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Factors affecting drug absorption part ii

The document discusses several physicochemical properties of drugs that influence drug absorption, including drug solubility, particle size, polymorphism, salt form, lipophilicity, pKa, and stability. It focuses on how the pH-partition hypothesis relates drug pKa and lipophilicity to gastrointestinal (GI) pH and passive drug absorption across the GI epithelium. The pH-partition hypothesis states that only the unionized, lipid-soluble form of a drug can passively diffuse across membranes. The document also notes limitations of this hypothesis and discusses how dosage form characteristics like disintegration time and excipients can impact drug absorption.

Science◦
Dr. Nilesh S. Kulkarni Associate Professor in Pharmaceutics PES Modern college of Pharmacy For Ladies Moshi Pune 9/21/2021
Physicochemical properties of drug 1. Drug solubility and dissolution rate 2. Particle size and effective surface area 3. Polymorphism and amorphism 4. Pseudopolymorphism (hydrates/solvates) 5. Salt form of the drug 6. Lipophilicity of the drug 7. pKa of the drug and gastrointestinal pH 8. Drug stability 9. Stereochemical nature of the drug PHARMACEUTICAL FACTOR 9/21/2021
Drug pKa and Lipophilicity and GI pH—pH Partition Hypothesis - According to the pH-partition hypothesis, the gastrointestinal epithelia acts as a lipid barrier towards drugs which are absorbed by passive diffusion, and those that are lipid soluble will pass across the barrier. Brodie et al. “The theory states that for drug compounds of molecular weight greater than 100, which are primarily transported across the biomembrane by passive diffusion, the process of absorption is governed by: dissociation constant (pKa) of the drug, lipid solubility of the unionised drug (a function of drug Ko/w) and The pH at the absorption site. 9/21/2021
Most drugs are weak electrolytes (weak acids or weak bases), their degree of ionisation depends upon the pH of the biological fluid. If the pH on either side on the membrane is different, then the compartment whose pH favours greater ionisation of the drug will contain greater amount of drug, and only the unionised or undissociated fraction of drug, if sufficiently lipid soluble, can permeate the membrane passively until the concentration of unionised drug on either side of the membrane becomes equal i.e. until equilibrium is attained. The above statement of the hypothesis was based on the assumptions that: 1. The GIT is a simple lipoidal barrier to the transport of drug. 2. Larger the fraction of unionised drug, faster the absorption. 3. Greater the lipophilicity (Ko/w) of the unionised drug, better the absorption. 9/21/2021
Drug pKa and Gastrointestinal pH The lower the pKa of an acidic drug, stronger the acid i.e. greater the proportion of ionised form at a particular pH. Higher the pKa of a basic drug, stronger the base i.e. greater the proportion of ionised form at a particular pH. The knowledge of pKa of drug and pH at the absorption site (or biological fluid), the relative amount of ionised and unionised drug in solution at a particular pH and the percent of drug ionised at this pH can be determined by Henderson-Hasselbach equations: 9/21/2021
WEAK ACIDS WEAK BASE If there is a membrane barrier that separates the aqueous solutions of different pH such as the GIT and the plasma, then the theoretical ratio R of drug concentration on either side of the membrane can be given by equations derived by Shore et al: WEAK ACIDS WEAK BASE 9/21/2021
Drugs pKa pH/site of absorption Very weak acids e.g. Pentobarbital Hexobarbital >8 Unionized at all pH values; Absorbed along the entire length of GIT Moderately weak acids e.g. aspirin Ibuprofen 2.5 – 7.5 Unionized in gastric pH & ionized in intestinal pH; better absorption from stomach Stronger acids E.g. disodium Cromogylate < 2.0 Ionized at all pH values; Poorly absorbed from GIT Very weak bases e.g. Theophylline Caffeine < 5.0 Unionized at all pH values; Absorbed along entire GIT Moderately weak bases e.g. codeine 5 – 11 Ionized at gastric pH, unionized at intestinal pH; better absorption from intestine. Stronger bases e.g. Guanethidine > 11 Ionized at all pH values; Poorly absorbed from GIT 9/21/2021
Influence of Drug pKa and absorption 9/21/2021
Total aqueous solubility, ST, of an IONISABLE DRUG is an important factor in the passive absorption of drugs. It is defined as the SUM OF CONCENTRATION OF IONISED DRUG IN SOLUTION AND CONCENTRATION OF UNIONISED DRUG IN SOLUTION. The solubility of unionised form of the drug is known as the intrinsic solubility of the drug. If Sa is the intrinsic solubility of weakly acidic drugs and Sb that of weakly basic drugs, TOTAL AQUEOUS SOLUBILITY ACIDS BASE 9/21/2021
9/21/2021
Lipophilicity and Drug Absorption The degree of ionisation at a particular pH and that only the unionised drug, if sufficiently lipid soluble, is absorbed into the systemic circulation. if the drug exists in the unionised form, it will be poorly absorbed if it has poor lipid solubility (or low Ko/w) Systemic Circulation GASTROINTESTINAL TRACT CELL MEMBRANCE 9/21/2021
ACIDS BASE 9/21/2021
Limitations of the pH-partition hypothesis 1. Presence of virtual membrane pH 2. Absorption of ionised drug 3. Influence of GI surface area and residence time of drug 4. Presence of aqueous unstirred diffusion layer PRESENCE OF VIRTUAL MEMBRANE pH 9/21/2021
PRESENCE OF AQUEOUS UNSTIRRED DIFFUSION LAYER Aqueous Bulk Fluid of the GIT Aqueous Unstirred Layer Lipoidal Layer (Cell Membrane) Blood Limitations of the pH-partition hypothesis 9/21/2021
ABSORPTION OF IONISED DRUG INFLUENCE OF GI SURFACE AREA AND RESIDENCE TIME OF DRUG Limitations of the pH-partition hypothesis 9/21/2021
DRUG PERMEABILITY AND ABSORPTION M = amount of drug absorbed Peff = effective membrane permeability A = surface area available for absorption Capp = Apparent Luminal Drug Concentration tres = residence time of Drug in GI lumen The three major drug characteristics that determine the passive transport or permeability of drugs across intestinal epithelium are Lipophilicity of drug expressed as log P. Polarity of drug which is measured by the number of H-bond acceptors and number of H-bond donors on the drug molecule. Molecular size. 9/21/2021
Rule of Five by LIPINSKI ET AL which is written as – Molecular weight of drug ≤ 500 Lipophilicity of drug, log P ≤ 5 Number of H-bond acceptors ≤ 10 Number of H-bond donors ≤ 5 For a given drug, if any two of these values is greater than that specified above, then oral absorption may be significant problem. DRUG PERMEABILITY AND ABSORPTION 9/21/2021
Dosage form, dosage form related, pharmaceutical excipient (Pharmaco Technical Factor) 1. Disintegration time (tablets/capsules) 2. Dissolution time 3. Manufacturing variables 4. Pharmaceutical ingredients (excipients/adjuvants) 5. Nature and type of dosage form 6. Product age and storage conditions PHARMACEUTICAL FACTOR 9/21/2021
1. Disintegration Time: Coated tablets especially sugar coated have longer DT. DT is directly proportional to the amount of binder present and the compressional force of the tablet. 2. Manufacturing /Process variables: Manufacturing process that affects the DT are : a. Method of granulation. b. Compressional force. 9/21/2021
3. Pharmaceutical ingredients: Excipients used to ensure the acceptability, physicochemical stability during the shelf life, uniformity of composition and dosage, and optimum bioavailability and functionality of the drug product. a. Vehicles b. Diluents c. Binder and granulating agents d. Disintegrants e. Lubricants f. Coating g. Suspending Agents h. Surfactants 4. Nature and type of Dosage form: As a general rule, the bioavailability of a drug from various dosage form decreases in the following order: Solution > Emulsion > Suspension > Capsules > Tablets > Coated tablets > Enteric Coated tablets > Sustained Release products. 9/21/2021