Bulk Crystallization of Indomethacin from Simple and Complex Solvents

Bulk crystallization is the commonest method for the high-volume production of pharmaceutical ingredients. As the complexity of both active pharmaceutical ingredient and solvents increases, the behavior of the solute within the solvents may also increase in complexity. This paper compares the nucleation and growth processes of a pharmaceutical ingredient, indomethacin, in three solvents, which span the range of simple to complex. Much of the behavior of indomethacin is mimicked across the solvents, with the γ form of indomethacin crystallizing at low to medium supersaturations. At higher supersaturations, the complex solvents behave as do many other simple solvents in that the solvated β form of indomethacin is found. The great difference in induction time for nucleation and growth time scales for the simple and complex solvents is considered as a function of supersaturation and viscosity and shows that transport processes within the solution play an important role in the crystallization behavior of indomethacin.