CHEE 440 1

Pathway of AbsorptionPathway of Absorption

bloodendothelium

epithelium

connective tissue, muscle

CHEE 440 2

Cell MembraneCell Membrane

CHEE 440 3

AbsorptionAbsorption

Affected 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

dm

dt=

DACsat

h=kACsatNoyes-Whitney Eqn

CHEE 440 6

Dissolution RateDissolution Rate

But, surface area changes with time. for spherical particles

for N particles

r =ro −kCsatt

ρ

r = radius at time tro= initial radius ρ = density

M o

13 −M

13 =κt

M = mass of particlesκ = 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[ ]oil

drug[ ]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[ ]o

HA[ ]w

K app=HA[ ]o

HA[ ]w + A−[ ]w

CHEE 440 23

as change pH, add common ion, [HA]w changes

logK =logK app−log1

1+10pH−pK a

⎛ ⎝

⎞ ⎠

logK =logK app−log1

1+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 =C1

Cd

=C2

Cr

CHEE 440 27

Diffusion across a membraneDiffusion across a membrane

when Cr << Cd

P = permeability (cm/s)

= Ko/w D/x

dm

dt=APCd