JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD B. Pharmacy IV BIOPHARMACEUTICS AND PHARMACOKINETICS Previous Question Paper (February-2022 - R17)

The gastrointestinal (GI) absorption of drugs is significantly influenced by various physico-chemical properties of the drug molecule. These factors determine the drug's ability to dissolve, partition across biological membranes, and remain stable in the GI environment.

Key physico-chemical factors include:

• Drug Solubility and Dissolution Rate: According to the Noyes-Whitney equation, the dissolution rate is directly proportional to the surface area and solubility of the drug. Poorly water-soluble drugs (BCS Class II and IV) often exhibit dissolution-rate-limited absorption. Micronization or salt formation can enhance dissolution.
• Particle Size: Reducing particle size increases the effective surface area available for dissolution. This is particularly critical for drugs with low aqueous solubility, where a smaller particle size leads to a faster rate of drug release into the GI fluids.
• Lipophilicity and Partition Coefficient: The lipid bilayer of the GI membrane acts as a lipophilic barrier. A drug must possess an optimal balance of lipophilicity to partition into the membrane. This is typically measured by the octanol-water partition coefficient (log P). Highly hydrophilic drugs have poor membrane permeability, while excessively lipophilic drugs may have poor aqueous solubility.
• Degree of Ionization (pKa): The pH-partition hypothesis states that only the unionized form of a drug can readily permeate the lipid membrane. The ratio of ionized to unionized drug is determined by the pKa of the drug and the pH of the GI environment (e.g., pH 1-3 in the stomach, pH 6-7.5 in the intestine) according to the Henderson-Hasselbalch equation. Weak acids are better absorbed in the stomach, while weak bases are better absorbed in the intestine.
• Molecular Weight and Size: Small molecules (generally < 500 Daltons) diffuse more easily across the GI membrane. Larger molecules or those with high molecular volume face increased resistance to passive diffusion.
• Chemical Stability: Drugs must remain stable in the acidic environment of the stomach and resist degradation by GI enzymes or microbial flora. Acid-labile drugs (e.g., omeprazole) require enteric coating to prevent premature degradation.
• Polymorphism and Amorphous Form: Different crystalline forms (polymorphs) of a drug exhibit different lattice energies and solubilities. The amorphous form is generally more soluble and has a higher dissolution rate than the crystalline form, though it may be less stable.
• Complexation and Adsorption: The formation of drug complexes (e.g., with bile salts or dietary components) can either enhance or inhibit absorption. Adsorption onto excipients like charcoal or kaolin can significantly reduce the bioavailability of the drug.

Drug absorption is the process by which a drug proceeds from the site of administration to the site of measurement (usually blood). The mechanisms of drug absorption across biological membranes are as follows:

1. Passive Diffusion (Non-ionic Diffusion)
It is the most common mechanism where drug molecules move from a region of higher concentration to lower concentration along the concentration gradient. It is a non-energy-requiring, non-saturable process.

Advantages: Simple, does not require energy, and is not saturable.

Disadvantages: Limited by the lipid solubility of the drug and the concentration gradient; not suitable for large or polar molecules.

2. Pore Transport (Convective/Filtration)
Small, water-soluble molecules pass through aqueous pores or channels in the membrane. It is driven by hydrostatic or osmotic pressure.

Advantages: Allows rapid transport of small, hydrophilic molecules like urea and water.

Disadvantages: Restricted by pore size; only effective for molecules with a low molecular weight.

3. Facilitated Diffusion
This involves a carrier protein that helps transport the drug across the membrane without consuming energy, moving down the concentration gradient.

Advantages: Faster than passive diffusion for specific molecules; highly selective.

Disadvantages: Saturable and subject to competitive inhibition by structurally similar compounds.

4. Active Transport
This mechanism uses energy (ATP) to transport drugs against a concentration gradient using carrier proteins.

Advantages: Allows absorption of drugs even against high concentration gradients; highly specific.

Disadvantages: Requires energy; saturable; susceptible to competitive inhibition.

5. Endocytosis (Pinocytosis/Phagocytosis)
The cell membrane engulfs the drug molecule, forming a vesicle that enters the cytoplasm. This is used for large macromolecules or particulate matter.

Advantages: Enables the transport of large, complex molecules or proteins that cannot cross membranes otherwise.

Disadvantages: Slow process; limited capacity; potential for degradation within lysosomes.

6. Ion-Pair Transport
Lipid-insoluble drugs form neutral ion pairs with endogenous substances (like mucin), increasing their lipid solubility to cross the membrane.

Advantages: Facilitates absorption of highly polar or ionized drugs.

Disadvantages: Dependent on the availability of counter-ions in the gastrointestinal tract.