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Anhydrous

4.74 ±

1003

Monoethanol solvate

1.83 ±

1003

Hemichloroform solvate

7.40 ±

1001

a Modified from B. E. Ballard and J. Biles, Steroids, 4, 273 (1964).

dissolution rates of the benzene and cyclo-hexane solvates (B and C respectively) are apparent but, of course, the possible use of the solvates is prohibited because of their likely toxicity.

Differences in solubility and dissolution rate between solvates can lead to measurable differences in their bioavailabilities. You can see in Table 1.5 the differences in in vivo absorption rates of solvates of prednisolone tertiary butyl acetate and hydrocortisone tertiary butyl acetate after implantation of pellets of these compounds. Note, for example, that the monoethanol solvate of prednisolone has an absorption rate in vivo which is nearly five times greater than that of the anhydrous

Figure 1.14 Serum levels (pg cm~3) obtained after oral administration of a suspension containing 250 mg ampicillin as the anhydrate and as the trihydrate.

Reproduced from J. W. Poole et al., Curr. Ther. Res., 10, 292 (1968).

Figure 1.14 Serum levels (pg cm~3) obtained after oral administration of a suspension containing 250 mg ampicillin as the anhydrate and as the trihydrate.

Reproduced from J. W. Poole et al., Curr. Ther. Res., 10, 292 (1968).

tertiary butyl acetate. Differences in the absorption of ampicillin and its trihydrate can be observed (Fig. 1.14), but the extent of the difference is of doubtful clinical significance. The more soluble anhydrous form appears at a faster rate in the serum and produces higher peak serum levels.

1.5 Dissolution of solid drugs

Whether the solution process takes place in the laboratory or in vivo, there is one law which defines the rate of solution of solids when the process is diffusion-controlled and involves no chemical reaction. This is the

Noyes-Whitney equation, which may be written dw

where k = DA/6. The equation is the analogue of equation (1.1) discussed previously. Figure 1.15 shows the model on which this equation is based. The terms of the equation are: dw/dt, the rate of increase of the amount of material in solution dissolving from a solid; k, the rate constant of dissolution (timecs, the saturation solubility of the drug in solution in the diffusion layer; and c the concentration of the drug in the bulk solution. A is the area of the solvate particles exposed to the solvent, 6 is the thickness of the diffusion

Table 1.6 How the parameters of the dissolution equation can be changed to increase (+) or decrease (-) the rate

of solution

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