Oral Absorption Flashcards
Required process for oral absorption of monolithic dosage forms
- Drug molecules at surface dissolve to form saturated solution
- Dissolved drug molecules diffuse from high to low concentration
- Drug moecules diffuse through bulk solution (GI fluids) to the absorbing mucosa and are absorbed
- Replenishment of drug molecules in diffusion layer achieved by further dissolution
Dissolution
Solid tablet -> gradient -> bulk solution (GI fluids)
Effect of particle size
-increased surface area leads to increased dissolution rate
-break into smaller pieces to increase surface area
Rate of dissolution
-(dM/dt)
-change in amount of mass that appears in solution over time
Rate of dissolution equation (Noyes-Whitney)
dM/dt = (DS/h) (Cd-Ca)
D=diffusion coefficient (Fick’s 1st)
S= surface area
h= thickness of stationary layer
Cd = concentration of drug in donor
Ca = concentration in bulk solution
Dissolution rate is proportional to
-rate of diffusion (D)
-surface area
-difference in concentration gradient
-increase in one will increase dissolution vice versa
Dissolution rate is inversely proportional to
-h
-increase h = less steep gradient
-take more time for molecule to move
increase stirring rate
-decreases h
-increases dissolution rate
Permeability vs dissolution
diffusion across a barrier instead of an unstirred layer
Partition coefficient
must be included in permeability to account for changes in environment between insise and outside membrane
Can remove Ca if we assume sink condition
concentration in membrane is negligible compared to GI fluids
Permeability equation
dM/dt = (DSKCd/h) = PSCd
dC/dt = PSCd/V
D=diffusivity
S=surface area of boundary
K= partition coefficient (solubility inside barrier/solubilty outside)
Cd = donor (GI) concentration
h= thickness of barrier (GI cell membrane
P= (DK)/h = permeability
Factors limiting oral drug absorption
- solubility (cant get enough drug in solution)
- Dissolution (cant get drug out of tablet)
- Permeability (cant get across Gi membrane)
Solubility limited
-characteristic of drug itself
-poorly soluble drugs limited as candidates
-small Cd value
-form dissolves fast and drug permeates readily
-increasing dose doesnt increase blood levels as GI fluids are already saturated
Dissolution Limited
-drug unable to dissolve into solution from dosage form in sub-saturated fluid
-takes longer than absorption in intestines
-due to poor formulation/manufacturing
-tablet needs to dissolve but survive shipping and handling
Permeability limited
-characteristic of drug itself
-dissolution fast with sub-saturated fluids
-increasing amount of drug (Cd) increases absorption (dM/dt)
Physiochemical constraints of solubility limited factors
-dissolution fast
-permeability fast
solubility limited observations
-gut saturated by high does
-absorption does NOT increase with increase dose
Physiochemical constraints of dissolution limited factors
-Tdiss greater than residence time in small instestine
-permeability fast
dissolution limited observations
-can be enhanced by particle size reduction
-absorption increases with increased dose