Pathway of Absorption

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
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
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 801C for NaCl)
• stable structure
• hard, brittle

11
Crystalline Solids

• Van der Waals, H-bonds
• ex. organic compounds
• weak bonds
• low Tf, low (ex. Tf 238C 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 25C
• Al(OH)3 ? Al3(L) 3OH-(L)
• Ksp Al3 OH-3 7.7(10-13) at 25C
• 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, HAw 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 ltlt Cd
• P permeability (cm/s)
• Ko/w D/x