(446d) When Crystalline Solids Are Wanted in Specific Sizes, Forms, and Purities

Crystallization finds use throughout the chemical, pharmaceutical, and many other industries. In most applications, its function often has been to separate and/or purify a specific chemical species, which may either be an intermediate or a final product. Such roles continue to exist, and it is arguable that crystallization has greater utility than any other separation technique. Advances in the control of crystal size distribution, often based on newly developed measurement capabilities, continue to provide challenges to practitioners utilizing crystallization as part of the commodities business.

Another role has begun to taken on great importance, however. As pointed out by Charpentier and McKenna,¹ “today, 60% of all products sold by chemical companies are crystalline, polymeric or amorphous solids. These must have a clearly defined physical shape to meet quality standards [and] are much more complex than traditional, industrial chemicals.” Indeed it has been postulated that the basis of many new products is their reformulation in more readily accessible forms rather than the development of new chemistry. When this possibility is added to those associated with needs related to the growth of biologically synthesized and often quite complex species, crystallization is indeed taking on greater importance.

In this presentation, some of the variables that can be manipulated to guide a system to a specific crystal form will be described. The discussion will be placed in the context of experimental observations involving a range of pharmaceutical compounds. It will be shown, for example, that both solution composition and temperature determine the stable form of these species; indeed, adding a solvent, such as methanol, to aqueous solutions changes may result in the formation of an unexpected polymorph. Moreover, competing crystallization kinetics can result in complex phenomena involving the formation of both stable and unstable crystal forms. As an example, a methodology by which an unstable form can be produced will be described, although in the system studied the unstable form rapidly disappeared in favor of the stable form.

1. J.C. Charpentier, T.F. McKenna, Chemical Engineering Science, 59, 1617(2004).