Relative rates of dissolution of several crystalline steroids, xanthines, and other solid drugs have been measured to determine the effect of solvate formation on this property. Equations have been derived relating the solubility products and diffusional constants to rates of solution of or anic solvates. The results suggest that the tendency of many drugs to form such atducts provide harmaceutical investigators a powerful tool in effecting rapid dissolution of higtly insoluble substances.
ANY ORGANIC and inorganic compounds are capable of existing in more than one crystalline form having different physical properties. In some cases these states are the result of solvate formation; in others the molecular arrangement within the crystal lattice is responsible for the differences in the properties of crystal modifications. The pharmaceutical importance of variations in the thermodynamic properties associated with the differences in crystal forms have been recently pointed out. It has been suggested by Higuchi (1) that the differences in the free energy of polymorphs, for example, can be an extremely important factor in determining the stability and availability of certain pharmaceuticals. The present report is concerned with the results of theoretical and experimental studies conducted to determine the magnitude of the differences in the thermodynamic and dissolution properties arising from the formation of such crystalline variants of a drug.
Organic medicinal compounds appear to be particularly prone to both formation of polymorphs and solvates and to have large differences in energy associated with such crystalline modifications. This can be ascribed to the size and general complexity of molecules having medicinal value and to their polyfunctionality. Such structures do not usually favor rapid crystalline nucleation and growth. These forms which are favored from the rate of crystal growth viewpoint often turn out to be metastable compared to more ditscultly produced polymorphs. It is apparent that the appropriate selection of the most witable crystalline modification, whether arising from polymorphic differences or as a result of ,solvate complex formation, can often significantly