Controlling Crystallization via Organic Solvent Nanofiltration: The Influence of Flux on Griseofulvin Crystallization

Organic solvent nanofiltration (OSN) is suggested as a method for enhancing crystallization in the pharmaceutical industry. OSN crystallization has the potential to reduce energy and/or chemical inputs and allows for control of process conditions and crystal morphology. This work focuses on the crystallization of the pharmaceutical compound griseofulvin using OSN membranes to concentrate solutions via solvent removal. Griseofulvin solutions were concentrated in a pressure-driven dead-end nanofiltration cell, and crystals were allowed to spontaneously nucleate. The process was carried out using a range of different pressures to manipulate the solvent flux through the membrane. It was found that two distinct crystal types could be produced by altering the process solvent flux. At high flux, large crystals (approximate to 1 mm) were produced, whereas, at low flux, small crystals (2-25 mu m), which grew in clustered formations, were observed. The large crystals produced a previously unreported X-ray powder diffraction pattern, suggesting a slightly different morphology of griseofulvin than that resulting from traditional crystallization methods. The difference in crystallization morphologies could be attributed to the effect of preferential surface and bulk phase crystal nucleation and growth. The precise control of process conditions afforded by OSN crystallization might lead to rapid discovery of new morphologies of pharmaceutical compounds.