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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
B. Amsden
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,BCd 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
const ant
a c ,w
ideal and ideally dilute solutions :
drug oi l
K o/ w
drugwate r
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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 0.156pKa 6.8 0.366logK o/ w 0.755
absorption of basic drugs from small intestine
log%abs 0.131logK o/ w 0.362logKo / w
2
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Partition Coefficient and Absorption
Optimum Ko/w
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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 DACsa t
kACsa t
dt
h
CHEE 440
Dissolution Rate
But, surface area changes with time;
for spherical particles:
kCsa t t
r ro
r = radius at time t
ro= initial radius
= density
for N particles:
M o M t
1
B. Amsden
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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CHEE 440
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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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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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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CHEE 440
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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CHEE 440
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 l og
So
weakly basic drug
pHp the pH above which the drug precipitates from
solution
So
pHp pKw pKb l og
S So
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CHEE 440
Drug Salt Form
salt solubility depends on nature of counter-ion
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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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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
HAo
K o/ w
HAw
Apparent partition coefficient
HAo
K app
HAw 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 logK app log
1 10pH pK a
1
log K logK app log
1 10pK a 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
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CHEE 440