FACTORS AFFECTING ABSORPTION OF DRUGS

1. FACTORS AFFECTING ABSORPTION OF DRUGS

2. FACTORS AFFECTING GI ABSORBTION OF A DRUG FROM ITS DOSAGE FORM PATIENT RELATED FACTORS PHARMACEUTIC FACTORS PHSICOCHEMICAL PROPERTIES OF DRUG SUBSTANCES DOSAGE FORM CHARACTERISTICS &PHARMACEUTICAL INGREDIENTS

3. PHARMACEUTIC FACTORS

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6. Physicochemicalproperties of drugsubstances

7. 1.Drug Solubility and Dissolution Rate : • For hydrophobic drugs i.e. poorly aqueous soluble drugs dissolution is the rate determining step (RDS). • Absorption of such drugs is called as dissolution rate limited. • Eg : Griseofulvin, Spironolactone. • For hydrophilic drugs i.e. drugs with high aqueous solubility permeation through biomembrane is the RDS. • Absorption of such drugs is called as permeation rate limited or trans membrane rate limited. • Eg: Cromolyn Sodium, Neomycin.

8. The two rds in the absorption of drugs from orally administered formulations disintegration or permeation across deaggregation dissolution the biomembrane RDS for RDS for hydrophobic hydrophilic drugs drugs Drug in solution at the absorption site Drug in the body Solid dosage from Solid drug particles

9. Based on the intestinal permeability and solubility of drugs, Amidon et al developed Biopharmaceutics Classification System (BCS).

10. Definitions Absolute/intrinsic solubility Defined as maximum amount of solute dissolved in a given solvent under standard condition of temperature pressure and pH static property. Dissolution Process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase.

11. Rate of dissolution: The amount of drug substance that goes in solution per unit time under standardized conditions of temperature, pH, constant solid surface area and solvent composition. Dynamic property. Ex:Cisaparide low solubility- but sufficient oral bioavailability. This because rapid dissolution rate despite low intrinsic solubility.

12. Theories of Drug Dissolution • Diffusion layer model/Film theory. • Danckwert’s model/Penetration or surface renewal theory. • Interfacial barrier model/Double barrier or Limited solvation theory.

13. Diffusion layer model/Film Theory It involves two steps : • Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug at the solid liquid interface. • Diffusion of the soluble solute from the stagnant layer to the bulk of the solution, this is RDS in drug dissolution.

14. The rate of dissolution is given by Noyes and Whitney : dc dt Where, dc/dt= dissolution rate of the drug K= dissolution rate constant Cs= concentration of drug in stagnant layer Cb= concentration of drug in the bulk of the solution at time t K (Cs- Cb) =

15. Modified Noyes-Whitney’s Equation : dc dt Where, D= diffusion coefficient of drug. A= surface area of dissolving solid. Kw/o= water/oil partition coefficient of drug. intrinsic dissolution rate constant V= volume of dissolution medium. h= thickness of stagnant layer. (Cs – Cb )= conc. gradient for diffusion of drug. DAKw/o(Cs – Cb) Vh =

16. This is first order dissolution rate process, for which the driving force is concentration gradient. • This is true for in-vitro dissolution which is characterized by non-sink conditions. • The in-vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation i.e. Cb=0 and rate of dissolution is maximum. • Under sink conditions, if the volume and surface area of the solid are kept constant, then dC dt • This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics. = K

17. Dissolution rate under non-sink & sink conditions

18. Hixson-Crowell’s cubic root law • The Noyes-Whitney’s equation assumes that the surface area of the dissolving solid remains constant during dissolution, which is practically not possible for dissolving particles. • Hixson-Crowell’s cubic root law accounts for particle size decrease and change in surface area accompanying dissolution. W01/3 – W1/3 = Kt Where, W0=original mass of the drug. W=mass of drug remaining to dissolve at time t K=dissolution rate constant.

19. Danckwert’s model / Penetration or surface renewal theory • Danckwert’s did not approve the existence of stagnant layer because of liquid turbulence. • Takes into account the eddies or packets that are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution. • These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory.

20. D dm dt A (Cs - Cb). = = γ V The Danckwert’s model is expressed by equation dc dt Where, D= Diffusivity m = mass of solid dissolved Gamma (γ) = rate of surface renewal

21. Interfacial barrier model/Double barrier or limited solvation theory • Diffusion layer model and the Danckwert’s model were based on two assumptions: • The rate-determining step that controls dissolution is the mass transport. • Solid-solution equilibrium is achieved at the solid/liquid interface. • An intermediate concentration can exist at the interface as a result of solvation mechanism • As the activation energy required is more for solid therefore the rate of solubility of solid in the liquid becomes rate limiting rather then diffusion of dissolved solids

22. The concept of this theory is explained by following equation G = Ki (Cs - Cb) G = dissolution rate per unit area Ki = effective interfacial transport constant.

23. Particle size & Effective surface area • Particle size and surface area of a solid drug are inversely related. • Two types of surface area • Absolute surface area • Effective surface area • Absolute surface area which is the total area of solid surface of any particle. • Effective surface area which is the area of solid surface exposed to the dissolution medium.

24. Hydrophilic Drugs • Micronisation reduce particle size & surface of such particles have high energy than the bulk of the solid resulting increased interaction with the solvent • Micronisation of hydrophilic drugs results in ↑ dissolution rate in comparison to the simple milled form of these drugs. • Decreased dose, increased absorption efficiency Ex: Griseofulvin reduced to half and Spironolactone decreased 20 times

25. Hydrophobic drugs • Micronisation of hydrophobic drugs (aspirin, phenacetin) decrease effective surface area of powders resulting fall in dissolution rate Reasons: • Surface of the drug adsorbs air onto their surface which inhibits wettability. • The particles re-aggregate to form larger particles due to their high surface free energy which either float on the surface or settle down

26. Overcome • Use of surfactant as a wetting agent, decreases the interfacial tension & displaces the adsorbed air with the solvent. • Polysorbate80 increases the bioavailability of phenacetin • Adding hydrophilic diluents such as PEG, PVP, Dextrose etc which coat the surface of hydrophobic drug particles and render them hydrophilic.

27. 3.Polymorphism • Depending on the internal structure a solid can exist either in a crystalline or amorphous. • Substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as polymorphism Polymorphs are two types • Enantiotropic polymorphis the one which can be reversibly changed into another form by altering the temperature or pressure. ex: sulphur • Monotropic polymorphis the one which is unstable at all temperatures and pressures eg: glyceryl stearates.

29. Polymorphism • Polymorphs differs in physical properties, solubility, Melting point, density, hardness and compression characteristics • They are determined by techniques like optical crystallography, x-ray diffraction, differential scanning calorimetry etc. • One of the polymorphic forms will be physically more stable than others such a stable polymorphic represents the lowest energy state, has highest MP & least aqueous solubility. • other forms are metastable, low MP have greater solubility they show better availability and are preferred in formulation • Ex. chloramphenicol palmitate A,B,C,D. B shows best bioavailability & A is virtually inactive biologically

30. 3.1 Amorphous form • Drugs also exist as amorphous form have greater aqueous solubility than the crystalline forms energy required to transfer a molecule from lattice is greater than that required for amorphous • Ex: Cortisone acetate is 3 times more soluble than crystalline form • Order of dissolution is Amorphous>metastable>stable

31. 4.Pseudopolymorphism • When the solvent molecules are incorporated in the crystal lattice of the solid - solvates • Solvates can exist in different crystalline form called as pseudopolymorphs. The phenomenon is called pseudopolymorphism. 4.1.Hydrates and Solvates • In case entrapped Solvent is water then it is referred as Hydrate • Anhydrous form of the drug has greater aqueous solubility then the hydrates. (because already in interaction with water have less energy for crystal break up in comparison to the anhydrates). • Solvates differ in their physical parameters.

32. 5.Salt form of the drug • Most of the drugs are either weak acids or weak bases. One of the easiest approaches to enhance the solubility and dissolution rate is convert them into their salt forms. • Weakly acidic drugs, a strong base salt is prepared such as the sodium and potassium salts of barbiturates and sulphonamides. • Weakly basic drugs a strong acid salt is prepared like the hydrochloride or sulphate salts of several alkaloidal drugs. • At a given pH , the solubility of a drug, whether acidic/basic or its salt form is a constant.While considering the salt form of drug, pH of the diffusion layer is imp not the pH of the bulk of the solution

33. Consider the case of a salt of a weak acid. At any given pH of the bulk of the solution, the pH of the diffusion layer (saturation solubility of the drug) of the salt form of a weak acid will be higher than that observable with the free acid form of the drug (can be practically observed in the laboratory). Owing to the increased pH of the diffusion layer, the solubility and dissolution rate of a weak acid in this layer is promoted; since it is a known fact that higher pH favours the dissolution of weak acids. The hydrogen ion concentration of the bulk is [H+] , is not equal to hydrogen concentration of the diffusion layer [H+] d . [H+] d < [H+] for weak acid. [H+] d >[H+] for weak bases.

34. Increases or decrease in the pH of the diffusion layer is due the buffering action of strong cation or anion, which promotes ionization hence ↑ solubility and dissolution of weak acid or base. • When soluble ionic form moves into the bulk solution the pH is lower or higher resulting in ppt of weak acid or base in form of fine particles which has increased surface area resulting in increased solubility

35. Factor that influences the solubility of salt forms of the drug is the size of the counter ion. Generally speaking smaller the size of the counter ion, greater the solubility of the salt 35

36. The principle of in situ salt formation has been utilized to enhance the dissolution and absorption rate of certain drugs like aspirin and penicillin from buffered alkaline tablets. The approach is to increase the pH of the microenvironment of the drug by incorporating buffer agents and promote dissolution rate. Apart from the enhanced bioavailability, buffered aspirin tablets have two more advantages: firstly, the gastric irritation and ulcerogenic tendency of the drug is greatly reduced, and secondly, the problem with the use of sodium salt of aspirin (to enhance the solubility) which otherwise has poor hydrolytic stability, is overcome by in situ salt formation.

37. pH PARTITION THEORY : The theory states that for drug compound of moleculerweight greater than 100, which are primarily transported across the bio-membrane by passive diffusion ,the process of absorption is governed by • Dissociation constant pKa of drug. • Lipid solubility of the unionized drug (KO/W). • pH of absorption site. Hypothesis was based on the assumptions: • GIT is simple lipoidal barrier. • Larger the fraction of unionized drug, faster the absorption. • Greater the lipophilicity (KO/W) of unionized drug better the absorption.

38. HENDERSON HASSELBATCH EQUATION Amount of drug that exist in unionized and ionized form is a function of pKa of drug & pH of the fluid at the absorption site.It can be determined by Henderson-Hasselbach equation pH = pKa +log [ionized form] For, Acidic drugs [Unionized form] pH = pKa + log [unionized form] For, Basic drugs [Ionized form] Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have > 99% of unionized form . Weak base quinine (pKa=8.5) will have very high ionization in gastric pH .

39. INFLUENCE OF DRUG DISSOCIATION & GI PH ON ABSORPTION

40. Lipid solubility of drugs: • Some drugs are poorly absorbed after oral administration even though they are unionized in small intestine. Low lipid solubility 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 • Optimum absorption occurs, if the structure has aqueous solubility to dissolve & lipid solubility to facilitate partition lipoidal membrane ie. HLB in structure for optimum bioavailability

41. Limitations pH partition hypothesis: 1 Presence of Virtual Membrane • S- shaped pH absorption curves obtained due dissociation for experimented & predicted are different • Presence of Virtual Membrane pH or the micro-climate pH, different from the luminal pH which exists at the membrane surface.

42. 2. Absorption of the ionized drug • Despite of the assumption that only un-ionized and lipophilic drugs are absorbed to a greater extent, some drugs e.g. Morphinan derivatives which are much more ionized are absorbed passively • Structure has very high lipophilicity. • 3. Influence of the GI surface area and residence time of the drug: • Irrespective of the GI pH and degree of ionization, both acidic and basic drugs are more rapidly absorbed from the intestine. • Primarily because of its large surface area and secondly, because of the long residence time of the drug in the intestine.

43. 4. Presence of Aqueous Unstirred Diffusion Layer: • Drugs having a large partition co-efficient can readily penetrate the lipid membrane. • But the predicted & obtained are different • Diffusion through the unstirred water layer is the rate limiting step in their absorption. • Particular true for high molecular weight fatty acids and bile acids.

44. 8.Drug stability • A drug for oral use may destabilize either during its shelf-life or in the GIT resulting in poor bioavailability. • Degradation of drug into inactive form by interaction with one or more different component(s) to form a complex that is poorly soluble or is un-absorbable 9.Stereochemical nature of drug: • Enantiomers possess identical physical and chemical properties despite significant differences in spatial configuration. • Stereoselectivityis not expected effect during passive absorption of enatiomers.

45. This is not generally true if an active or receptor-mediated process is involved. • Absorption may exhibit stereo selectivity , giving rise to the possibility of competitive interaction between enatiomers. • Ex. intestinal absorption of D-cefalexin via dipeptide transport system can be inhibited by its L-enatiomer.

46. DOSAGE FORM CHARACTERISTICS AND PHARMACEUTICINGREDIENTS

47. 1. DISINTEGRATION TIME

48. Solid dosage form should conform to disintegration time, otherwise leads to slower dissolution resulting in insufficient the absorption resulting in bioavailability problems • Rapid disintegration is important in therapeutic success of solid dosage form. • Disintegration time of the tablet is directly related to the amount of binder present and compressional force of the tablet. • Disintegration can be aided by incorporating disintegrants in suitable amounts during formulation. • Dissolution in such fine particles is faster than that from granules.

49. 2.MANUFACTURING VARIABLES Solid dosage form related factors that influence dissolution: • Excipients • Manufacturing process Manufacturing processes • Tablet : method of granulation ,compression force • Capsule: intensity of powder packing Method of granulation Wet granulation Limitations • Formation of crystal bridge by the presence of liquid • Liquid may cause process like hydrolysis • Dry step may effect thermolabile substances • Method & duration of blending • Method, time & temperature of drying

50. Direct compression • Agglomerative phase of communition • Involves grinding of drugs in a ball mill for time long enough to affect spontaneous agglomeration. • Tablet produced will be stronger and show rapid dissolution • Attributed- increase in internal surface area Compression force(CF) • CF employed in tableting influences density, porosity, hardness - DT and dissolution of tablets. • Higher CF increases density & hardness of tablet, decreases porosity and hence↓ penetrability