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Pathway of Absorption

Pathway of Absorption. epithelium. connective tissue, muscle. endothelium. blood. Cell Membrane. Absorption. Affected by drug chemical physical properties dissolution rate (solids) hydrophilicity/hydrophobicity physiological factors route of administration drug distribution.

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Pathway of Absorption

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  1. Pathway of Absorption epithelium connective tissue, muscle endothelium blood

  2. Cell Membrane

  3. Absorption Affected by • drug chemical physical properties • dissolution rate (solids) • hydrophilicity/hydrophobicity • physiological factors • route of administration • drug distribution

  4. Solubility • significance • drugs must be in solution before they can be absorbed • drugs of low aqueous solubility present formulation problems • saturation concentration, Csat • limit of solubility of a solute in a solvent at a given T

  5. Csat C = Cb Dissolution Rate • important for tablets, solids • slow dissolution rate = low bioavailability • consider a solid particle in water stagnant water layer Noyes-Whitney Eqn

  6. Dissolution Rate But, surface area changes with time. • for spherical particles • for N particles r = radius at time t ro= initial radius r = density M = mass of particles k = cube-root dissolution constant

  7. Factors influencing Csat • crystal structure : polymorphism • salt form • pH • solvate formation

  8. crystal solid + solvent + dissolved solute Process of Dissolution

  9. Crystalline Solids • regular, ordered structure • composed of identical repeating units - unit cell • ex. cubic, rhombic, tetragonal • have distinct melting pts • strength of bonds between atoms, molecules determines : • geometry of unit cell • Tf,

  10. Crystalline Solids • Electrostatic, Covalent Bonds • ex. NaCl, graphite (C4) • strong bonds - cubic unit cell • hi Tf, hi (eg. Tf= 801°C for NaCl) • stable structure • hard, brittle

  11. Crystalline Solids • Van der Waals, H-bonds • ex. organic compounds • weak bonds • low Tf, low (ex. Tf = 238°C for caffeine) • soft materials • metastable structures

  12. Polymorphism • molecule can crystallize into more than one crystal structure • metastable form transforms to stable form over time • usually nonreversible process - monotropic polymorphism • many polymorphic forms possible • progesterone - 5 • nicotinamide - 4 • dissolution rate changes with polymorphic form

  13. Amorphism • no crystal structure • no distinct Tf • supercooled liquids - subdued molecular motion • flow under an applied pressure • generally easier to dissolve

  14. Crystal Hydrates • solvent trapped when compound crystallizes - solvates • solvent is water - hydrates • no water - anhydrate • solvent-compound interactions • H2O further stabilizes lattice - polymorphic solvates • H2O occupies void spaces - pseudopolymorphic solvates

  15. anhydrate has higher Tf, generally dissolves faster

  16. Significance • incorporation of H2O affects bioabsorption rate and  bioactivity

  17. Drug Salt Form • salt solubility depends on nature of counter-ion

  18. Slightly Soluble Electrolytes • ex. Al(OH)3, Ca2CO3, ZnO AgCl(s) Ag+(L) + Cl-(L) Ksp = [Ag+] [Cl-] = 1.25(10-10) at 25°C Al(OH)3 Al3+(L) + 3OH-(L) Ksp = [Al3+] [OH-]3 = 7.7(10-13) at 25°C beware of common ion effect (salting-out)

  19. pH and solubility • weakly acidic drug • pHp  the pH below which the drug precipitates from solution • weakly basic drug • pHp  the pH above which the drug precipitates from solution

  20. Other solubility issues • cosolvents • solvents which, when combined, increase the solubility of a given compound • ex. phenobarbital in water has a solubility of 0.1g/100 ml, in alcohol 1 g in 10 ml, and in 20% alcohol/water 0.3 g/100 ml • combined effect of pH and cosolvent • adding alcohol to buffered solution of weak electrolyte increases solubility of undissociated form • decreases pHp for a weakly acidic drug

  21. distribution coefficient, K • for absorption into cell, drug must pass through lipid cell membrane • consider two immiscible phases (oil and water) and a drug which is soluble in both (ex. cyclosporine), at equilibrium. oil water ideal and ideally dilute solutions :

  22. pH and Ko/w • dissociated portion of drug does not dissolve in oil phase • true distribution coefficient • effective distribution coefficient

  23. as change pH, add common ion, [HA]w changes weak acid : weak base :

  24. Clinical Significance of Ko/w • prediction of absorption of drugs through various tissues • absorption of acidic drugs from colon • absorption of basic drugs from small intestine

  25. absorption of components into polymers • plastic bottles • PVC i.v. bags • desorption of plasticizers from polymers • PVC i.v. bags

  26. Diffusion across a membrane • skin, buccal mucosa, cell membrane… Cd C1 C Cr C2 x distance

  27. Diffusion across a membrane • when Cr << Cd • P = permeability (cm/s) = Ko/w D/x

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