Physicochemical properties of small drugs

Question 1

Drug release from the dosage form

Answer 1

For a drug to elicit its pharmacological effect, it must be released from its dosage form and dissolve in the milieu at the site of administration.
The manner in which the drug is made available for absorption in this way is called release (or liberation).
This step, which can have a major impact on the drug’s eventual bioavailability, can be influenced by the choice of:
* the site of administration,
* the dosage form,
* the excipients used, and
* the method of manufacture

Question 2

for a fast-release tablet, the principal steps are

Answer 2

disintegration of the tablet into granules or aggregates
disaggregation into small particles
dissolution of drug crystals

Dissolution proceeds more efficiently as disintegration and disaggregation advance, and particle size decreases

Question 3

For coated tablets, disintegration is proceeded by dissolution of the coating

Answer 3

the slowest step controls the release rate

Question 4

For gastro-resistant tablets, the coating is stable in the stomach

Answer 4

Disintegration does not begin until dosage form reaches small intestine.
Drug release is therefore delayed, and the rate at which the drug becomes available is reduced

Question 5

Release from an aqueous suspension depends only on the rate of dissolution

Answer 5

Release from aqueous solutions is fastest, as there is no dissolution step, and the drug is already manufactured in solution form.
For effervescent tablets, dissolution is accomplished immediately prior to administration, but the dosage form manufactured is solid.

Question 6

The dissolution process- Noyes-Whitney equation

Answer 6

Dissolution of a solid crystal in a liquid involves two successive steps:
solvation of drug at crystal surface to create a stagnant layer of saturated solution;
diffusion of dissolved molecules across this layer into bulk solution.
observed rate of dissolution depends on the slowest of these two steps.
Overall rate of dissolution, at constant temp., can be described by the Noyes-Whitney equation

Question 7

Noyes-Whitney equation

Answer 7

dissolution rate =
D . S / h ( Cs- Cb)

S= surface area of the drug
Cs= solubility of the drug
D= diffusivity of drug in solution
h= thickness of diffusion layer
Cb= conc of drug in bulk solution

Cb is smaller than Cs

in solution solubility is constant and dissolution rate is variable

dm/dt = k A (Cs - C)
c= conc of drug in solution

Question 8

After extravascular administration, drug appearance in blood requires two steps.

Answer 8

1. Release: drug dissolves at administration site.
2. Absorption: drug crosses biomembrane(s) to reach blood.
   Slowest step controls overall rate of absorption.

Question 9

Membrane transport

Answer 9

Membrane transport is achieved by one of two principal mechanisms
- passive and active
which call upon different driving forces

Transport may also be ‘facilitated’…

Molecules are “blind” and move randomely
diffusion is not therefore a fully efficient process

Question 10

Stokes-Einstein equation

Answer 10

Relates diffusivity (or the diffusion coefficient) to
environmental conditions
properties of medium through which diffusion is taking place
properties of diffusing molecule
Theoretically applies to ‘spherical’ molecules in solution
D increases with increasing temperature (T)
molecules move faster when warmer
D is inversely proportional to solvent viscosity (η)
diffusion in gas phase easier than in liquid, easier than in a polymer
D decreases with increasing molecular volume (V = 4πr3/3)
big molecules diffuse slower than small ones

Question 11

Passive transport - Fick’s 1st law:

Answer 11

D = diffusivity of drug in membrane.
D depends upon nature of membrane, and
on drug size (molecular volume ≈ molecular weight)
Flux increases with membrane surface area (A).
surface area of small intestine (with its villi and microvilli) is much greater than that of stomach.
Flux is inversely proportional to membrane thickness (Δx).
compare bronchial membrane with stratum corneum of skin
Flux is directly correlated to the drug’s concentration difference across the membrane (C1 - C2).
A and Δx are characteristics of biomembrane.
in contrast, K is a property of drug; and D is influenced both by drug and membrane properties

Question 12

Partition coefficient (K)

Answer 12

K quantifies distribution of drug between membrane and aqueous phases which it separates; for example…
A drug’s partition coefficient between oil and water is defined:
K = Coil/Cw
K also equals ratio of the drug’s solubilities in two phases
K = drug’s relative affinity for oil as compared to water
Octanol-water partition coefficient (log P) is often used to characterize a drug’s lipophilicity