxyanisole 50 mgNordihydroguaiaretic acid 100 mgEthylenediamineetraacetic acid,calcium disoldium alt 10 mgParabens 200 mgPolysorbate 80 8 mlWater 8 mlGlycerol 24 mlPropylene glycol 24 ml75% sorbitol solution ad 100 ml

The stability of vitamins B1 and C inmultivitamin drops of pH 4.5 was aboutthe same when sorbitol and sucrose wereused. The results with glucose were lessgood [152].For further examples of its use in liquidformulations, see ascorbic acid, B com-plex, and dexpanthenol.

Spray-dryingSpray-drying is of only indirect import-ance in the manufacture of vitamin pro-ducts. Together with spray-cooling, it is

an important technique in the productionof dry powders of some vitamins.In the case of vitamin E, spray-drying canbe used to produce a dry powder contai-ning more than 50 % oily tocopheryl ace-tate. Only by use of a dry powder of thistype is it possible to produce high-con-centration vitamin E tablets (for an ex-ample, see cellulose and Ludipress�).

StabilityThere can scarcely be a group of pharma-ceuticals which involves as many pro-blems with stability as do the vitamins.The problems are compounded by thefact that, unlike other active substances,often a single product combines manyvitamins. A multivitamin product con-tains at least ten vitamins and may besupplemented by a number of mineralsor trace elements.Even in single-vitamin products, apartfrom those of the vitamin E esters, theremay be adverse effects on the stability ofthe vitamins owing to at least one of thefollowing factors: light, oxidation, reduc-tion, and heavy metals. Vitamin B12 givesrise to the most difficulty, but vitaminsA, B1, C and D must also be regarded ashighly sensitive.The stability problems are usually verymuch greater with liquid drug forms thanwith solid forms because chemical inter-actions and hydrolisis cannot be avoidedin the presence of water. As the chemicalstructures of the vitamins differ, a di-stinction has to be made between theproblems of physical and chemical stabi-lity. The important factors for solutionsdiffer somewhat from those for tablets, asshown by the table on the next page.A stress test is almost always helpful forexamining the effects of these factors(see prediction of stability).

115 Stability

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Factors affecting vitamin stability

Liquidforms

Solid forms

Physicalstability

SolubilitySolubiliza-tionVitaminderivative

Particle size dis-tributionMethod oftablettingMoisture con-tent of granulesVitaminderivative

Chemicalstability

pHSolventVitaminderivativeAntioxidantChelatingagentLightSugarSolubilizerInteractionPackaging

Water contentVitaminderivativeTablet coatingMethod oftablettingInteractionPackaging

In solid drug forms the most importantfactors for the chemical stability are thecontent of free water in the formulationand the adsorption of water form the at-mospheric humidity [277]. All other in-fluences almost always are connectedwith these factors. Crystalline water e.g.in lactose monohydrate normally doesnot cause any problem as it is not availa-ble as free water.

StarchCorn, wheat, and potato starch, in pureand modified forms, are used in pharma-cy. All pure starches are composed oflinear amylose chains and branched amy-lopectin chains.The molecular weight of amylose is50,000±200,000, and that of amylopectinis 150,000±2,000,000.Starches are fine, white, odo(u)rless pow-ders which are virtually insoluble in coldwater and ethanol. They swell in hotwater. They are somewhat hygroscopic(for water adsorption plot for corn starch,see hygroscopicity).Starches are used almost exclusively insolid drug forms containing vitamins asfillers, binders, and disintegrants. Cornstarch is most often used.For use as binder, in wet granulation,normally a 10 to 25 % starch paste inwarm water is prepared for the traditionaltechniques, and one containing less than10% starch is prepared for fluidized bedgranulation.When used as filler, the starch can beadded not only after, but also before thegranulation as shown by the followingexample of a vitamin B6 tablet.

Starch 116

Vitamin B6 tablet (40 mg)

I. Pyridoxine hydrochloride 40 mgCorn starch 300 mg

II. Polyvinylpyrrolidone K30 15 mgIsopropanol + water (1+1) q.s.

III. Silica, highly disperse 2 mgMagnesium stearate 1 mg

Starch can also be used for direct tablet-ting, in which a modified type is oftenpreferred (for examples of use, see ascor-bic acid and tocopheryl succinate).For use as a disintegrant, either 20 to40% starch is incorporated into the inte-rior of the tablet, or 5 to 15% is addedafter granulation. The amylopectin is re-sponsible for the disintegrant action sinceit swells with water. Hence amylopectinderivatives have been developed, e.g.carboxymethylamylopectin, which aremore powerful disintegrants than is purepotato starch.Granules which are very suitable as a directtabletting auxiliary can be produced bygranulating corn starch with 5% polyvinyl-pyrrolidone K 30 in a fluidized bed.

Stearic acid

The commercially available stearic acidalways contains a certain percentage ofpalmitic acid. It is a white powder.Stearic acid is used in the same way as itsmagnesium salt in tablets as a lubricant.For examples of its use, see ascorbicacid, calcium pantothenate, and sodiumascorbate.

SterilizationThe head sterilization of vitamin injec-tables may give rise to problems sinceany energy input increases the rate of

thermolysis of the less stable vitamins,e.g. vitamin A or cyanocobalamin. Thisis evident by the results of heat-steriliza-tion given in the following two tables.

Influence of heat sterilisation on the vit-amin A stability

Solution Loss of vit-amin A(120�C, 20min)

Oily, 50,000 I. U./ml(0.1% BHT)

3.9 %

Aqueous, 50,000 I. U./ml(0.1% BHT)

5.6 % (pH 5.4),3.8 % (pH 6.5)

Aqueous, 100,000 I. U./ml(0.3% BHT)

4.8 % (pH 5.6),4.6 % (pH 6.5)

Vitamin losses on heat sterilization of avitamin B1 + B6 + B12 solution in water

Vitamin Vitamin loss(120�C, 20min)

B1 (3 %) 0 %B6 (3 %) 0 %B12 (0.006 %) 40%

Radiolysis of vitamins on sterilization bygamma irradiation has been reported insome publications.

Publications on the effects of gamma irra-diation on vitamins

Vitamin Reference

Vitamin A 200Vitamin B1 196Vitamin B2 196Vitamin B6 196Calcium D-pantothenate 201Nicotinamide 196Folic acid 196Vitamin C 199Cyanocobalamin 195Hydroxocobalamin 231

117 Sterilization

S

Gamma sterilization of vitamins in dryformulations results in no decomposition,which is why this is particularly recom-mended for lyophilisates. It is also possi-ble in a few cases to use gamma rays tosterilize a vitamin solution without loss-es: there were no changes in the molecu-lar structure of retinyl palmitate in oilysolutions at a radiation dose of 5 Mrad =50 kGy [200]; likewise there were virtua-lly no losses form 20% aqueous calciumpantothenate solutions. However, reduc-tion of the calcium pantothenate concen-tration to 1 % resulted in extensive (70%)radiolysis [201].Filtration is the least deleterious methodof sterilization, causing virtually no vit-amin losses. Care must be taken that notraces of metals from the apparatus passinto the solutions, because these may ca-talyze vitamin breakdown.Also the microwave sterilization is repor-ted as an able method [274].

Stress testA stress test of vitamin products is ashort-term storage test at elevated tempe-rature. Its main aim is to reveal the ef-fects of various auxiliaries and/or otherfactors on vitamin stability in a shorttime. A typical example is the examina-tion of the effect of glucose, sucrose andsorbitol at various pH values on the sta-bility of vitamins B1 and C in multivit-amin drops [152]. For further details, seeprediction of stability.

Sucrose

Sucrose (syn. saccharose, sugar) is avai-lable in the form of a white powder orcolo(u)rless crystals. It is very freely so-luble in water, and also dissolves in 70 %ethanol. Sucrose is not hygroscopic up toa relative humidity of 80% (for wateradsorption plot, see hygroscopicity).Sucrose is used as a syrup in liquid oraldrug forms, because the increase in vis-cosity and the reduction in diffusion im-prove the stability of some vitamins, e.g.vitamin A [178], vitamin B1 [152, 206],and vitamin C [17, 70]. A syrup contai-ning sorbitol may sometimes be better.No great differences in the stability ofvitamins B1 and C in multivitamin dropswere found between the use of sucroseand sorbitol when the pH was 4.5. Glu-cose was much less satisfactory [152].The purity of the sucrose syrup has aneffect on the stability of vitamin A. Puri-fication of the sucrose on an ion exchan-ger greatly improved the stability [174].For examples of use, see B complex, dex-panthenol, and syrup.Sucrose has a variety of functions in soliddrug forms. It can be used as a filler, abinder, a masking flavo(u)r, e.g. in vit-amin C tablets, a stabilizer, and as a coa-ting agent in sugar-coating. For examplesof its use, see effervescent tablets, copo-vidone, instant granules, tartaric acid,and sugar-coating.

Stress test 118

SugarVarious types of sugar are used in liquidand solid vitamin products.

Types of sugar in vitamin products

LactoseSucroseGlucoseFructoseSorbitolMannitolMaltoseXylitol

For details of the use of sugar, see underthe individual headings.

Sugar-coatingTraditional sugar-coating is still of valuefor multivitamin tablets, and cannot al-ways be replaced by film-coating, be-cause the colo(u)red covering offers ef-fective protection against light and humi-dity. In addition, it is possible with thesugar-coated tablet, much as with the softgelatin capsule, to incorporate one ormore vitamins into the covering insteadof into the core. This eliminates chemicalinteractions and avoids unfavo(u)rablepH values. The maximum stability ofvitamins A, D, calcium D-pantothenate,vitamin B12 and folic acid was achievedwhen hey were separated from the othervitamins by incorporation in the sugar-coating [155]. In this case, it may bebetter to use dexpanthenol than calciumpantothenate.A possible alternative to the traditionalsugar-coating is an automated version[192].The following sugar film-coating suspen-sion is very suitable for use in a conti-nuously operation Accela-Cota.

Suspension for automated sugar film-coa-ting

Sucrose 400 gCopovidone 100 gPolyethylene glycol 6000 80 gBeta-carotene 1 % CWD [1] 30 gTalc 60 gTitanium dioxide 100 gWater ad 2400 g

When coating vitamin C cores, it is ne-cessary to remember that ascorbic acidreduces most colorants [222±224]. Thusan uncolo(ur)ed subcoating is absolutelynecessary. However, the individual colo-rants differ in stability even when thismeasure is employed [67].

Substained release tabletsThe sustained release effect is almost notknown for vitamin tablets. The only ex-ception is vitamin C for which a formula-tion is given in the following table:

Vitamin C sustained release tablets(200 mg)

Ascorbic acid, crystalline 200 mgPolyvinyl acetate + PovidoneK 30, 8+2), spray dried 200±350 mgMagnesium stearate 9 mg

Manufacturing: Direct compression

Release of vitamin C from sustained releasetablets:

119 Substained release tablets

S

SynergistsSynergists are generally defined as sub-stances which increase the effect of an-other substance. In the specific case ofantioxidants, synergists are substanceswhich increase their effects either by re-generating the antioxidant, which hasbeen consumed during the reaction, orby providing a pH suitable for the actionof the antioxidant. Chelating agents areincluded among the synergists becausethey form complexes with substances,e.g. heavy metals, which promote oxida-tion and thus prevent the latter. Theboundaries between antioxidants and syn-ergists are not well-defined; there aremany transitional cases.Synergists important in vitamin productsare citric acid, lecithin, and ethylenedia-minetetraacetic acid. In addition, ascor-byl palmitate has a synergistic action ontocopherol.

SyrupThe problems with the stability of liquidoral products containing vitamin combi-nations increase with the number of vit-amins present. Syrups produced with suc-rose, sorbitol or glucose are still the bestin these cases, because the high viscosityreduces the diffusion in the system.Nevertheless, it is in any case advisableto find an alternative to the liquid drugform, for example effervescent or instantgranules, or effervescent tablets, whichare likewise taken in the liquid form bythe patient.For further details, see sucrose, glucose,and sorbitol.

For examples of the uses of syrups, seeascorbic acid, B complex, dexpanthenol,and sorbitol.For an example of a multivitamin syrupsee the table below.

Multivitamin syrup (1±2 RDA/20 ml)

I. Vitamin A palmitate1.7 mio I. U./g 100 mgVitamin D 40 mio I. U./g 0.5 mgVitamin E acetate 1000 mgPEG glyceryltrihydroxystearat 45 g

II. Water 100 g

III. Sucrose 450 gMethyl parabene 2 gCitric acid 800 mg

IV. Glycerol 96 gWater 250 g

V. Thiamine hydrochloride 150 mgRiboflavin 5-phosphate Na 150 mgNicotinamide 550 mgPyridoxine hydrochloride 150 mgAscorbic acid 3000 mgSorbic acid 1 gPropylene glycol 50 g

Total amount 1000 g

Manufacturing: Heat I and II separately to60�C and mix both well stirring. DissolveIII in the hot solution IV. Mix the coolsolutions I/II, III/IV and V and adjust thepH to about 4. Pass nitrogen through thesyrup before and during filling in flasks.

Chemical stability:After the storage at room temperature thefollowing vitamin contents were found byHPLC

9 months 12 monthsVitamin A 86% 73%Vitamin B1 88% 83%Vitamin B2 96% 92%Vitamin C 78% 77%

Synergists 120

T

Tablet(s)Tablets are the most widely used formcontaining vitamins. There is no doubtthat this is partly due to the relativelyhigh stability of vitamins in this form,compared with drops, syrups, injectables,and other solutions.

Tablets commonly used for vitamins

Normal tabletsChewable tabletsLozengesEffervescent tabletsLaminated tabletsMultilayer tabletsCores for coated tablets

The stability of vitamins in tablets withfilm-coating and, in particular, with su-gar-coating is usually improved due tothe reduction in the permeability to oxy-gen, or, when one or two vitamins areincorporated into the coating, due to theelimination of chemical interactions.This is also the aim of laminated or mul-tilayer tablets.The vitamin compositions which are sui-table for tablets sometimes differ fromthose used in solutions. For details, seevitamin derivatives.In addition to the many formulations givenin this book, a large number of suggestedformulae for vitamin tablets can be found inthe literature supplied by the individual vit-amin manufacturers and in the general lite-rature [e.g. 71, 180, 202, 279].

Tablet coatingsee film-coating and sugar-coating.

Tablet disintegrantssee disintegrants.

Tablet disintegrationThe disintegration of a vitamin tablet inan aqueous medium into its primary par-ticles can be regarded as the first step inthe bioavaibility of vitamins, and thus isan important criterion of the quality of avitamin tablet. The current pharmacopei-as specify the apparatus to be used formeasuring it.Both the nature of the test medium andthe desirable disintegration time dependon the type of vitamin tablet:1. All tablets which are to be swallowed (e.g.

film- or sugar-coated tablets and normaltablets) are tested in simulated gastric fluid(or water). The maximum disintegrationtime is 15 minutes.

2. Chewable tablets and lozenges are testedin water. The disintegration time is be-tween 15 and 60 minutes.

3. Effervescent tablets are tested in water.The maximum dissolution time is usually3 minutes.

The formulations suggested in this bookmet these requirements.Since for other active drug substances theimportance of the control of the tabletdisintegration has been reduced and ismore and more substituted by the dissolu-tion test a similar situation can be obser-ved in the case of vitamin tablets.

Tablet friabilityThe friability is an important parameterfor assessing the physical properties of

121 Tablet friability

T

tablets. It is measured by the percentageloss when tested by rolling and shaking.The equipment used for this test is usual-ly of the rotary type (friabilator).Friability of 0.8 to 1.0% regarded as theupper limit for normal tablets. It is almostalways possible to develop a formulationfor vitamin tablets which meets this re-quirement.The friability in the Roche friabilator isbelow 1% for all the tablet formulationsdetailed in this book.

Tablet hardnessThe hardness is one of the most impor-tant parameters for characterizing thephysical properties of a tablet. It is deter-mined by measuring the force actingalong the diameter of a tablet at the in-stant it fractures. The hardness is usuallyreported in kg or N (1 kg is equivalent to9.81 N). The results of measurement ofhardness may depend on the apparatus,and thus may not be generally applicable.Tablets with a very high content of oilyvitamins are least hard. It is usually pos-sible to solve this problem, as shown bythe example of the vitamin E tablet de-tailed under the heading Ludipress�,which had a measured hardness of 60 to70 N.Large amounts of added magnesium stea-rate may adversely affect the tablet hard-ness.The hardness of chewable tablets andlozenges usually is greater than that ofnormal tablets to prevent disintegrationin the mouth. This is achieved by higherconcentrations of binders or fillers, suchas mannitol or sorbitol.The formulae for tablets suggested in thisbook all had a hardness between 50 and150 N in a Heberelin/Schleuniger appara-tus.

TablettingA variety of methods is available fortabletting vitamins. For details, see directtabletting, granulation, tablets, and ta-bletting pressure.

Tabletting pressureThe pressure applied during the produc-tion of tablets may affect the chemicalstability of the vitamins they contain.This particularly applies to the unstablelipophilic vitamins A, D and K1 whichare used as dry powder. A high tablettingpressure may expel a certain amount ofthe oily vitamins A or K1 from the drypowder matrix, which increases the con-tact with atmospheric oxygen and othervitamins. There may also be fracturing ofthe dry powder particles, which has thesame effect on the vitamins.A high tabletting pressure alters the ap-pearance of dexpanthenol or vitamin Etablets, for example. That tablets acquirea ªgreasyº, i.e. somewhat shiny, appea-rance, due to extrusion of the vitaminsfrom their dry powders, and their hard-ness diminishes. On the other hand, thesetablets, in particular, require a minimumpressure to reach an adequate hardness.The effect of the tabletting pressure onthe tablet hardness, the tablet disintegra-tion and the tablet friability has beenexamined on the vitamin C formulation(see next page).The hardness and the disintegration arenot always directly proportional to thecompressive force over a range as wideas in this case. If, for example, the ascor-bic acid content of the following formu-lation is increased from 30% to 45%, thehardness will exponentially increase withthe compressive force and the figure at23 kN will be much higher.

Tablet hardness 122

Formulation

Ascorbic acid, fine powder 60 mgLudipress� 139 mgMagnesium stearate 1 mg

Properties

Effects of the tabletting pressure on theproperties of a vitamin C tablet (60 mg).

TalcTalc is magnesium hydroxide polysili-cate. It is a white powder, which has aslightly greasy feel, and is insoluble inwater.Talc is used as glidant and lubricant invitamin tablets. The usual concentrationsare in the range 1 to 4% of the tabletweight. As with all lubricants, talc shouldbe added to the tablet mixture after gra-nulation and before compression.For examples of its use in tablets, seecrospovidone, direct compressible vit-amins, and hydroxypropyl(methyl)cellu-lose.Talc is also used in film-coatings as anantistick agent. For examples of its use,see ethylcellulose, film-coating, and su-gar-coating.

Tartaric acid

Tartaric acid is used as an auxiliary ineffervescent tablets where it brings aboutthe effervescent effect by reacting withsodium bicarbonate to liberate carbon di-oxide. In some formulations, tartaric acidhas proved to be better at producing sa-tisfactory tablets than has citric acid,which is used for the same purpose.The liberation of carbon dioxide maytake place somewhat slower with tartaricacid than with citric acid unless anotheracid, such as ascorbic acid, is present inthe formulation [259].

Vitamin B complex + C effervescent tablet

I. Thiamine mononitrate 30 mgRiboflavin 5 mgPyridoxine hydrochloride 10 mgNicotinamide 66 mgCalcium pantothenate 16 mgTartaric acid, powder 350 mgSodium bicarbonate 450 mgSucrose, crystalline 750 mgPolyvinylpyrrolidone K 30 30 mgSorbitol 200 mg

II. Isopropanol + methylenechloride (1+1) q.s.

III. Ascorbic acid, crystalline 500 mgRiboflavin 2 mgPolyethylene glycol 6000,powder 50 mgCyanocobalamin 0.1 %,gelatin-coated [3] 10 mgOrange flavo(u)r 10 mgSaccharin, sodium salt 2 mgCyclamate, sodium salt 5 mg

Granulate mixture I with II, screen, mixwith III, and compress.

123 Tartaric acid

T

An example of its possible use is thepreceding composition for a vitamin Bcomplex + C effervescent tablet.For further examples of its use, see com-paction, effervescent tablets and multivit-amin solid preparations.

Tastesee flavo(u)ring.

Thermolysissee prediction of stability and heat.

Thiamine disulfide

Thiamine disulfide (syn. vitamin B1 dis-ulfide, aneurine disulfide) is a white cry-stalline powder. When anhydrous, it issparingly soluble in water, but crystalswhich contain water are freely soluble.Thiamine disulfide is only rarely used invitamin products in the FRG.

Thiamine hydrochloride

Thiamine hydrochloride (syn. vitamin B1hydrochloride, thiamine chloride hydro-chloride, aneurine hydrochloride) is awhite microcrystalline powder with a ty-pical odo(u)r and a bitter taste. It is very

freely soluble in water. About 5 % solu-tions in glycerol and about 1 % solutionsin ethanol can be prepared.Thiamine hydrochloride is preferred toother vitamin B1 derivatives in liquiddrug forms because of its solubility. Thestability in solution gives rise to difficul-ty. Quite stable formulations containingvitamin B1 and no other vitamins can beprepared by maintaining a very low pH[220], excluding light and oxidizingagents, and possibly adding an antioxi-dant and chelating agent. A reducingagent such as sodium sulfite must not beused as antioxidant, because it will im-mediately decompose thiamine. A 1%thiamine solution was obtained by using5% low-molecular-weight polyvinylpyr-rolidone to improve the taste, 0.05% pro-pyl gallate and 0.005% ethylenediamine-tetraacetic acid and adjusting the pH to4; it had been stable by organoleptic andchemical criteria, for 2 years [64]. Thereare also some other substances which areable to improve the stability of thiaminesolutions. These include sucrose and gly-cerol [206].It is much more difficult, and may bevirtually impossible to develop a multi-vitamin or B complex + C syrup with astable vitamin B1 content, because thereare numerous chemical interactions withother vitamins. Comparison of glucose,sorbitol and sucrose in multivitamindrops revealed that sorbitol was the beststabilizer of vitamin B1 at pH 3.2. Solu-tions containing sorbitol and sucrose atpH 4.5 were of approximately equal sta-bility. The results with glucose were al-ways worse [152].The losses of thiamine from the formula-tions of vitamin B complex + C andmultivitamin syrups detailed under theheadings B complex, dexpanthenol andsyrup after storage in the dark at roomtemperature for 12 months were 15, 19

Taste 124

and 17%, respectively. This means thatwith an overage of 20% thiamine hydro-chloride these products may be expectedto have a shelf-life of only 18 months, atthe outside. The purity of the thiaminehydrochloride also appears to influenceits stability in injectables [207].This is why a more stable alternative to amultivitamin solution should always besought, e.g. instant granules, an oralpowder or effervescent granules.The only solid drug forms, in which thia-mine hydrochloride is normally used, arepure vitamin B1 products and simple Bcomplex tablets, because it contains 3 or4% water, unlike thiamine mononitrate,and this promotes undesired chemical in-teractions. The following composition isan example of its use in a vitamin B1tablet.

Vitamin B1 tablet (100 mg)

I. Thiamine hydrochloride(or thiamine mononitrate) 100 mgLactose, monohydrate 100 mgCellulose, microcrystalline 100 mg

II. Polyvinylpyrrolidone K 30 10 mgIsopropanol q.s.

III. Crospovidone 10 mgSilica, highly disperse 1 mg

Granulate mixture I with solution II, mixwith III, and compress.

After these tablets had been stored at30�C and 70% relative humidity for 6months, there was no loss of vitaminand no difference was found betweenthiamine hydrochloride and thiamine mo-nonitrate.For further examples of its use in tablets,see direct tabletting auxiliaries, lactose,and thiamine mononitrate.

Thiamine mononitrate

Thiamine mononitrate (syn. vitamin B1nitrate, thiamine nitrate, aneurine nitrate)is a white, microcrystalline powder witha bitter taste. 2 or 3% solutions in watercan be prepared and it is slightly solublein ethanol.Thiamine mononitrate is used only insolid drug forms, in which its stability isequal to or greater than that of thiaminehydrochloride [131]. The grater stabilityderives from the very low water contentof the nitrate, which means that it is lessprone to chemical interactions than is thehydrochloride, which contains water.This is particularly evident in vitamin Bcomplex and multivitamin tablets [156].

Vitamin B complex tablets

Composition

Thiamine hydrochloride or thia-mine mononitrate

25 mg

Riboflavin 25 mgNicotinamide 80 mgCalcium pantothenate 40 mgPyridoxine hydrochloride 16 mgCyanocobalamin 0.1 % gelatin-coated [3]

16 mg

Cellulose, microcrystalline 286 mgPolyvinylpyrrolidone K 30 16 mgSilica, highly disperse 3 mg

Thiamine stability

The losses of the thiamine derivativesafter storage at 40 �C for 6 months wereas follows:Thiamine hydrochloride: 68% decreaseThiamine mononitrate: 17% decrease

125 Thiamine mononitrate

T

The stability of thiamine mononitrate hasalso been found to be greater in multi-vitamin soft gelatin capsules [41, 208].The same applies to hard gelatin capsu-les [208].The difference in stability between vit-amin B1 hydrochloride and mononitratein the preceding vitamin B complex for-mulation for direct tabletting has beendetermined.For further examples of its use in vitamintablets, see B complex, instant granules,multivitamin solid preparations, thiaminehydrochloride, and tartaric acid.

Thiamine pyrophosphatesee cocarboxylase.

Thiochrome

Thiochrome is a colo(u)red product of theoxidation of thiamine derivatives [132],as may occur in multivitamin solutionsdue to chemical interactions with other

vitamins or to oxidation (not by atmo-spheric oxygen). The solution turnsbrown and sometimes a precipitate maybe formed.

Tocopherol

Alpha-tocopherol (syn. vitamin E) hasthe highest activity of the vitamin E de-rivatives. The commercially availableforms are D-alpha and DL-alpha-toco-pherol.The former is the RRR form, and is ob-tained from a natural mixture of tocophe-rols (alpha, beta, gamma and delta) bymethylation. The all-racemic DL form isa synthetic product. Both types are oily,yellow to brownish liquids. Tocopherol isinsoluble in water, and soluble in fats andoils. It is one of the lipophilic vitamins.1 mg DL-alpha-tocopherol = 1.1 USPunits vitamin E1 mg D-alpha-tocopherol = 1.49 USPunits vitamin E(1 USP unit is equivalent to 1 formerinternational unit vitamin E)

Thiamine pyrophosphate 126

Oxidation of vitamin E.

Tocopherols are very sensitive to oxida-tion and thus rapidly darken when expo-sed to oxygen. This is why tocopherol isonly very rarely used as vitamin E inpharmacy. It is employed as an antioxi-dant (free radical trap) in pharmaceuti-cals, food products (E number E 307),and plastics with tocopherol quinonebeing produced.Tocopherol is particularly used in vit-amin products for the stabilization of vit-amin A. Addition of 3 % tocopherol to avitamin A solubilizate results in very sa-tisfactory stability [209]. The loss of vit-amin A in a syrup stored at room tempe-rature for 180 days was reduced from20% to 6 % by addition of 16.8% toco-pherol, 1% butylated hydroxyanisole and1% propyl gallate (all figures being ba-sed on vitamin A) [168].

Tocopheryl acetate

Tocopheryl acetate (syn. D- or DL-alpha-tocopheryl acetate, vitamine E acetate) isa pale yellow, viscous, oily liquid whichis freely soluble in fats and oils. It isinsoluble in water.1 mg DL-alpha-tocopheryl acetate =1.0 USP unit vitamin E1 mg D-alpha-tocopheryl acetate =1.36 USP units vitamin E(1 USP unit = 1 former international unit)Tocopheryl acetate differs from tocophe-rol in being insensitive to oxidation, and

thus one of the few stable vitamins. Thisis also why it has no antioxidant effect,unless it is hydrolyzed by saponification.It can be incorporated into soft gelatincapsules, or oily products either undilu-ted or mixed with oils (e.g. peanut oil).A dry powder must be used for solid drugforms (adsorbate, spray-dried material,etc.). Commercially available productsmainly contain 33 or 50% and some ofthem are dispersible in cold water. Forexamples of its use, see adsorbate, ascor-bic acid, calcium hydrogen phosphate,instant granules, Ludipress�, multivit-amin solid preparations, and sorbitol.A solubilizer is necessary when tocophe-ryl acetate is used in aqueous solutions.The figure which follows shows theamount of PEG glyceryl trihydroxystea-rate [1] needed for solubilization.

Solubilization of tocophyerol acetate withPEG glyceryl trihydroxystearate.

For further examples of the use of toco-pheryl acetate in aqueous solutions, seebutylated hydroxytoluene, emulsion, PEGglyceryl trihydroxystearate, PEG glyce-ryl triricinoleate, and two-chamber am-pules.

127 Tocopheryl acetate

T

Tocopheryl nicotinate (syn. alpha-tocophe-ryl nicotinate) consists of pale beige cry-stals which are insoluble in water. Only theDL form is available commercially.Tocopheryl nicotinate is hardly ever usedas a vitamin, being employed to treatdisturbances of peripheral blood flow.The main drug forms are capsules andtopical products.

TocopherylquinoneTocopherylquinone is produced duringthe oxidation of tocopherol (q.v.).

Tocopheryl PEG succinateTocopheryl PEG succinate (syn. succinicester of tocopherol and polyethylene glycol)is a white powder. It is a water-soluble formof tocopheryl succinate [211]).

Tocopheryl succinate

Tocopheryl succinate (syn. DL-alpha-toco-pheryl succinate, DL-alpha-tocopheryl hy-drogen succinate) is a white powder whichis insoluble in water but soluble in oils.1 mg DL-alpha-tocopheryl succinate =0.89 USP units vitamin E(1 USP unit = 1 former international unit)Tocopheryl succinate can, unlike toco-pheryl acetate, be converted directlyinto tablets without the necessity to pre-pare a dry powder [271], as shown by theformulation which follows.

Vitamin E tablet (100 mg)

I. Tocopheryl succinate 112 mgII. Copovidone 2 mg

Water q.s.III. Lactose, monohydrate 300 mg

corn starch 100 mg

Granulate I with solution II, mix with III,and compress.

Tocopheryl nicotinate 128

Tocopheryl nicotinate

Tocopheryl succinate calcium

Calcium tocopheryl succinate (syn. DL-alpha-tocopheryl calcium succinate) is awhite powder which is insoluble in water,like tocopheryl succinate. Its uses andpharmaceutical properties are similar tothose of tocopheryl succinate.

Trace elementsIn contrast to the minerals, also calledmacroelements, the trace elements areessential for the human body but only in�g to mg quantities. The most importanttrace elements are listed in the table be-low.

Important trace elements

ChromiumCobaltCopperIodineIronManganeseMolybdenumSeleniumZinc

Inclusion of trace elements in vitaminproducts frequently leads to problemswith stability, because some of them areheavy metals which catalyze the oxidati-ve breakdown of some vitamins.This is why trace elements and vitaminsshould not be present in the same solu-tion in liquid drug forms.If direct combination of the two classesof substances in solid forms is necessary,the problem with stability can be greatlyreduced by minimizing the water content.This is shown by the following exampleof a vitamin C plus trace elements com-position for direct tabletting, which sho-wed no loss of vitamin C on storage atroom temperature for 12 months, eventhough ascorbic acid is the vitaminwhich is most sensitive to heavy metals.

Vitamin C tablet (500 mg) with trace ele-ments

Ascorbic acid, for direct com-pression (min. 95 %) 525.0 mgSorbitol 60.0 mgPolyethylene glycol 6000,powder 40.0 mgCyclamate, sodium salt 10.0 mgSaccharin, sodium salt 1.0 mgIron (II) sulfate 10.0 mgManganese sulfate 0.4 mgCopper sulfate 0.4 mgZinc oxide 0.05 mgMagnesium carbonate 10.0 mgOrange flavo(u)r 5.0 mgColorant q.s.

Of course, it is also possible to keep thetrace elements separate. This is possibleby producing separate granules of thevitamins and of the trace elements, whichare then converted into a normal tablet, abilayer tablet or a laminated tablet. Thetrace elements can also be incorporatedinto the tablet coating. The most elabo-rate but most effective method, which issuitable for multivitamin solid prepara-tions in particular, is the production ofseparate vitamin and trace element ta-blets or capsules, which are then pack-aged in combination.

Tretinoin

Tretinoin (syn. all-trans retinoic acid, all-trans vitamin A acid) is one of the reti-noids. Because of its toxicity, it is notused as vitamin A but is used for thetopical treatment of acne.For an example of its use, see dexpan-thenol.

129 Tretinoin

T

Tween�

Tween is a registered trademark for poly-sorbates [6]. The type which is mostcommonly used for the solubilization ofvitamins is Tween 80.

Two-chamber ampulesIt is necessary when developing parente-ral products containing vitamin combina-tions (e.g. multivitamin injectables) totake measures to improve the very poorstability of some vitamins in this type ofdrug form. Apart from lyophilization, oneoption is the use of compartmented ortwo-chamber ampules [34, 147, 150].The reasons for separating two solutions

are mainly the different pH values requi-red by the various vitamins and the che-mical interactions between the vitamins.The two-chamber ampules, which are no-wadays commercially available, areusually of the design shown in the figurewhich follows.During injection from the two-chamberampule, the screwing-in of the plungerpushes the central partition forwards untilit reaches the ªbypassº. The mixing ofthe solutions then starts and continuesuntil the plunger reaches the partitionand advances it further.The following example of multivitamintwo-chamber ampules can, of course,also be used for compartmented ampules[147].

Tween� 130

Two-chamber ampule for multivitamin solutions.

Multivitamin two-chamber ampule

Chamber 1 Chamber 2

Retinyl palmitate 10,000 I. U. Thiamine hydrochloride 10 mgCholecalciferol 500 I. U. Riboflavin-phosphate sodium 10 mgTocopheryl acetate 30 mg Nicotinamide 55 mgSodium ascorbate 300 mg Dexpanthenol 10 mgFolic acid 1 mg Pyridoxine hydrochloride 15 mgNicotinamide 20 mg Cyanocobalamin 15 �gPolysorbate 80 100 mg Iron citrate 46 �gBenzyl alcohol 10 mg Benzyl alcohol 10 mgPropylene glycol 100 mg Water 1 mlWater 1 ml

pH optimum for chemicalstability: 6.8±7.6

pH optimum for chemicaland physical stability: 4.5

V

ViscosityDepending on the vitamin product an in-crease in the viscosity may be desirableor undesired.A high viscosity of oral solutions isusually regarded as an advantage, be-cause it stabilizes some vitamins. This isparticularly evident in multivitamin solu-tions such as syrups. The reason is notonly the protection conferred by the suc-rose or sorbitol but also the reduction ofdiffusion in a viscous solution. This ef-fect may also explain why the rate ofdecomposition of ascorbic acid in vis-cous solutions of the solubilizer polysor-bate 80 is markedly reduced [179].The viscosity of parenteral solutionsought not to exceed 30 mPa.s. This re-quirement may be a problem with solu-bilizates. PEG 15 hydroxystearate hasproved to be the most favourable solubi-lizer in this respect, because even a 30 %solution does not reach this viscosity li-mit.

Vitamin Asee retinol, retinyl acetate, retinyl pal-mitate, and retinyl propionate.

Vitamin A acidsee isotretinoin and tretinoin.

Vitamin B1

see cocarboxylase, thiamine hydrochlori-de, and thiamine mononitrate.

Vitamin B2

see riboflavin and riboflavin-phosphatesodium.

Vitamin B3

former name for nicotinamide and nico-tinic acid.

Vitamin B5

former name for pantothenic acid.

Vitamin B6

see pyridoxal phosphate and pyridoxinehydrochloride.

Vitamin B12

see cyanocobalamin and hydroxocobala-min.

Vitamin B13

former name for orotic acid.

Vitamin B15

former name for pangamic acid.

Vitamin Bc

see folic acid.

131 Vitamin Bc

V

Vitamin Csee ascorbic acid, calcium ascorbate andsodium ascorbate.

Vitamin D2

see ergocalciferol.

Vitamin D3

see cholecalciferol.

Vitamin derivativesBy choosing the correct vitamin derivati-ves for the intended drug form, it is pos-sible to optimize both the processing andthe physical and chemical stability. Thusa wide variety of vitamin compositionsare commercially available for virtuallyevery type of product. A distinction hasto be made between a chemical derivati-ve and a physically modified composi-tion.

Vitamin C 132

Uses of commonly used chemical derivatives of vitamins (pure substances)

Vitamin derivative Solidforms

Soft gelatincapsules

Solutions Semisolidforms

Retinol ± ± ± ±Retinyl acetate ± (+) ± ±Retinyl palmitate ± + + +Retinyl propionate ± + + (+)Beta-carotene ± ± + (+)Thiamine hydrochloride (+) ± + ±Thiamine mononitrate + + ± ±Cocarboxlase ± ± + ±Riboflavin + + ± ±Riboflavin-phosphate Na ± ± + +Nicotinamide + + + ±Calcium pantothenate + + ± ±Sodium pantothenate ± ± + ±Dexpanthenol (±) + + +Pyridoxal phosphate ± ± + ±Pyridoxine hydrochloride + + + ±Cyanocobalamin ± ± + ±Hydroxocobalamin ± ± + ±Folic acid + + + ±Ascorbic acid + + + ±Sodium ascorbate + + + ±Calcium ascorbate + + ± ±Cholecalciferol ± ± + ±Ergocalciferol ± ± + ±Tocopherol ± + + +Tocopheryl acetate ± + + +Tocopheryl succinate + ± ± ±Biotin ± + + ±Phytomenadione ± + + ±

133 Vitamin derivatives

Solubilization of retinyl palmitate and propionate with PEG-40 glyceryl trihydroxstearate.

Uses of commonly used physical vitamin derivatives

Vitamin derivative Solidforms

Softgelatincapsules

Solutions Semi-solidforms

Retinyl acetate, dry powder + ± ± ±Retinyl acetate, oily solution ± + ± (+)Retinyl palmitate, dry powder (CWD) + ± ± ±Retinyl palmitate, oily solution ± + +

(oily)+

Beta-carotene, dry powder (CWD) + ± ± ±Beta-carotene, oily dispersion ± + +

(oily)+

Thiamine mononitrate, dry powder + ± ± ±Riboflavin, dry powder + ± ± ±Pyridoxine hydrochloride, dry powder + ± ± ±Dexpanthenol adsorbate + ± ± ±Dexpanthenol in propylene glycol ± + + +Cyanocobalamin, dry powder + ± ± ±Ascorbic acid, coated + ± ± ±Ascorbic acid for direct compression + ± ± ±Ascorbic acid, crystalline + ± + ±Ascorbic acid, fine powder + + (±) ±Ergocalciferol, dry powder + ± ± ±Ergocalciferol, oily solution ± + +

(oily)±

Cholecalciferol, dry powder + ± ± ±Cholecalciferol, oily solution ± + +

(oily)±

Tocopheryl acetate, dry powder + ± ± ±Biotin, dry powder + ± ± ±Phytomenadione, dry powder + ± ± ±

V

The preceding table lists the most impor-tant chemical derivatives of vitamins andtheir uses.The greater stability is the reason forusing vitamin A esters in place of retinol,vitamin E esters in place of tocopherol,and dexpanthenol in place of D-pantothe-nates in multivitamin solutions, and thia-mine mononitrate in place of the hydro-chloride in multivitamin tablets, ascorbicacid in place of calcium ascorbate insolutions, etc. However, the physical dif-ferences are also important: riboflavin-phosphate sodium is more soluble thanriboflavin and solubilizates of much hig-her concentration can be prepared withvitamin A propionate rather than withthe palmitate, as shown by the figureabove [173].The physical vitamin derivatives, whoseuses are listed in the table which follows,mainly have the aim of facilitating pro-cessing or even of making it possible.

Vitamin Esee tocopherol, tocopheryl acetate, andtocopheryl succinate.

Vitamin Fsee fatty acid, polyunsaturated.

Vitamin Hsee biotin.

Vitamin mixture (premix)In the market individual vitamin mixturesproduced according to the requirementsof the pharmaceutical manufacturer are

available for the production of vitaminpreparations e.g. multivitamin tablets. Atypical formulation is given in the tablewhich follows.

Multivitamin + copper + zinc mixture andtablets

Vitamin mixture:

Thiamine mononitrate 3.9 %Riboflavin 0.4 %Nicotinamide 10.1%Calcium D-pantothenate 2.9 %Pyridoxine hydrochloride 1.2 %Cyanocobalamin gelatincoated (0.1%) 2.6 %Folic acid 0.1 %Ascorbic acid 63.4%Vitamin E acetate drypowder (50%) 9.1 %Copper oxide 0.3 %Zinc sulphate 6.0 %

Tablets:

Vitamin mixture 1000 mgSilicagel, highly disperse 5 mgLudipress 150 mgCellulose, microcrystalline 120 mgCopovidone 25 mgMagnesium stearate 10 mgTalc 10 mg

Manufacturing: Direct compression

Vitamin Psee bioflavonoids and rutin.

Vitamin PPsee nicotinamide and nicotinic acid.

Vitamin E 134

W

Water contentIn just the same way as the humidity, thewater content may have strong adverseeffects on the stability on many vitaminsin solid drug forms. Only when free wa-ter is present, can chemical interactions,hydrolisis or oxidation catalyzed by hea-vy metals take place, for example.The residual water content in the productmay derive from the processing, such aswet granulation, from high humidity du-ring manufacture, and/or from the watercontent of the vitamins or auxiliaries.A certain residual moisture content isnecessary in tablets for the developmentof stable binding between the solid par-ticles. The processes used for minimizingit must be non-deleterious but efficient,such as granulation and drying in, forexample, a fluidized bed. Another wayof minimizing the water content of ta-blets is direct tabletting. Dry granulationwithout a solvent may be another way ofachieving this. Unfortunately, the latterprocess does not always result in tabletshaving the same good physical propertiesas those obtained with traditional wetgranulation.

The content of free water in uncolo(u)redvitamin C tablets, effervescent tablets andall solid multivitamin forms ought not toexceed 0.2 % [34]. It may be up to 1 % inother vitamin tablets without greatly af-fecting the stability [24]. The effects ofresidual water are seen earliest in unco-lo(u)red vitamin C tablets, which mayquickly turn yellow or brownish due tohydrolysis of ascorbic acid.The high water content of thiamine hy-drochloride (3 or 4%) is the reason whyit is not used in multivitamin tablets orcapsules. Thiamine mononitrate, whichcontains virtually no water, is preferredfor these.The water content in liquid products alsoaffects the stability of the disolved vit-amins (see also solvents). The stability ofvitamin A in ethanol/water solubilizatesincreases with decreasing water content[182]. The same is true of other vitaminsin multivitamin solutions where glyceroland propylene glycol are used [59, 75].

Water-soluble vitaminssee hydrophilic vitamins.

135 Water-soluble vitamins

W

List of Suppliers[1] BASF AG, Division ME, D-67056 Ludwigs-

hafen[2] FMC Corp., Food and Pharmaceutical Pro-

ducts Div., 2000 Market Street, Philadelphia,PA 19103, USA

[3] BASF Health & Nutrition A/S, Malmparken5, DK-2750 Ballerup

[4] Degussa AG, Industrie- und Feinchemika-lien, Postfach 13 45, D-63 457 Hanau

[5] ISP Corp., 140 West 51st St., New York, NY10 020, USA

[6] Atlas Chemie, Goldschmidtstraûe 100, D-45 127 Essen

[7] Th. Goldschmidt AG, Goldschmidtstraûe100, D-45 127 Essen

[8] Shinetsu Chem. Company, Cellulose Div.,Asahi-Tokai Building; 6±1, 2-chome, Otema-chi, Chiyoda-Ku, Tokyo, Japan

[9] Hüls AG, Postfach, D-45 764 Marl[10] Nipa Laboratories Ltd., Nipa Industrial Estate,

Llantwit Fardre, Nr Pontypridd, Mid-Glamor-gan CF38 2SN, Wales, Great Britain

[11] Henkel KgaA, Postfach 1100, D-40 191 Düs-seldorf

[12] Hercules Aldag GmbH, Curslacker NeuerDeich 66, D-21 029 Hamburg

137 List of Suppliers

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