• 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 base
Henderson-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
Absorption
Drugs pKa pH/site of absorption
Very weak acids (pKa > 8.0)
Pentobarbital 8.1 Unionized at all pH values
Hexobarbital 8.2 absorbed along the entire length of GIT
Phenytoin 8.3
Ethosuximide 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; better
Ibuprofen 4.4 absorbed from stomach
Phenylbutazone 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 values
Caffeine 0.8 absorbed along the entire length of GIT
Oxazepam 1.7
Diazepam 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 Ingredients
Disintegration time (tablets/capsules)
Dissolution time
Manufacturing variables
Pharmaceutic ingredients (excipients/adjuvants)
Nature and type of dosage form
Product age and storage conditions
II. Dosage Form Characteristics and
Pharmaceutic Ingredients
 Disintegration 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 agent
 Manufacturing 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 misible
Non aqueous water immiscible
 III.PATIENT RELATED FACTORS
Include factors relating to the anatomical physiological and
pathological characteristics of the patient
Age
Gastric emptying time
intestinal transit time
Gastrointestinal pH
Disease states
Blood flow through the GIT
Gastrointestinal contents