1. CHEE 4401 Pathway of Absorption blood endothelium epithelium connective tissue, muscle

2. CHEE 4402 Cell Membrane

3. CHEE 4403 Absorption Affected by u drug chemical physical properties ä dissolution rate (solids) ä hydrophilicity/hydrophobicity u physiological factors ä route of administration ä drug distribution

4. CHEE 4404 Solubility u significance ä drugs must be in solution before they can be absorbed ä drugs of low aqueous solubility present formulation problems u saturation concentration, C sat ä limit of solubility of a solute in a solvent at a given T

5. CHEE 4405 Dissolution Rate u important for tablets, solids u slow dissolution rate = low bioavailability u consider a solid particle in water stagnant water layer C sat C = C b Noyes-Whitney Eqn

6. CHEE 4406 Dissolution Rate But, surface area changes with time. u for spherical particles u for N particles r = radius at time t r o = initial radius  = density M = mass of particles  = cube-root dissolution constant

7. CHEE 4407 Factors influencing C sat u crystal structure : polymorphism u salt form u pH u solvate formation

8. CHEE 4408 Process of Dissolution + crystal solid solvent dissolved solute +

9. CHEE 4409 Crystalline Solids u regular, ordered structure ä composed of identical repeating units - unit cell »ex. cubic, rhombic, tetragonal u have distinct melting pts u strength of bonds between atoms, molecules determines : ä geometry of unit cell ä T f,

10. CHEE 44010 Crystalline Solids u Electrostatic, Covalent Bonds ä ex. NaCl, graphite (C 4 ) ä strong bonds - cubic unit cell  hi T f, hi  (eg. T f = 801°C for NaCl) ä stable structure ä hard, brittle

11. CHEE 44011 Crystalline Solids u Van der Waals, H-bonds ä ex. organic compounds ä weak bonds  low T f, low  (ex. T f = 238°C for caffeine) ä soft materials ä metastable structures

12. CHEE 44012 Polymorphism u molecule can crystallize into more than one crystal structure u metastable form transforms to stable form over time ä usually nonreversible process - monotropic polymorphism u many polymorphic forms possible ä progesterone - 5 ä nicotinamide - 4 u dissolution rate changes with polymorphic form

13. CHEE 44013 Amorphism u no crystal structure u no distinct T f u supercooled liquids - subdued molecular motion u flow under an applied pressure u generally easier to dissolve

14. CHEE 44014 Crystal Hydrates u solvent trapped when compound crystallizes - solvates ä solvent is water - hydrates ä no water - anhydrate u solvent-compound interactions ä H 2 O further stabilizes lattice - polymorphic solvates ä H 2 O occupies void spaces - pseudopolymorphic solvates

15. CHEE 44015 u anhydrate has higher T f, generally dissolves faster

16. CHEE 44016 u Significance  incorporation of H 2 O affects bioabsorption rate and  bioactivity

17. CHEE 44017 Drug Salt Form u salt solubility depends on nature of counter- ion

18. CHEE 44018 Slightly Soluble Electrolytes u ex. Al(OH) 3, Ca 2 CO 3, ZnO AgCl (s)  Ag + (L) + Cl - (L) K sp = [Ag + ] [Cl - ] = 1.25(10 -10 ) at 25°C Al(OH) 3  Al 3+ (L) + 3OH - (L) K sp = [Al 3+ ] [OH - ] 3 = 7.7(10 -13 ) at 25°C beware of common ion effect (salting-out)

19. CHEE 44019 pH and solubility u weakly acidic drug ä pH p  the pH below which the drug precipitates from solution u weakly basic drug ä pH p  the pH above which the drug precipitates from solution

20. CHEE 44020 Other solubility issues u cosolvents ä 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 u combined effect of pH and cosolvent ä adding alcohol to buffered solution of weak electrolyte increases solubility of undissociated form ä decreases pH p for a weakly acidic drug

21. CHEE 44021 distribution coefficient, K u for absorption into cell, drug must pass through lipid cell membrane u 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. CHEE 44022 pH and K o/w u dissociated portion of drug does not dissolve in oil phase u true distribution coefficient u effective distribution coefficient

23. CHEE 44023 u as change pH, add common ion, [HA] w changes weak acid : weak base :

24. CHEE 44024 Clinical Significance of K o/w u prediction of absorption of drugs through various tissues ä absorption of acidic drugs from colon ä absorption of basic drugs from small intestine

25. CHEE 44025 u absorption of components into polymers ä plastic bottles ä PVC i.v. bags u desorption of plasticizers from polymers ä PVC i.v. bags

26. CHEE 44026 Diffusion across a membrane u skin, buccal mucosa, cell membrane… C distance x CdCd CrCr C1C1 C2C2

27. CHEE 44027 Diffusion across a membrane u when C r << C d ä P = permeability (cm/s) = K o/w D/x