Selective Crystallization of the Metastable Anhydrate Form in the Enantiotropic Pseudo-Dimorph System of l-Phenylalanine using Concentration Feedback Control

A batch recipe for the selective crystallization of the metastable anhydrate form of an enantiotropic pseudo-dimorph system, L-phenylalanine, in a mixed solvent system (75 wt % water and 25 wt % 2-propanol) was implemented by controlled tracking of a designed trajectory in the phase diagram. The solubility curves of both the anhydrate and monohydrate forms were determined using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, coupled with chemometrics. Laser backscattering (focused beam reflectance measurement, FBRM) was used to determine the seeded metastable limit with the nucleated forms identified using in situ video microscopy. Batch operations seeded with the anhydrate form were implemented following various preset supersaturation profiles using concentration feedback control which regulated the cooling rate based on in situ measurement of the solute concentration. Undesired secondary nucleation at the metastable limit provided the operating constraints in terms of the maximum allowable supersaturation. Batch crystallization implemented at low constant absolute supersaturation with respect to the unwanted monohydrate form was successful in preventing cross nucleation and in selectively growing large anhydrate crystals with relatively uniform size. This methodology extended the useful range of the phase diagram to temperatures below the transition point, where the anhydrate form is metastable, to increase product yield compared to operations utilizing only the temperature range above the transition temperature, where the anhydrate form is stable.