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Absorption
Affected by:
1. Physiological factors
 route of administration
 drug distribution
2. Drug chemical physical properties
 dissolution rate (solids)
 hydrophilicity/hydrophobicity
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CHEE 440
Pathways of Oral Absorption
Two main mechanisms of transport across
the gastrointestinal membrane:
1.
2.
Transcellular diffusion
Paracellular diffusion
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CHEE 440
Transcellular Diffusion
The transcellular pathway is composed of 3 mechanisms:
passive diffusion, carrier-mediated transport, endocytosis
Passive diffusion
dm AK o / w DA,BCd  C r 

dt
x

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CHEE 440
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
a c, o
 cons tan t
a c ,w
ideal and ideally dilute solutions :
drug oil

K o/ w 
drug wat er
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CHEE 440
Clinical Significance of Ko/w
prediction of absorption of drugs through various tissues
 absorption of acidic drugs from colon
log %abs  0.156pKa  6.8  0.366 log K o/ w  0.755
 absorption of basic drugs from small intestine
log %abs  0.131log K o/ w   0.362log Ko / w
2
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CHEE 440
Partition Coefficient and Absorption
Optimum Ko/w
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CHEE 440
Carrier-Mediated Transport
Active transport
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CHEE 440
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
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CHEE 440
Dissolution Rate
important for tablets, capsules, suspensions
slow dissolution rate = low bioavailability
consider a solid particle in water
stagnant
water layer
Csat
C = Cb
Noyes-Whitney Eqn
B. Amsden
dm DAC sat

 kAC sat
dt
h
CHEE 440
Dissolution Rate
But, surface area changes with time;
for spherical particles:
kCsat t
r  ro 

r = radius at time t
ro= initial radius
 = density
for N particles:
M o  M  t
1
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3
1
3
M = mass of particles
 = cube-root
dissolution constant
CHEE 440
Factors influencing Csat
 crystal structure: polymorphism, hydrates
 pH
 salt form
 common ion effect
 co-solvents
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Process of Dissolution
crystal solid
+
solvent
+
dissolved solute
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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, Hf
Hf Tf  T 
 ln X2 


R  Tf T 
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CHEE 440
Crystalline Solids
Electrostatic, Covalent Bonds
 ex. NaCl, graphite (C4)
 strong bonds - cubic unit cell
 hi Tf, hi Hf (eg. Tf= 801°C for NaCl)
 stable structure
 hard, brittle
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CHEE 440
Crystalline Solids
Van der Waals, H-bonds
 ex. organic compounds
 weak bonds
 low Tf, low Hf (e.g. Tf = 238°C for caffeine)
 soft materials
 metastable structures
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CHEE 440
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
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CHEE 440
Amorphism





no crystal structure
no distinct Tf
supercooled liquids - subdued molecular motion
flow under an applied pressure
generally easier to dissolve
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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
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Crystal Hydrates
anhydrate has higher Tf, generally dissolves faster
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Crystal Hydrates
Significance
 incorporation of H2O affects bioabsorption rate and
 bioactivity
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pH and drug solubility
weakly acidic drug
 pHp  the pH below which the drug precipitates from solution
S  So 

pHp  pKa  log
 So 
weakly basic drug
 pHp  the pH above which the drug precipitates from
solution
 So 

pHp  pKw  pK b  log 
S So 
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CHEE 440
Drug Salt Form
salt solubility depends on nature of counter-ion
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CHEE 440
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 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)
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CHEE 440
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
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CHEE 440
pH and Ko/w
Dissociated portion of drug does not dissolve in oil phase.
Partition coefficient
HA o
K o/ w 
HA w
Apparent partition coefficient
HAo
K app 
HA w  A w
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CHEE 440
pH and Ko/w
As pH changes, [HA]w changes:
weak acid :
weak base :
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1


log K  log K app  log
1 10pH pK a 
1


log K  log K app  log
1 10pKa pH 
CHEE 440
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
B. Amsden
CHEE 440