Pharmaceutical consequences of solvate formation

Modification of the solvent of crystallisation may result in different solvated forms. This is of particular relevance because the hydrated and anhydrous forms of a dmg can have melting points and solubilities sufficiently different to affect their pharmaceutical behaviour. For example, glutethimide exists in both an anhydrous form (m.p. 83°C, solubility 0.042% at 25°C) and a hydrated form (m.p. 68°C, solubility 0.026% at 25°C). Other anhydrous forms show similar higher solubilities than the hydrated materials and, as expected, the anhydrous forms of caffeine, theophylline, glutethimide and cholesterol show correspondingly higher dissolution rates than their hydrates. 

One can assume that as the hydrate has already interacted intimately with water (the solvent), then the energy released for crystal break-up, on interaction of the hydrate with solvent, is less than for the anhydrous material. The nonaqueous solvates, on the other hand, tend to be more soluble in water than the nonsolvates. The n-amyl alcohol solvate of fludrocortisone acetate is at least five times as soluble as the parent compound, while the ethyl acetate solvate is twice as soluble. 

The equilibrium solubility of the nonsol-vated form of a crystalline organic compound which does not dissociate in the solvent (for 

JCjh is then the solubility of the hydrate. The process of hydration of an anhydrous crystal in water is represented by an equation of the type 

AGtjjns C3n be obtained from the solubility data of the two forms at a particular temperature, as for theophylline and glutethimide in Table 1.3. 

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