chee 4401 pathway of absorption blood endothelium epithelium connective tissue, muscle
DESCRIPTION
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 distributionTRANSCRIPT
CHEE 440 1
Pathway of AbsorptionPathway of Absorption
bloodendothelium
epithelium
connective tissue, muscle
CHEE 440 2
Cell MembraneCell Membrane
CHEE 440 3
AbsorptionAbsorptionAffected by
drug chemical physical properties dissolution rate (solids) hydrophilicity/hydrophobicity
physiological factors route of administration drug distribution
CHEE 440 4
SolubilitySolubility 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
CHEE 440 5
Dissolution RateDissolution Rate important for tablets, solids slow dissolution rate = low bioavailability consider a solid particle in water
stagnant water layer
Csat
C = Cb
dmdt
=DACsat
h=kACsatNoyes-Whitney Eqn
CHEE 440 6
Dissolution RateDissolution RateBut, surface area changes with time. for spherical particles
for N particles
r =ro −kCsatt
r
r = radius at time tro= initial radius r = density
M o1
3 −M13 =kt
M = mass of particlesk = cube-root dissolution constant
CHEE 440 7
Factors influencing CFactors influencing Csatsat
crystal structure : polymorphism salt form pH solvate formation
CHEE 440 8
Process of DissolutionProcess of Dissolution
+
crystal solid
solvent
dissolved solute
+
CHEE 440 9
Crystalline SolidsCrystalline 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, ΔH f
−lnX2 =ΔH fR
Tf −TTfT
⎛ ⎝ ⎜
⎞ ⎠ ⎟
CHEE 440 10
Crystalline SolidsCrystalline Solids Electrostatic, Covalent Bonds
ex. NaCl, graphite (C4) strong bonds - cubic unit cell hi Tf, hi (eg. Tf= 801°C for NaCl) stable structure hard, brittle
ΔH f
CHEE 440 11
Crystalline SolidsCrystalline Solids Van der Waals, H-bonds
ex. organic compounds weak bonds low Tf, low (ex. Tf = 238°C for
caffeine) soft materials metastable structures
ΔH f
CHEE 440 12
PolymorphismPolymorphism 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
CHEE 440 13
AmorphismAmorphism no crystal structure no distinct Tf
supercooled liquids - subdued molecular motion
flow under an applied pressure generally easier to dissolve
CHEE 440 14
Crystal HydratesCrystal 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
CHEE 440 15
anhydrate has higher Tf, generally dissolves faster
CHEE 440 16
Significance incorporation of H2O affects bioabsorption
rate and bioactivity
CHEE 440 17
Drug Salt FormDrug Salt Form salt solubility depends on nature of counter-
ion
CHEE 440 18
Slightly Soluble ElectrolytesSlightly Soluble Electrolytes ex. Al(OH)3, Ca2CO3, ZnO
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)
CHEE 440 19
pH and solubilitypH 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
pHp =pKa + logS−So
So
⎛⎝⎜ ⎞
⎠⎟
pHp =pKw −pKb + logSo
S−So
⎛⎝⎜ ⎞
⎠⎟
CHEE 440 20
Other solubility issuesOther 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
CHEE 440 21
distribution coefficient, Kdistribution 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
K o/w = drug[ ]oildrug[ ]water
ac,o
ac,w=constant
ideal and ideally dilute solutions :
CHEE 440 22
pH and KpH and Ko/wo/w
dissociated portion of drug does not dissolve in oil phase
true distribution coefficient
effective distribution coefficient
K o/w = HA[ ]oHA[ ]w
K app=HA[ ]o
HA[ ]w + A−[ ]w
CHEE 440 23
as change pH, add common ion, [HA]w changes
logK =logK app−log 11+10pH−pK a
⎛ ⎝
⎞ ⎠
logK =logK app−log 11+10pKa −pH
⎛ ⎝
⎞ ⎠
weak acid :
weak base :
CHEE 440 24
Clinical Significance of KClinical Significance of Ko/wo/w
prediction of absorption of drugs through various tissues absorption of acidic drugs from colon
absorption of basic drugs from small intestine
log%abs( ) =0.156pKa −6.8( )−0.366logK o/w +0.755
log%abs( ) =−0.131logK o/w( )2 +0.362logKo/w
CHEE 440 25
absorption of components into polymers plastic bottles PVC i.v. bags
desorption of plasticizers from polymers PVC i.v. bags
CHEE 440 26
Diffusion across a membraneDiffusion across a membrane skin, buccal mucosa, cell membrane…
dmdt =AK o/wDAB
Cd −Cr( )x
C
distance
x
Cd
Cr
C1
C2
K o/w =C1Cd
=C2Cr
CHEE 440 27
Diffusion across a membraneDiffusion across a membrane when Cr << Cd
P = permeability (cm/s) = Ko/w D/x
dmdt
=APCd