Tiamina, IP

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Monographs: Pharmaceutical substances: Thiamini hydrochloridum

- Thiamine hydrochloride

Molecular formula.C12H17ClN4OS,HCl

Relative molecular mass.337.3

Graphic formula.

Chemical name.Thiamine chloride, hydrochloride; 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolium chloride, mono-hydrochloride; CASReg. No. 67-03-8.

Requirements

Definition.Thiamine hydrochloride contains not less than 98.0% and not more than 101.0% ofC12H17ClN4OS,HCl, calculated with reference to the dried substance.

Assay.Dissolve about 0.25 g, accurately weighed, in 30 ml of glacial acetic acid R1, add 10 mlof mercuric acetate/acetic acid TS, and titrate with perchloric acid (0.1 mol/l) VS as describedunder2.6 Non-aqueous titration,Method A. Each ml of perchloric acid (0.1 mol/l) VS isequivalent to 16.86 mg of C12H17ClN4OS,HCl.

Mercuric acetate/acetic acid TS.

Procedure.Dissolve 50 g of mercuric acetate R in sufficient glacial acetic acid R1, that has beenneutralized, if necessary, to crystal violet/acetic acid TS with perchloric acid (0.1 mol/l) VS, toproduce 1000 ml.

Acetic acid, glacial, R.

C2H4O2(SRIP, 1963, p. 25); d~ 1.048.

Acetic acid, glacial, R1.

Glacial acetic acid R, that complies with the following tests:

Substances reducing dichromate.To 10 ml add 1.0 ml of potassium dichromate (0.0167 mol/l)

VS and cautiously add 10 ml of sulfuric acid (~1760 g/l) TS. Cool the solution to roomtemperature and allow to stand for 30 minutes. While swirling the solution, dilute slowly and

cautiously with 50 ml of water, cool, and add 1.5 ml of freshly prepared potassium iodide (80g/l) TS. Titrate the liberated iodine with sodium thiosulfate (0.1 mol/l) VS, adding 3 ml of starchTS as the end-point is approached. Perform a blank titration and make any necessarycorrections. Not less than 0.60 ml of sodium thiosulfate (0.1 mol/l) VS is consumed.

Substances reducing permanganate.Add 40 ml to 10 ml of water. Cool to 15C, add 0.30 ml ofpotassium permanganate (0.02 mol/l) VS, and allow to stand at 15C for 10 minutes; the pinkcolour is not entirely discharged.
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Crystal violet R.

C25H30ClN3(SRIP, 1963, p. 73).

Crystal violet/acetic acid TS.

A solution of crystal violet R dissolved in glacial acetic acid R1 containing about 5 g/l.

Methods of Analysis: 2. Chemical methods: 2.6 Non-aqueoustitration

Acids and bases have long been defined as substances that, when dissolved in water, furnishhydrogen and hydroxyl ions, respectively. This definition, introduced by Arrhenius, fails torecognize the fact that properties characteristic of acids or bases may also be developed in othersolvents. A more generalized definition is that of Brnsted, who defined an acid as a protondonor, and a base as a proton acceptor. Even broader is the definition of Lewis, who defined anacid as any material that will accept an electron pair, a base as any material that will donate anelectron pair, and neutralization as the formation of a coordination bond between an acid and abase.

The apparent strength of an acid or base is determined by the extent of its reaction with asolvent. In aqueous solution all strong acids appear equally strong because they react with thesolvent to undergo almost complete conversion to hydronium ion (H3O

+) and the acid anion. In aweakly protophilic solvent such as acetic acid, the extent of formation of the acetonium ion(CH3COOH2

+) due to the addition of a proton provides a more sensitive differentiation of thestrength of acids and shows that the order of decreasing strength for acids is perchloric,hydrobromic, sulfuric, hydrochloric, and nitric.

Acetic acid reacts incompletely with water to form hydronium ion and is, therefore, a weak acid.In contrast, it dissolves in a base such as ethylenediamine, and reacts so completely with thesolvent that it behaves as a strong acid.

This so-called levelling effect is observed also for bases. In sulfuric acid almost all bases appearto be of the same strength. As the acid properties of the solvent decrease in the series sulfuricacid, acetic acid, phenol, water, pyridine and butylamine, bases dissolved in them becomeprogressively weaker and the differences between bases are accentuated. In order of decreasingstrength, strong bases of value for non-aqueous titrations are potassium methoxide, sodiummethoxide, lithium methoxide, and tetrabutylammonium hydroxide.

Many water-insoluble compounds acquire enhanced acidic or basic properties when dissolved inorganic solvents. Thus the choice of the appropriate solvent permits the determination of avariety of such materials by non-aqueous titration. Further, depending upon which part of acompound is physiologically active, it is often possible to titrate that part by proper selection ofsolvent and titrant. Pure compounds can be titrated directly, but it is often necessary to isolatethe active ingredient in pharmaceutical preparations from interfering excipients and carriers.

The types of compounds that may be titrated as acids include acid halides, acid anhydrides,carboxylic acids, amino acids, enols such as barbiturates and xanthines, imides, phenols,pyrroles, and sulfonamides. The types of compounds that may be titrated as bases includeamines, nitrogen-containing heterocyclic compounds, quarternary ammonium compounds, alkalisalts of organic acids, alkali salts of inorganic acids, and some salts of amines. Many salts ofhalogen acids may be titrated in acetic acid or acetic anhydride after the addition of mercuricacetate, which removes halide ion as the unionized mercuric halide complex. In the case ofhydrochlorides of weak bases not containing acetylatable groupings it is also possible to titrate inacetic anhydride without the addition of mercuric acetate and using an indicator such asmalachite green or crystal violet. Titrations carried out in the presence of an excess of acetic


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anhydride must be applied cautiously, however, since any reaction of the anhydride with thesubstance being titrated may give rise to low results.

In the titration of a basic compound, a volumetric solution of perchloric acid in glacial acetic acid

is usually used, although perchloric acid in dioxan may be useful in special cases. In the titrationof an acidic compound, a volumetric solution of lithium methoxide in a methanol-toluene solventis often used. For many applications it is convenient to use a solution of tetrabutylammoniumhydroxide in toluene; sodium methoxide, formerly in wide use, may often give rise totroublesome gelatinous precipitates.

Because of interference by carbon dioxide, solvents for acidic compounds must be protectedfrom excessive exposure to the atmosphere by a suitable cover or by an inert atmosphere duringthe titration. A blank determination should be carried out and the volume generally should notexceed 0.01 ml of a 0.1 mol/l titrant for each ml of solvent.

The end-point may be determined visually by colour change, or potentiometrically. If the calomelreference electrode is used, it is advantageous to replace the aqueous potassium chloridesolution in the salt bridge with lithium perchlorate/acetic acid TS for titrations in acidic solvents,or potassium chloride in methanol for titrations in basic solvents. It should be recognized thatcertain indicators in common use (crystal violet, for example) undergo a series of colour changes

and, in establishing a non-aqueous titration method for a particular use, care should be taken toensure that the colour change specified as the end-point of the titration corresponds to themaximum value of dE/dV(where Eis the electromotive force and Vthe volume of titrant) in apotentiometric titration of the substance under consideration.

When using titrants prepared with solvents that may have a relatively high coefficient ofexpansion, for example, glacial acetic acid, toluene, etc., care should be taken to compensate fordifferences in temperature that may exist between the time the titrant is used and that at whichit was standardized.

Recommended procedure

Method A (for bases and their salts)

Prepare a solution as specified in the monograph or dissolve the substance being examined in asuitable volume of glacial acetic acid R1, previously neutralized to crystal violet/acetic acid TS,warming and cooling if necessary. Alternatively the titration blank for the solvent and indicatormay be established in a separate determination. When the substance is a salt of a hydrohalicacid, add 10 ml of mercuric acetate/acetic acid TS. When the end-point is determined visually bycolour change, add 2-3 drops of crystal violet/acetic acid TS, and titrate with perchloric acid ofthe specified concentration (mol/l) to the appropriate colour change of the indicator. When adifferent indicator is specified in the monograph, this indicator should also be used for theneutralization of the glacial acetic acid R1, and mercuric acetate/acetic acid TS, and thestandardization of the titrant.

When the equivalence point is determined potentiometrically, the indicator is omitted andneutralization of the solution and standardization of the titrant are also carried outpotentiometrically. A glass electrode and a saturated calomel cell (containing potassium chloride(350 g/l) TS) as reference electrode, are used. The junction between the calomel electrode andthe titration liquid should have a reasonably low electrical resistance and there should be aminimum of transfer of liquid from one side to the other. Serious instability may result unlessthe connections between the potentiometer and the electrode system are in accordance with themanufacturer's instructions.


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When the temperature (t2) at which the titration is carried out differs from the temperature (t1)at which the titrant was standardized, multiply the volume of the titrant required by [1 +0.001(t1- t2)] and calculate the result of the assay from the corrected volume.

Monographs: Pharmaceutical substances: Thiamini mononitras -Thiamine mononitrate

Molecular formula.C12H17N5O4S

Relative molecular mass.327.4

Graphic formula.

Chemical name.Thiamine nitrate (salt); 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolium nitrate (salt); CAS Reg. No. 532-43-4.

Requirements

Definition.Thiamine mononitrate contains not less than 98.0% and not more than 101.0% ofC12H17N5O4S, calculated with reference to the dried substance.

Assay.Dissolve about 0.1 g, accurately weighed, in 30 ml of glacial acetic acid R1, add 0.15 ml

of l-naphtholbenzein/acetic acid TS, and titrate with perchloric acid (0.1 mol/l) VS to a green

end-point, as described under2.6 Non-aqueous titration,Method A. Each ml of perchloric acid

(0.1 mol/l) VS is equivalent to 16.37 mg of C12H17N5O4S.

1-Naphtholbenzein R.

C27H20O3.

Description.A reddish-brown powder.

Solubility.Practically insoluble in water; soluble in ethanol (~750 g/l) TS, benzene R, ether R,and glacial acetic acid R.

1-Naphtholbenzein/acetic acid TS.

Procedure.Dissolve 0.2 g of 1-naphtholbenzein R in sufficient glacial acetic acid R to produce100 ml.
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