IV. Pre Formulation

7/25/2019 IV. Pre Formulation

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DOSAGE FORM CONSIDERATION:

PREFORMULATION

By: LOUJESSA D. ARCELO



DOSAGE FORM CONSIDERATION

The need for dosage forms

General considerations in dosage

form designPreformulation Studies

Drug and Drug Product StabilityPharmaceutical ingredients and

excipients



Dosage Form Design

PHARMACEUTICS

• study on the: formulation, manufacture, stability, andeffectiveness of pharmaceutical dosage forms

Pharmaceutical ingredients or

excipients• solubilize thicken stabilize flavor

• suspend dilute preserve efficacious

• suspend emulsify color appealing closure forms.



Requirements of a proper design &

formulation of dosage form

Considerationof drug

substances:

compatible with oneanother - stable,

efficacious,attractive, easy toadminister & safe

*manufacturedunder appropriate

measures of qualitycontrol & packaged

in containers to

make product stable *labeled to promotecorrect use & storedunder conditions tomaximize shell life



THE NEED FOR DOSAGE

FORMS



Mechanism for safeand convenientdelivery of

accurate dosage

Protection ofdrug from

atmosphere (CT)

Protection ofdrug from

gastric acid(EC)

Conceal bitter,salty, or

offensive taste

or odor

Provide liquidpreparations ofinsoluble drugs

THE NEED FOR DOSAGE FORMS



Provide clearliquid dosage

forms

Provide rate-

controlled drugaction

Provide topicaldrug action

Provide for

insertion intobody cavity

Provide forplacement intobloodstream

Provide for

inhalationtherapy

THE NEED FOR DOSAGE FORMS



GENERAL CONSIDERATIONS

IN DOSAGE FORM DESIGN



General Considerations in Dosage

Form Design

Determine desired product type

• framework for product development.

Develop and examine initial formulations ofthe product:

• desired features: drug release profile, bioavailability,

clinical effectiveness• pilot plant studies and production scale-up.

MASTER FORMULA

- formulation that best meets the goals of the product



General Considerations in Dosage

Form Design

Factors to consider before formulationof a medicinal agent in one or more

dosage forms

• Therapeutic matters (nature of the illness)

• manner it is treated (locally or throughsystemic action)

• age and anticipated condition of the

patient.



Design

of DrugProducts

Effectiveness

Safety

Reliability Stability

Pharma-ceutical

elegance

Convenience



PREFORMULATION



PREFORMULATION

Is branch of Pharmaceutical science that utilizes

biopharmaceutical principles in the determination of

physicochemical properties of the drug substance.



Safe handlingof ingredients

andequipments

Propersequence of

addition ofingredients

Optimumenvironmental

conditions

Precautions tobe observed

Expectedinteraction

Need foroverages

PREFORMULATION



Preformulation Studies1. Physical Description

• Description, particlesize, crystalline

structure, meltingpoint, solubility

• Ability to get tosite of action andelicit a response

• Structure,form,reactivity

• Liquid drugsare used to amuch lesserextent thansolid drug Solids,

liquids,gases

ChemicalProperties

PhysicalProperties

BiologicalProperties



COLOR ODOUR TASTE

OFF-WHITE PUNGENT ACIDIC

CREAM-YELLOW SULFUROUS BITTER

SHINY FRUITY SWEET

AROMATIC TASTELESS

ODOURLESS TASTELESS

Preformulation Studies1. Physical Description: ORGANOLEPTIC PROPERTIES



Particle size

Particle size

range

Crystal

structure

Particle

shape

Preformulation Studies2. Microscopic Examination



Preformulation Studies3. Heat of Vaporization

Vapor pressure

Volatile drugscan migratewithin a soliddosage form

Personnelexposure



Puritydetermination

Identity

Preformulation Studies4. Melting point depression



Phase diagrams constructed determines:

existence & extent of the presence of solid and liquid

phases in binary, ternary & other mixtures

Preformulation Studies5. Phase Rule



affects : physical – chemical properties of drug

substances:

*dissolution rate bioavailability content uniformity

stability taste texture

flow properties absorption sedimentation rate

Preformulation Studies6. Particle Size



Preformulation Studies7. Polymorphism

substances can existin more than onecrystalline form

Polymorphic forms –

diff. physical-chemicalproperties (melting pt.

& solubility)

Crystalline andAmorphous

Evaluation of:*crystal structure(microscopy, IRspectroscopy, thermal

analysis, x-ray diffraction)

POLYMORPHS



If solubility is

<1mg/ml

Solubility:4°C and 37°C.

Preformulation Studies8. Solubility




Description Parts of solvent required for

one part of solute

Very soluble < 1

Freely soluble 1 - 10

Soluble 10 - 30

Sparingly soluble 30 - 100Slightly soluble 100 - 1000

Very slightly soluble 1000 - 10,000

Insoluble > 10,000



SOLUBILITY

Some aqueoussolubility

required fortherapeuticefficacy

Chemicalnature and

type of drug;chemical

modification

SOLUBILITYand PARTICLE

SIZE

SOLUBILITY

and pH




Points to consider:

• Salts prepared from strong acids orbases• Salts prepared from weaker acid or

base• Injections should ideally lie in the pH

range 3-9• Oral syrups should not be too acidic

Preformulation Studies8. Solubility: SALTS



SURFACTANT

low

concentration?

Very high

concentration?

Preformulation Studies8. Solubility: SURFACTANT



Endothermicreaction

Exothermicreaction

Preformulation Studies8. Solubility: EFFECT OF TEMPERATURE



PARTICLESIZE

Very coarse(#8)

Coarse(#20)

Moderatelycoarse(#40)

Fine (#60)

Very fine(#80)

Preformulation Studies8. Solubility: PARTICLE SIZE



Dissolution

rate Suspendability

Uniform

distribution

Penetrability Lack ofgrittiness

Preformulation Studies8. Solubility: PARTICLE SIZE



Preformulation Studies8. Solubility and pH

adjustment ofpH of solventwhere drug is

dissolved toadjustsolubility

Weak acidic

or basic drugs

pH onsolubility and

stability

cosolvents ,complexation,micronization,

or soliddispersion



Addition ofco-solvent

pH changemethod

Reduction ofparticle size

Temperaturechange

method

Addition ofSurfactant

Complexation

Preformulation Studies8. Solubility: INCREASE SOLUBILITY




PG, ehtanol,

glycerin, sorbitol,PEG, Glyceryl

formal, glycofurol,

ethyl carbamate,ethyl lactate and

dimethyl

acetamide.

For weak acidic

drug? For weak base

drug?

CO-SOLVENT pH CHANGE METHOD



Preformulation Studies8. Solubility: CO-SOLVENT

It must be non-toxic. Non-

irritating.

It should be

able tosolubilize thedrug in given

solvent.

It should be

able to crossthe

membrane.




ENDOTHERMICREACTION?

EXOTHERMICREACTION?




SURFACTANT

IONIC

Cationic

Anionic

ZwitterionicNON-IONIC




CATIONIC

Cetyl TrimethylAmmoniumBromide (CTAB)HexadecylTrimethylAmmonium

Bromide, andotherAlkyltrimethylAmmoniumSalts,CetylpyridiniumChloride (cpc)

ANIONIC

Sodium DodecylSulphate (SDS),AmmoniumLauryl Sulphateand other alkylsulfate salts,

SodiumLaurethSulphate, alsoknown asSodium LaurylEther Sulphate

(SLES).

ZWITTERIONIC

DodeclyBetamineand Dodecly

Dimethylamine Oxide



Preformulation Studies8. Solubility: SURFACTANT (HLB SCALE)

Most antifoaming agents

W/O Emulsifying agents

Wetting and Spreading agents

O/W Emulsifying agents

Detergents and Solubilizing agents

0

3

6

9

12

15

18

TWEEN(polyoxyethylen

ederivative of

span)

sorbitan

ester



Time for the drug to dissolve in the fluids atthe absorption site

• (rate-limiting step in absorption)• Can affect onset, intensity, and duration of response and

control overall bioavailability of the drug from the dosageform

Increasing dissolution rate:

• decreasing the particle size.

• use a highly water soluble salt of the parent substance.

Preformulation Studies9. Dissolution Rate

f l i S di



• 1st law: relates to a steady stateflow

• 2nd law: relates to a change in conc.of drug with time, at any distance,or a nonsteady state of flow

Fick’s law(law of

diffusion)

• Describes the relationship between

particle size, diffusion layercoefficient, and drug saturatedsolubility (Dissolution)

Noyes-WhitneyEquation

Preformulation Studies9. Dissolution Rate

P f l i S di



MembranePermeability

early assessmentof passage ofdrug moleculesacross biologic

membranes

drug molecule

must cross abiologic

membrane

The biologicmembrane (lipid

barrier) pKa, solubility, anddissolution rate

data can provide anindication ofabsorption.

EVERTEDINTESTINAL

SAC

Preformulation Studies10. Membrane Permealibility

P f l i S di



Preformulation Studies11. Partition Coefficient

octanol – water

partitioncoefficient

P f l i S di



Preformulation Studies12. pKa / Dissociation Constants

Extent ofdissociation or

ionization

Dependenton pH ofmedium

Can affect

absorption,distribution,

andelimination

P f l i S di



Can be calculated by Henderson Hasselbach

equation-

For acidic drugs….pH= pKa+ log [ionized drug]

[unionized drug]

For basic drugs….pH= pKa+ log[unionized drug]

[ionized drug]

Preformulation Studies12. pKa / Dissociation Constants



DRUG AND DRUG PRODUCT STABILITYStability is the extent to which a product retains within specified

limits and throughout its period of storage and use (i.e., its shelf

life) the same properties and characteristics that it possessed at the

time of its manufacture.



INSTABILITY

Undesired

change inperformance

Substantialchanges in

physicalappearance ofthe dosage form

Cause product

failures

Drug Stability: Mechanisms



Drug Stability: Mechanisms

of Degradation

Hydrolysis(solvolysisprocess)

(drug) moleculesinteract with watermolecule to yield

breakdown product.

esters, substitutedamides, lactones,

and lactams

Oxidation

loss of electronsfrom an atom or

molecule; involvesfree radicals

aldehydes, alcohols,phenols, sugars,

alkaloids &unsaturated fats &

oils

Photolysis

decompositionby light

1. suitable packing in

amber-coloured

bottles

2. cardboard outers

3. aluminium foil over

wraps

D d D P d t St bilit



Drug and Drug Product Stability:

A. Kinetics and Shelf Life

• active ingredient retains chemical integrityand labeled potency within the specifiedlimits.

CHEMICAL STABILITY

• original physical properties, appearance,palatability, uniformity, dissolution and

suspendability are retained.

PHYSICAL STABILITY

• sterility/resistance to microbial growthMICROBIOLOGICAL

STABILITY

• therapeutic effect remains unchangedTHERAPEUTIC

STABILITY

• no significant increase in toxicity occurs.TOXICOLOGIC

STABILIY





B. Rate Reactions

description of the drugconcentration with respect to time

ZERO ORDERKINETICS

(NONLINEARPHARMACOKINETICS)

FIRST ORDERKINETICS

(LINEARPHARMACOKINETICS)





C. Q10 METHOD

Q10

METHOD

AcceleratedStabilityStudies

estimate the shelflife of a product thathas been stored or

to be stored under adifferent set of

conditions.

the rate constantincreases for a

100C temp.increase



E N H

A N C I N

G D

R U

G

S T A B I

L I T Y



HYDROLYSIS OXIDATION

ENHANCING STABILITY



ENHANCING STABILITY

HYDROLYSIS

Reduction orelimination of

water

Tablet:

waterproofprotective

coating

pH: pH 5 & 6

Buffer ing

agent



ENHANCING STABILITY

HYDROLYSIS

unstable antibioticdrugs (aq. prepn

desired)

Tightly closedcontainers

l iqu id

formulat ion:

water replacedby substitute

liquids.

in jectable

produc ts :

anhydrous

vegetable oilsmay be used assolvent



ENHANCING STABILITY

OXIDATION

prepared indry state

packaged insealed

containers withair replaced by

inert gas

addantioxidants



alpha tocopherol,butylhydroxyanisole &

ascorbylparmitate

AQUEOUS PREPARATIONOLEAGINOUS/UNCTOUSPREPNS:

Na2SO3, NaHSO3,Na2S2O5, ascorbic

acid

ENHANCING STABILITY



OXIDATION

TRACE METALS

purification ofsource of

contaminant

complexing or

binding metal(chelating agents)

Ca disod edetate

& EDTA)

LIGHTlight-resistant or

opaquecontainers

TEMPE-RATURE

Cool place

pH Buffering agent

ENHANCING STABILITY



Conditions Temperature

Freezer -20°C – (-10°C)

Refrigerator 2°C - 8°C

Cold Not exceeding 8°C

Cool 8°C – 15°C

Warm 30°C – 40°C

Excessive Heat Above 40°C

NOTE: Article for storage in cool place – stored in refrigerator.

Article for storage in a controlled room temperature may be stored

in a cool place.

STORAGE TEMPERATURE

Other destructive process in



Other destructive process inpharmaceutical preparations

Reaction between

two or moreidentical molecules

with resultant

formation of new &

generally larger

molecule

(formaldhyde)

Decarboxylation

decomposition ofRCOOH & release of

CO2

Deamination

removal of nitrogencontaining group from

organic amine (ex.

Insulin)

POLYMERIZATION OTHER PROCESSES



Enumerate 3 The instability possibilities in

different formulations: (1 whole yellow paper)

1. Oral Solutions

2. Parenteral Preparations

3. Suspension

4. Emulsion

5. Semi-solid Preparations

6. Capsule and Tablets

ASSIGNMENT.



STABILITY TESTING

Requisite data to demonstrate and



Before approval for marketing, a product’s stability must

be assessed with regard to its formulation;

the influence of its pharmaceutical ingredients;

the influence of the container and closure;

the manufacturing and processing conditions (e.g., heat);

packaging components;

conditions of storage;

anticipated conditions of shipping, temperature, light, andhumidity;

and anticipated duration and conditions of pharmacy shelf

life and patient use

q

document the product’s stability



Expiration Date

The date placed on the immediate container

label of a drug product that designates thedate through which the product is expected

to remain within specifications

STABILITY TESTING



Duration Storage

Condition

Humidity

Long Term 12 mos. 25°C±2 60±5% RH

Intermediate 6 mos. 30°C±2 60±5% RH

Short Term 6 mos. 40°C±2 75% RH

STABILITY TESTING

Scientific data pertaining to the stability



Scientific data pertaining to the stability

of a formulation

leads to:

*prediction of the expected shelf-life of the

proposed product

*redesign of the drug (to more stable salt or

ester form)

*reformulation of the dosage form.



PHARMACEUTICAL INGREDIENTS

(EXCIPIENTS)

PHARMACEUTICAL INGREDIENTS &




EXCIPIENTS

Stabilizers (antioxidants and

chelating agents) – prevent

decomposition Solvents – used to dissolve the

drug substance

Flavors and Sweeteners – make

product more palatable

Colorants – enhance appeal

Preservatives – prevent

microbial growth

Diluents or fillers – to increase

bulk of the formulation

Binders – adhesion of thepowdered drug and

pharmaceutical substances

Antiadherents or lubricants –

assist smooth tablet formation

Disintegrating agents –

promote tablet breakup after

administration

FOR SOLUTIONS FOR TABLETS




HARMONIZATION OF STANDARDS

United States Pharmacopeia – National

Formulary (USP-NF)

British Pharmacopeia

European Pharmacopeia

Japanese Pharmacopeia


EXCIPIENTS

A d P l bili



Appearance and Palatability

Flavoring PharmaceuticalsColor, odor, texture, and taste must coincide/balance

In general, LMW salts are salty while HMW salts are bitter.

In organic chemistry, the more hydroxyl group present,

increase sweetness.

Different types of flavors: Natural, Artificial, Spice

Delaney Clause

Flavor Type of Drug

Cocoa Bitter drugs

Fruit or citrus Sour and acid-tasting drugs

Cinnamon, Orange, Raspberry &

others

Salty drugs

D l Cl



Delaney Clause

"No additive shall be deemed to besafe if it is found to induce cancer

when ingested by man or laboratoryanimals or if it is found, after tests

which are appropriate for theevaluation of the safety of food

additives, to induce cancer in man oranimals."

Fl S l i G id



Salty Butterscotch/Maple

Bitter Wild Cherry/Licorice

Chocolate Mint

Acrid/Sour Raspberry/Fruit

Berry/Acacia Syrup

Oily Peppermint/Anise

Wintergreen

Sweet Fruit/Berry/Vanilla

Acid Citrus

Flavor Selection Guide

S i Ph i l



Sweetening Pharmaceuticals

Dextrose

Mannitol

SaccharinSorbitol

Sucrose

S t i Ph ti l



Aspartame – - 1st artificial sweetener (1958 amendment)

w/ requirement for pre-marketing proof of safety.

- Aspartame breaks down in the body into three basic components:

phenylalanine, aspartic acid, and methanol.- Acesulfame potassium (nonnutritive sweetener)

- structurally similar to saccharin (USP approved)

-180 – 200 times as sweet as sucrose, excreted unchanged in

the urine;- more stable than aspartame

- Stevia (Stevia rebaudiana bertoni)

– new sweetening agent: natural, nontoxic, safe,

30x sweeter than cane sugar/sucrose


S t i Ph ti l



Saccharin & cyclamate - used in foods

-“generally recognized as safe” (before the

amendment’s passage)- use on rats: developed incidence of bladder

tumors (cancer)

- continued availability but warning labels be used

-cyclamates (banned) - possible carcinogenicity,

genetic damage, testicular atrophy


C l i Ph ti l



Coloring PharmaceuticalsUsed in pharmaceutical preparations for esthetics

Certain agents that are not pharmaceutical

colorantsSulfur (Yellow)

Riboflavin (Yellow)

Cupric sulfate (Blue)

Ferrous sulfate (Bluish green)

Cyanocobalamin (Red)

Red Mercuric iodide (Vivid Red)

Aniline dyes

Coloring Pharmaceuticals

C l i Ph ti l




Coal tar (pix carbonis)

- thick black viscid liquid

- by product of destructive distillation of coal.- source of synthetic coloring agents in pharm.

products in the middle of the 19th century

Dyes – added to pharmaceutical preps. in the

form of diluted solutions

Lakes - commonly used in the form of fine

dispersions or suspensions.

C l i Ph ti l




90% of the dyes used in the products - synthesized from

derivative of benzene (aniline)

FDA - regulates use color additives in foods, drugs, and

cosmetics (Federal Food, Drug, and Cosmetic Act of 1938)- FD&C color additives - foods, drugs, and cosmetics

- D&C color additives - drugs, some in cosmetics &

medical devices

- external D&C color additives - restricted to external parts

of the body (not including the lips and other parts that

are covered by mucous membrane)

F t i l ti d



Factors in selecting dyes

Solubility ofprospective dye

pH & pH stabilityof the preparation

to be colored

Dyes must bephotostable

PRESERVATIVES



PRESERVATIVES

liquid and semisolid preparations

- must be preserved against microbialcontamination.

St ili ti d P ti



Sterilization and Preservation

some types of pharmaceutical products

(ex. Ophthalmic and injectable

preparations)

- sterilized by physical methods :

*autoclaving (20min at 15 lb. press. &121°C, dry heat at 180°C for 1 hr)

*bacterial filtration.

Sterili ation and Preser ation



Preparations that provide excellent growth

media for microbes

- aqueous preparations: syrups, emulsions,

suspensions

- semi solid preparations particularly creams.

- hydro-alcoholic & most alcoholic preparation

*may not require addition of chemical

preservative





prevent microbial growth:

*15% alcohol in acid media

*18% alcohol in alkaline media.

Alcohol-containing pharmaceuticals (elixirs, spirits,

and tinctures) - self sterilizing and do not require

additional preservation.


Preservative Selection




Considerations in selecting preservative inpharmaceutical preparations:

1. Prevents the growth of the type ofmicroorganisms ( contaminants of the

preparations)2. Soluble enough in water to achieve adequate

concentrations in aqueous phase with two or morephase systems

3. Proportion of preservative remainingundissociated at the pH of preparation (canpenetrate the microorganism & destroy itsintegrity).





4. Concentration of the preservative does not

affect the safety/comfort of the patient

5. With adequate stability and not reduced in

concentration by chemical decomposition/volatilization

6. Compatible with all other formulative

ingredients and does not interfere with them7. Does not adversely affect the preparation’s

container or closure.





Dosage formRoute of

administration

Compatibilitywith

excipients

Container andclosure

compatibility

General Preservative Considerations



Range of

activity

Concentration

required

pHrequirements

Compatibility

General Preservative Considerations

Mode of action: Mechanisms preservative interfere



with microbial growth, multiplications, and metabolism:

1. Modifications of cell membranepermeability & leakage of cell constituents(partial lysis)

2. Lysis and cytoplasmic leakage

3. Irreversible coagulation of cytoplasmicconstituents

4. Inhibition of cellular metabolism byinterfering with enzyme systems/inhibition ofcell wall synthesis

5. Oxidation of cellular constituents andHydrolysis

PRESERVATIVES



PRESERVATIVES

Benzoic acid/sodium benzoateAlcohol Phenylmercuric nitrate/acetate

PhenolCresolChlorobutanol Benzalkonium chlorideMethylparaben/propylparabenOthers

PRESERVATIVES



PRESERVATIVE PROBABLE MODE OF ACTION

Benzoic acid, Boric acid, p-

hydroxybenzoates

Denaturation of proteins

Phenols and chlorinated phenoliccompounds

Lytic & denaturation action on cytoplasmicmembranes and for chlorinated preservatives,

also by oxidation of enzymes

Alcohols Lytic & denaturation action on membranes

Quaternary compounds Lytic action on mebranes

Mercurials Denaturation of enzymes by combining withthiol (-SH groups)

PRESERVATIVES



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IV. Pre Formulation