So far we have looked at the transfer of drugs in solution in the G-I tract, through a membrane, into solution in the blood. However, many drugs are given in solid dosage forms, and therefore must dissolve before absorption can take place.
Dissolution Absorption SOLID -----------> SOLUTION ----------> BLOOD G-I Tract
If absorption is slow relative to dissolution then all we are concerned with is absorption. However, if dissolution is the slow, rate determining step (the step controlling the overall rate) then factors affecting dissolution will control the overall process. This is a more common problem with drugs which have a low solubility (below 1 g/100 ml) or which are given at a high dose, e.g. griseofulvin.
There are number of factors which affect drug dissolution and we can look at this process as diffusion controlled.
Diagram XII-4 of Stagnant Layer
A physical model is shown in Diagram XII-4.
First we need to consider that each particle of drug formulation is surrounded by a stagnant layer of solution.
After an initial period we will have a steady state set-up where drug is steadily dissolved at the solid-liquid interface and diffuses through the stagnant layer. If diffusion is the rate determining step we can use Fick's first law of diffusion to describe the overall process.
Figure XII-3 Plot of Concentration Gradient
If we could measure drug concentration at various distances from the surface of the solid we would see that a concentration gradient is developed.
By Fick's first law of diffusion then:-
Rate of solution =
where D is the diffusion coefficient, A the surface area, Cs the solubility of the drug, Cb the concentration of drug in the bulk solution, and h the thickness of the stagnant layer. If Cb is much greater than Cs then we have so-called "Sink Conditions" and the equation reduces to
Rate of solution =
with each term in this equation contributing to the dissolution process.
The surface area per gram (or per dose) of a solid drug can be changed by altering the particle size. For example, a cube 1 cm on each side has a surface area of 6 cm2. If this cube is broken into cubes with sides of 0.1 cm, the total surface area is 60 cm2. Actually if we break up the particles by grinding we will have irregular shapes and even larger surface areas. Generally as A increases the dissolution rate will also increase. Improved bioavailability has been observed with griseofulvin, digoxin, etc.
Methods of particle size reduction include mortar and pestle, mechanical grinders, fluid energy mills, solid dispersions in readily soluble materials (PEG's).
This thickness is determined by the agitation in the bulk solution. In vivo we usually have very little control over this parameter. It is important though when we perform in vitro dissolution studies because we have to control the agitation rate so that we get similar results in vitro as we would in vivo.
Figure XII-4, Plot of Concentration versus Distance for Dissolution into a Reactive Medium
The apparent thickness of the stagnant layer can be reduced when the drug dissolves into a reactive medium. For example, with a weakly basic drug in an acidic medium, the drug will react (ionize) with the diffusing proton (H+) and this will result in an effective decrease in the thickness of the stagnant layer.
The effective thickness is now h' not h. Also the bulk concentration of the drug is effectively zero. For this reason weak bases will dissolve more quickly in the stomach.
The value of D depends on the size of the molecule and the viscosity of the dissolution medium. Increasing the viscosity will decrease the diffusion coefficient and thus the dissolution rate. This could be used to produce a sustained release effect by including a larger proportion of something like sucrose or acacia in a tablet formulation.
Solubility is another determinant of dissolution rate. As Cs increases so does the dissolution rate. We can now look at ways of changing the solubility of a drug.
Figure XII-5, Plot of Concentration versus Time
Salts of weak acids and weak bases generally have much higher aqueous solubility than the free acid or base, therefore if the drug can be given as a salt the solubility can be increased and we should have improved dissolution. One example is Penicillin V.
If we look at the dissolution profile of various salts.
Figure XII-6 Plot of Cp versus Time
This can lead to quite different Cp versus time results after oral administration.
The t peak values are similar thus ka probably the same. C peak would show a good correlation with solubility. Maybe site limited (only that in solution by the time the drug gets to the 'window' is absorbed). Use the potassium salt for better absorption orally. Use benzathine or procaine for IM depot use.
Figure XII-7, Plot of Cp versus Time for Three Formulations of Chloramphenicol Palmitate
(a sketch of Fig 6. in the paper by Aguiar et al.*)
Some drugs exist in a number of crystal forms or polymorphs. These different forms may well have different solubility properties and thus different dissolution characteristics. Chloramphenicol palmitate is one example which exists in at least two polymorphs. The B form is apparently more bioavailable*.
The recommendation might be that manufacturers should use polymorph B for maximum absorption. However, a method of controlling and determining crystal form would be necessary in the quality control process.
* Aguiar, A.J., Krc, J., Kinkel, A.W., and Samyn, J.C. 1967. Effect of Polymorphism on the Absorption of Chloramphenicol from Chloramphenicol Palmitate, J. Pharm. Sci., 56(7), 847-853
Copyright 2001 David W.A. Bourne