• Drug-solubility and dissolution rate• Particle size and effective surface area• Polymorphism and amorphism• Pseudopolymorphism (hydrates/solvates)• Salt form of the drug• Lipophilicity of the drug

• Drug pKa and pH

• Drug stability

Drug pKa and Lipophilicity and GI pH—pH Partition Hypothesis

The pH partition theory (for molecular weight greater than 100) explain the process of absorption of drug is governed by:

• The dissociation constant (pKa) of the drug.

• The lipid solubility of the unionized drug (a function of drug Ko/w)

• The pH at the absorption site.

drugs are weak electrolytes hypothesis was based on the assumption that:• The GIT is a simple lipoidal barrier to the

transport of drug.• Larger the fraction of unionized drug, faster

the absorption.

• Greater the lipophilicity (Ko/w) of the unionized drug, better the absorption.

Drug pKa and Gastrointestinal pH lower the pKa of an acidic drug, stronger the acid higher the pKa of a basic drug, the stronger the baseHenderson-Hasselbach equations for weak acids. ionized drug concentration

PH = pKa+ log --------------------------- unionized drug concentration 10 pH - pKa

% Drug Ionized = ----------------- x 100 1 + 10pH – pKa

for weak bases, unionized drug concentration

pH = pKa + log ----------------------------------- ionized drug concentration 10pKa - pH

% Drug Ionized = -------------- x 100 1 +10pKa-pH

Influence of drug pKa and GI pH on Drug AbsorptionDrugs pKa pH/site of absorptionVery weak acids (pKa > 8.0)Pentobarbital 8.1 Unionized at all pH valuesHexobarbital 8.2 absorbed along the entire

length of GITPhenytoin 8.3Ethosuximide 9.3

Moderately weak acid (pKa 2.5 to 7.5)Cloxacillin 2.7 Unionized in gastric pH and Aspirin 3.5 ionized in intestinal pH; betterIbuprofen 4.4 absorbed from stomachPhenylbutazone 4.5

Stronger acids (pKa < 2.5)

Disodium cromoglycate 2.0 Ionized at all pH values; poorly Absorbed from GIT

Very weak bases (pKa < 5.0)Theophylline 0.7 Unionized at all pH valuesCaffeine 0.8 absorbed along the entire length

of GITOxazepam 1.7Diazepam 3.7

Moderately weak bases (pKa 5 to 11.0)Reserpine 6.6 Ionized at gastric pH,Heroin 7.8 relatively unionized at intestinal

pH;Codeine 8.2 better absorbed from

intestine.Arnitriptyline 9.4

Stronger bases (pKa > 11.0)Mecamylamine 11.2 Ionized at all pH values;Guanethidine 11.7 poorly absorbed from GIT.

II. Dosage Form Characteristics and Pharmaceutic IngredientsDisintegration time (tablets/capsules)Dissolution timeManufacturing variablesPharmaceutic ingredients

(excipients/adjuvants)Nature and type of dosage formProduct age and storage conditions

II. Dosage Form Characteristics and Pharmaceutic IngredientsDisintegration time (DT)(tablets/capsules)

DT Dissolution Absorption Bioavailability

sugar coated tablet have long DT

DT of tablet dependent on binder/Compression Force (Hardness)

Disintegration is increase by using disintegrants agentManufacturing variables

Method of granulation

Wet granulation Dissolution more as compare to Dry granulation

Compression

Influence porosity, density, hardness, DT and dissolution

Higher compression

Pharmaceutic ingredients (excipients/adjuvants)

Vehicle – Aqueous Non aqueous water misibleNon aqueous water immiscible

III.PATIENT RELATED FACTORS Include factors relating to the anatomical

physiological and pathological characteristics of the patient

AgeGastric emptying timeintestinal transit timeGastrointestinal pHDisease statesBlood flow through the GITGastrointestinal contents