Absorption

1
Absorption

• Affected by
• 1. Physiological factors
• route of administration
• drug distribution
• 2. Drug chemical physical properties
• dissolution rate (solids)
• hydrophilicity/hydrophobicity

2
Pathways of Oral Absorption

• Two main mechanisms of transport across
• the gastrointestinal membrane
• Transcellular diffusion
• Paracellular diffusion

3
Transcellular Diffusion
The transcellular pathway is composed of 3
mechanisms passive diffusion, carrier-mediated
transport, endocytosis
Passive diffusion
4
Partition coefficient, Ko/w

• 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
5
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

6
Partition Coefficient and Absorption
Optimum Ko/w
7
Carrier-Mediated Transport

• Active transport

8
Drug Solubility

• Solubility the extent to which a drug dissolves
  under a given set of conditions of solvent and
  temperature
• 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

9
Dissolution Rate

• important for tablets, capsules, suspensions
• slow dissolution rate low bioavailability
• consider a solid particle in water

stagnant water layer
Noyes-Whitney Eqn
10
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
11
Factors influencing Csat

• crystal structure polymorphism, hydrates
• pH
• salt form
• common ion effect
• co-solvents

12
Process of Dissolution
13
Crystalline Solids

• Have a regular, ordered structure
• composed of identical repeating units - unit cell
• ex. cubic, rhombic, tetragonal
• Have distinct melting pts (Tf).
• Strength of bonds between atoms, molecules
  determines
• geometry of unit cell
• Tf,

14
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

15
Crystalline Solids

• Van der Waals, H-bonds
• ex. organic compounds
• weak bonds
• low Tf, low (e.g. Tf 238C for
  caffeine)
• soft materials
• metastable structures

16
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 - 2
• nicotinamide - 4
• dissolution rate changes with polymorphic form

17
Amorphism

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

18
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

19
Crystal Hydrates

• anhydrate has higher Tf, generally dissolves
  faster

20
Crystal Hydrates

• Significance
• incorporation of H2O affects bioabsorption rate
  and ? bioactivity

21
pH and drug 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

22
Drug Salt Form

• salt solubility depends on nature of counter-ion

23
Slightly Soluble Electrolytes

• ex. Al(OH)3, Ca2CO3, ZnO, drug salts
• 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)

24
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

25
pH and Ko/w

• Dissociated portion of drug does not dissolve in
  oil phase.
• Partition coefficient
• Apparent partition coefficient

26
pH and Ko/w

• As pH changes, HAw changes

weak acid
weak base
27
Summary

• Absorption of drug is influenced by combination
  of permeability and solubility
• Implications of Low Drug Permeability
• incomplete absorption
• rapid, complete dissolution needed
• release may need to be modified
• increase exposure to an absorption window
• possible retarded release if a saturable
  transport phenomenon exists
• Implications of Low Drug Solubility
• poor absorption
• may need co-solvent or penetration enhancer