Physical-Chemical Factors Affecting Drug Absorption

1. SALMAN BIN ABDUL AZIZ UNIVERSITY COLLEGE OF PHARMACY Physical-Chemical Factors Affecting Drug Absorption • PHARMACEUTICS- IV • (PHT 414 ) • Dr. Mohammad Khalid Anwer L6

2. Physical-Chemical Factors Affecting Oral Absorption • Outline of Physical-chemical factors affecting oral absorption: • pH-partition theory • Lipid solubility of drugs • Dissolution and pH • Salts • Crystal form • Drug stability and hydrolysis in GIT • Complexation • Adsorption L6

3. pH - partition theory • For a drug to cross a membrane barrier it must normally be soluble in the lipid material of the membrane to get into membrane, also it has to be soluble in the aqueous phase as well to get out of the membrane. • Most drugs have polar and non-polar characteristics or are weak acids or bases. L6

4. pH - partition theory • For weak acid or basic drug, the solubility of the drug and the rate of absorption through the membranes (lining the GI tract) is controlled by: • the dissociation constant (pKa) of the drug • the pH of the fluid in the GI tract • the pH of the blood stream L6

5. pH of GIT & plasma fluid • control the process of its transfer across biomembrane. • This can be explained by the pH partition theory of Brodie (1957). • The theory is based on the assumption that only unionized drug moiety can cross biomembrane. L6

6. Distribution coefficient L6

7. Trans-membrane transfer L6

8. Henderson - Hasselbach equation • The amount of drug that exists in unionized form is a function of dissociation constant (pKa) of the drug and pH of the fluid at the absorption site • The ratio of un-ionized and ionized drug [U]/[I] is a function of the pH of the solution and the pKa of the drug, as described by the Henderson - Hasselbach equation L6

9. pH-pKa Relationship, Henderson -Hasselbach equation For weak acidic drugs: where HA is the weak acid and A- is the salt or conjugate base For weak basic drugs: where B is the weak base and HB+ is the salt or conjugate acid L6

10. For weak acidic drugs: = Ionized unionized For weak basic drugs = Unionized Ionized L6

11. For weak acids: Very weak acid (pKa > 8) such as phenytoin, ethosuximide and several barbiturates are essentially unionized at all pH values and therefore their absorption is rapid, and independent of GI pH. Acid in the pKa range 2.5-7.5 are greatly affected by changes in pH and therefore their absorption is pH dependent, e.g. several NSAIDs like aspirin, ibuprofen, phenylbutazone and number of penicillin analogs. Such drugs are better absorbed from acidic conditions of stomach (pH<pKa) where they largely exists in unionized form. Stronger acids with pKa < 2.5 such as cromolyn sodium are ionized in the entire pH range of GIT and therefore remain poorly absorbed. L6

12. For Basic drugs: Very weak bases (pKa < 5) such as caffeine, theophylin and a number of benzodiazepines like diazepam, oxazepam, and nitrazepam are essentially unionized at all pH values and therefore their absorption is rapid, and independent of GI pH. Bases in the pKa range 5-11.0 are greatly affected by changes in pH and therefore their absorption is pH dependent, e.g. several morphine analogs, chloroquine, imipramine and amitriptyline. Such drugs are better absorbed from the relatively alkaline conditions of intestine where they largely exists in unionized form. Stronger bases with pKa > 11 like mecamylamine and guanethidine are ionized in the entire pH range of GIT and therefore remain poorly absorbed. L6

13. Lipid solubility of drugs Some drugs are poorly absorbed after oral administration even though they are non-ionized in small intestine. Low lipid solubility of them may be the reason. The best parameter to correlate between water and lipid solubility is partition coefficient. Partition coefficient (p) = [ L]conc / [W]conc, where [ L]conc is the concentration of the drug in lipid phase, [W]conc is the concentration of the drug in aqueous phase. The higher p value, the more absorption is observed. Prodrug is one of the option that can be used to enhance p value and absorption as sequence. L6

14. Dissolution, pH • However, many drugs are given in solid dosage forms and therefore must dissolve before absorption can take place. • However, if dissolution is the slow, rate determining step (the step controlling the overall rate) then factors affecting dissolution will control the overall process. • This is a more common problem with drugs which have a low solubility (below 1 g/100 ml) or which are given at a high dose, e.g. griseofulvin. L7

15. Granules De-aggregation Tablet Disintegration ENDO-DISINTEGRANT EXO-DISINTEGRANT Fine particles DISSOLUTION Drug in solution Dissolution, pH Schematic representation of dissolution of a drug particle in the G.I. fluid L7

16. Theory of dissolution There are a number of factors which affect drug dissolution. One model that is commonly used is to consider this process to be diffusion controlled through a stagnant layer surrounding each solid particle. L7

17. Stagnant Layer L7

18. Theory of dissolution • First we need to consider that each particle of drug formulation is surrounded by a stagnant layer of solution. After an initial period we will have a steady state where drug is steadily dissolved at the solid-liquid interface and diffuses through the stagnant layer. • The earliest equation to explain the rate of dissolution when the process is diffusion controlled and involves no chemical reaction was given by Noyes Whitney • dC/dt= dissolution rate of the drug • K= dissolution rate constant • Cs= conc. of drug in the stagnant layer • Cb= conc. of drug in the bulk of the solution L6

19. Diffusion gradient/Concentration Gradient L6

20. If diffusion is the rate determining step we can use Fick's first law of diffusion to describe the overall process. • If we could measure drug concentration at various distances from the surface of the solid we would see that a concentration gradient is developed. • If we assume steady state we can used Fick's first law to describe drug dissolution. • The Noyes and whitney’s equation was based on Fick's second law of diffusion. Brunner incorporate Fick's first law of diffusion and modified the Noyes and whitney’s equation. L6

21. Modified Noyes-Whitney equation • where dC/dt is the rate of dissolution • D is the diffusion coefficient of the drug in solution in g.i. fluid • A, is the effective surface area of drug particle in contact with the g.i. fluid, • Kw/o= water/ oil partition coefficient of drug • V= volume of dissolution medium • h= thickness of stagnant layer • (Cs –Cb)= concentration gradient for diffusion of drug L6

22. Influence of some parameters on dissolution rate of drug • The diffusion coefficient, D, of a drug in the g.i. fluid may be decreased by presence of substances which increase the viscosity of the fluids such as food. • The thickness of the diffusion layer, h, will be influenced by the agitation experienced by drug particles due to gastric and/or intestinal motility. L6

23. A is the surface area per gram (or per dose) of a solid drug • A can be changed by altering the particle size. • Generally as A increases the dissolution rate will also increase. • Improved bioavailability has been observed with griseofulvin, digoxin, etc. L6

24. The concentration of drug, C, • will be influenced by the rate of removal of dissolved drug by absorption through the g.i./blood barrier and • the volume of fluid available for dissolution (fluid intake). • A low value of C will increase the concentration gradient and this forms the basis for the dissolution under the so called “sink” condition. L6

25. Dissolution under Sink condition • If Cb is much smaller than Cs then we have so-called "Sink Conditions" and the equation reduces to • Under sink conditions, if the volume and surface area of solid are kept constant dC/dt = K • Dissolution rate is constant, and follows Zero order kinetic process. L6

26. Effect of drug dissolution • Factors affecting rate of release/dissolution and hence, bioavailability from solid dosage forms: • The rate and extent at which the drug in solution reaches the site (s) of absorption in absorbable form • The rate and extent of absorption across the gastro-intestinal barrier • The extent to which the drug is metabolized during passage through the g.i.t. and/or liver. L6

27. Factor affecting dissolution (Physicochemical properties of drug )Drug solubility, Cs, Salt form • Dissolution rate increases with Cs • Salts of weak acids and weak bases generally have much higher aqueous solubility than the free acid or base • If the drug can be given as a salt the solubility and dissolution rate can be increased . • For example, sodium salt of tolbutamide gave in vitro dissolution rate significantly greater than the acid form. • Other examples are salt forms of penicillin, novobiocin and barbiturates. L6

28. Effect of salt form on solubility L6

29. Effect of salt form on dissolution rate L6

30. Physicochemical properties of drug • Crystal form • Polymorphism – • Some drugs exist in a number of crystal forms or polymorphs. These different forms may well have different solubility properties and thus different dissolution characteristics. • Drugs exhibiting polymorphism include chloramphenicolpalmitate, cortisone acetate, tetracyclines, sulphathiazole and paracetamol. • Chloramphenicolpalmitate is one example which exists in at least two polymorphs. The B form is apparently more bioavailable. L6

31. Effect of Crystalline/polymorphic form on dissolution rate of Chloramphenicol palmitate L6

32. Amorphous form (noncrystalline form): Amorphous form of novobiocin is effective while its crystalline forms are ineffective. • Ester form – Chloramphenicol, erythromycin & Pivaloyloxymethylester of ampicillin (Pivampicillin). L6

33. Physicochemical properties of drug (Cont) Solvates and hydrates: • The stoichiometric type of abducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates . • When the solvents are water then it called as hydrates. • For instance, the hydrous form of ampicillin showed greater extent of absorption from hard gelatin capsule or aqueous suspension dosage forms than the less soluble, slower dissolving crystalline form. L6

34. Drug stability and hydrolysis in GIT • Acid and enzymatic hydrolysis of drugs in GIT is one of the reasons for poor bioavailability. • Penicillin G (half life of degradation = 1 min at pH= 1) • Rapid dissolution leads to poor bioavailability (due to release large portion of the drug in the stomach, pH = 1.2) • Pro-drug ( conversion in the GIT to parent compound is rate limiting step in bioavailability, either positively or negatively). L6

35. Pro-drugs • Rationale: • I. A drug may be too water insoluble for i.v. dosage form. • Chemical modification may produce significant water solubility for its i.v. formulation • II. A drug required to alter some CNS function may be too polar and therefore not well absorbed across the lipoidal blood-brain-barrier. • III. Rapid metabolism of a drug at the site of absorption leading to a decrease in systemic bioavailability after oral dosing. L6

36. Complex form • Molecular complex consists of components held together by weak forces such as hydrogen bond • Bonding interaction between the two molecules is rapidly reversible, provided the complex is soluble in biological fluids. • Properties of drug complexes such as solubility, molecular size and lipid-water partition coefficient differ significantly from those of the respective free drugs. • Complexation is often a deliberate attempt in dosage form design to increase solubility or stability of the drug e.g. solid-in-solid complex. L6

37. Complex form (Cont.) • Complexation of a drug in the GIT fluids may alter rate and extent of drug absorption. • Intestinal mucosa + Streptomycin = poorly absorbed complex • Calcium + Tetracycline = poorly absorbed complex (Food-drug interaction) • Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed complex (tablet additive – drug interaction) • Polar drugs + complexing agent = well-absorbed lipid soluble complex ( dialkylamides + prednisone) • Lipid soluble drug + water soluble complexing agent = well-absorbed water soluble complex ( cyclodextrine) L6

38. Adsorption • Concurrent administration of drugs and medicinal substances containing solid adsorbents (e.g. antidiarrhoeal mixtures) may result in interference with the absorption of drugs in the git. • Drug may be adsorbed onto kaolin, attapulgite or charcoal with consequent decrease in the rate and extent of its absorption. • Examples of documented interactions are promazine/charcoal, lincomycin/kaopectate, talc/cyanocobolamin. L6