In-situ measurement of the primary nucleation rate of the metastable polymorph B of L-histidine in antisolvent crystallization

Abstract

This research aims to investigate the nucleation kinetics of the metastable polymorph B of L-histidine (L-his). The nucleation rate of the metastable polymorph B of L-his was studied using water as a solvent and using various antisolvents to reduce the solubility and increase the supersaturation of L-his. Various methods can be used to determine the nucleation rate, e.g., induction time, metastable zone width, and direct measurement. However, direct measurement of the time evolution of the crystal size distribution by in-situ measurement is more suitable for scale-up purposes. The time evolution of the number of crystals was measured online via Focused Beam Reflectance measurement (FBRM). To investigate the nucleation rate, the antisolvent was added to the saturated solutions of L-his, then the crystals were allowed to nucleate under conditions of differing antisolvent type (methanol, ethanol, acetone, and acetonitrile), volume fraction of antisolvent to saturated solution (0.7 to 0.8), and the crystallization temperature (10, 25, and 40 °C). The nucleation rate increases with increasing volume fraction of antisolvent and supersaturation. The nucleation rate increases with higher temperature. The nucleation rates with acetonitrile and acetone antisolvents are very high whereas the nucleation rate with methanol is lowest because of the relatively high solubility of L-his in methanol at the same volume fraction. The interfacial energy of primary nucleation of the metastable polymorph B of L-his are different when using various antisolvents.