Formulation of Dosage Formulation of Dosage FormsForms

-Some Considerations-Some Considerations

Dr Naresh ChughDr Naresh Chugh

Ancee InternationalAncee International

MumbaiMumbai

Why Focus on PreformulationWhy Focus on Preformulation StabilityStability

Physical- (Interactions with excipients e.g. menthol and thymol)Physical- (Interactions with excipients e.g. menthol and thymol) Chemical – (interactions e.g.. Acids and bases)Chemical – (interactions e.g.. Acids and bases) Biochemical (Drug-drug incompatibilities)Biochemical (Drug-drug incompatibilities) Pharmacological (Stimulators and Depressors)Pharmacological (Stimulators and Depressors)

Safety (Therapeutic Index)Safety (Therapeutic Index) Acceptability Acceptability

(Palatability , size, dose etc e.g.. Piperazine citrate 30ml dose, (Palatability , size, dose etc e.g.. Piperazine citrate 30ml dose, Large tablets / Capsules etc) Large tablets / Capsules etc)

Desired Therapeutic ResponseDesired Therapeutic Response Immediate effect desired or long term relief desired e.g. relief of Immediate effect desired or long term relief desired e.g. relief of

pain from sports injuries or relief of pain due to arthritispain from sports injuries or relief of pain due to arthritis

What ParametersWhat Parameters

Study of evaluation Parameters likeStudy of evaluation Parameters like Possible Dosage formPossible Dosage form Dissolution KineticsDissolution Kinetics Disintegration of solid dosageDisintegration of solid dosage Suspension of drug powder Suspension of drug powder SolubilisationSolubilisation Drug IonisationDrug Ionisation Analytical MethodsAnalytical Methods

When PreformulationWhen Preformulation

After Impressive Biological ScreeningAfter Impressive Biological Screening After Development of Analytical MethodsAfter Development of Analytical Methods After Time related stability of drug After Time related stability of drug

componentcomponent Degradation components / StudiesDegradation components / Studies

Simultaneous studies should be conducted Simultaneous studies should be conducted for possible dosage form evaluationsfor possible dosage form evaluations

MethodologyMethodology

Sequencing Sequencing 1.1. Receipt of request for dosage formReceipt of request for dosage form

2.2. Determine the physical and chemical requirement of Determine the physical and chemical requirement of dosage form e.g. particle size, compressibility, etc.dosage form e.g. particle size, compressibility, etc.

3.3. Do literature survey on work done / methods Do literature survey on work done / methods adopted / suitable dosage formsadopted / suitable dosage forms

4.4. Determine Physical PropertiesDetermine Physical Properties

5.5. Macroscopic and microscopic examinationMacroscopic and microscopic examination

6.6. Polymorphs, solvatesPolymorphs, solvates

7.7. Solubility, pKa, Partition coefficient, Dissolution rateSolubility, pKa, Partition coefficient, Dissolution rate

MethodologyMethodology

1.1. Stability of pure drug component in normal and Stability of pure drug component in normal and exaggerated conditionsexaggerated conditions

2.2. Select the drug form most stable and check for Select the drug form most stable and check for biological efficacy biological efficacy

3.3. Go for checking lot to lot uniformity Go for checking lot to lot uniformity

4.4. Study of interaction with different excipients at Study of interaction with different excipients at normal conditions of temperature and humidity and normal conditions of temperature and humidity and at exaggerated conditionsat exaggerated conditions

5.5. Observe for new complexes and solvates being Observe for new complexes and solvates being formed formed

6.6. Prepare dosage forms Prepare dosage forms

Some ParametersSome Parameters Macroscopic ObservationsMacroscopic Observations

Crystalline or amorphous Crystalline or amorphous (for compression and suspensions)(for compression and suspensions)

AppearanceAppearance Colour (for liquid orals sp. e.g. charcoal )Colour (for liquid orals sp. e.g. charcoal ) Odour (for all except parenterals)Odour (for all except parenterals) Taste (For orals)Taste (For orals) Bulk density,Bulk density, Flow properties,Flow properties,

Microscopic ExaminationsMicroscopic Examinations Crystal form and sizesCrystal form and sizes Behaviour (agglomeration and aggregationBehaviour (agglomeration and aggregation Static charge developmentStatic charge development Physical impurities and / or chemical impurities Physical impurities and / or chemical impurities

and to certain extent % of total substance.and to certain extent % of total substance.

Some ParametersSome Parameters Particle SizeParticle Size

Drug DissolutionDrug Dissolution Phenacetin, Piroxicam, Phenacetin, Piroxicam,

Drug absorptionDrug absorption E.g. GriseofulvinE.g. Griseofulvin

Drug SolubilisationDrug Solubilisation Content uniformity, taste, Handling (e.g. Content uniformity, taste, Handling (e.g.

Amoxicillin and Ampicillin ) etc.Amoxicillin and Ampicillin ) etc.

Methods:Methods:i)i) Sieving (using different sieves)Sieving (using different sieves)ii)ii) Microscopy (calibrated slides)Microscopy (calibrated slides)iii)iii) Sedimentation (Using Stokes law)Sedimentation (Using Stokes law)iv)iv) Coulter Counter (Light Scattering)Coulter Counter (Light Scattering)

Some ParametersSome Parameters

pKa and Partition coefficientpKa and Partition coefficient pka important because related to the pka important because related to the

ionised and unionised form for drug ionised and unionised form for drug absorption and is affected by pH absorption and is affected by pH

pKa = pH –2.303 logpKa = pH –2.303 log1010( ionized )( ionized )

(unionized)(unionized) Partition coefficient shows the lipophilic / Partition coefficient shows the lipophilic /

Hydrophilic character of the drugHydrophilic character of the drug Complexing and release from complex (eg. Complexing and release from complex (eg.

Ionic complexes with resins for sustaining Ionic complexes with resins for sustaining or taste masking)or taste masking)

Some ParametersSome Parameters

Solubility: Solubility: Aqueous solubility essential for drug absorptionAqueous solubility essential for drug absorption Acid / Base solubility for stability e.g. vitaminsAcid / Base solubility for stability e.g. vitamins Ionic character of medium e.g. excess sodium Ionic character of medium e.g. excess sodium

ions cause solubilisation of drugs of acidic ions cause solubilisation of drugs of acidic character e.g. benzoic, citric, saccharin, chloride) character e.g. benzoic, citric, saccharin, chloride)

Salt or ester of drug for different property like Salt or ester of drug for different property like taste masking changes solubility and hence taste masking changes solubility and hence availabilityavailability

Drugs like Cetirizine (dihydrochloride), Drugs like Cetirizine (dihydrochloride), Piperazine (Citrate), Amodiaquine (di-HCl), etc.Piperazine (Citrate), Amodiaquine (di-HCl), etc.

pH based solubility e.g. Triametrene, Carbopol pH based solubility e.g. Triametrene, Carbopol