Biopharmaceutics of oral dose formulation Flashcards
What happens to drug formulations as they near dissolution?
Drug breaks up into small molecules which allow it to be solubilised and then absorbed
What can happen to drug molecules as they move further into the GI tract?
It is possible for molecules to become less soluble and precipitate out of solution
What layer surrounds the drug particle in solution?
Saturated diffusion layer with a high concentration. As you move further away from the diffusion layer down the concentration gradient, concentration decreases
What are sink conditions when describing the saturated diffusion layer?
As drug molecules diffuse away from the saturated diffusion layer into the bulk fluids, new drug molecules replace them, rapidly saturating the diffusion layer (SINK conditions)
What is the rate limiting step under sink conditions for dissolution?
The rate of dissolution
What can we assume when we have sink conditions in dissolution?
First order kinetics: [C] intestine > [C] blood
What is the dissolution rate of weak acids in the stomach?
Low, because the drug is unionised and therefore poorly soluble in the diffusion layer
How might the pH of the diffusion layer of a weak acid be increased?
By forming an alkaline salt of the weak acid. As it dissolves, hydroxide ions would be released, increasing pH and promoting dissolution
Why do Na and K salts dissolve more rapidly than free acids?
Because they release OH- ions which promotes drug ionisation (independent to local pH)
What route for drug molecules crossing the gut wall is most observed?
Most drug molecules cross the gut wall via a number of different drug transporters
What is Log P
Log P is a measure of lipophilicity: it is the partition coefficient of an unionised drug between aqueous and lipophilic phases
ONLY considers unionised drug, not drugs that may be partially ionised
What is pKa?
The dissociation constant, it describes the extent to which a drug is ionised
pKa is the pH at which …?
[ionised]=[unionised]
What is used instead of LogP to take into account ionised forms of drug?
LogD
What is D?
Distribution coefficient (D) is the “effective” partition coefficient accounting for the degree of ionisation
What is the equation for Weak acids D?
D = [HA org] / {[HA aq] + [A- aq]}
What is the equation for weak bases D?
D = [B org] / {[B aq] + [BH+ aq]}
What is D dependent on?
pH
What is the equation for logD?
Log D = log P – log {1 + antilog (pKa - pH)}
What are the limitations associated with log D?
- unstirred conditions
- convective flow
- absorption of ionised species
- different pH at the membrane surface
- disruption of the lipid membrane
What is required for carrier-mediated transport?
Energy
What is the absorption rate in carrier-mediated transport assumed to be?
It is assumed to be the rate of carrier mediated membrane transport
What is the absorption rate in carrier-mediated transport equal to?
Absorption rate = Vmax . C /(Km + C)
What is C?
C is the unbound drug concentration at the site of absorption (i.e. GI luminal side of the biomembrane of the epithelial cell)
What is Vmax?
Vmax is a constant relating to the maximum rate of transport or saturation of the carriers (cf enzyme kinetics)
What is Km?
Km is a ‘constant’ relating to the affinity of the carrier binding the drug (cf enzyme kinetics)
Where are weakly basic drugs soluble?
In the stomach
What conditions in the stomach alter the weakly basic drug?
Food increases time for dissolution, stays in the stomach for a longer period of time. Also, acidity increases % protonated base and solubility of drug. Protonated (charged) base is less lipophilic and less permeable.
RNH2 + H+ –> RNH3+
What happens to the weakly basic drug when it moves into the small intestine?
o Emptying into increased pH reduces % protonated base and solubility, precipitate particles may form (worse solubility)
o Uncharged base is more lipophilic and permeable
o Rapid blood flow maintains high diffusion gradient from particles (sink conditions) – good absorption
o Blood flow is variable between people – after food, blood flow is high in the intestine
o Decreases if resting or ill
RNH3+ –> RNH2 + H+
What happens to weakly acidic drugs in the stomach?
RCOO- + H+ –> RCOOH (HA)
Food increases time for dissolution, acidity increases % uncharged acid (further reduces pH) and further delays dissolution. More lipophilic and permeable, but decreases solubility, precipitate particles may form. Less surface area - poor absorption
What happens to weakly acidic drugs in the small intestine?
RCOOH –> RCOO- + H+
o Emptying into increased pH reduces % uncharged acid, increases % ionised and solubility – favourable o Charged (ionised) acid less lipophilic and lower partition into lipid – more soluble o Uncharged form is what is permeated through the gut wall – small proportion rapidly absorbed and replaced o Even though absorption is unfavourable because there is a higher amount of IONISED form, there is enough UNIONISED to be absorbed and create a concentration gradient o Rapid blood flow maintains high diffusion gradient for solubilised and permeable fraction of drug
What is the pKa of very weak acids?
> 8, unionised at most pH values
What is the pKa of moderately weak acids?
2.5-7.5, unionised at gastric pH, ionised at intestinal pH
What is the pKa of strong acids?
<2, ionised at most pH values
What is the pKa of very weak bases?
<7, unionised at most pH values
What is the pKa of moderately weak bases?
7-10, ionised at gastric pH, largely unionised at intestinal pH
What is the pH of strong bases?
> 11, ionised at most pH values
