Nucleation kinetics-based solvent selection for the liquid antisolvent crystallization of a lipophilic intermediate

The fundamental understanding of solubility and nucleation kinetics are two primary pillars for liquid antisolvent crystallization (LASC) process development. In our present work, the solubility of intermediate A in four different solvents and binary mixtures with water, in the temperature range from 273 K to 323 K, was determined using a liquid chromatographic method to acquire the fundamental thermodynamic information for the LASC process. Intermediate A was monitored both in the solid phase and in the liquid phase by in line Raman spectroscopy. The importance of selection of the optimum scale and mixing conditions (volume and fluid dynamics dependency) for conducting metastable zone width (MSZW) measurements for the nucleation kinetics study, due to stochastic nature of nucleation, has been demonstrated to translate the findings to larger industrial scales. The 3.5 mL volume in reactor with a 3 blade downflow overhead impeller in the Crystalline™ (Technobis) was found to be an optimal platform for the data generation for the extraction of nucleation kinetics. The minimum detection threshold value (fN) reported in the literature was experimentally derived for the intermediate A-solvent systems used, covering the effect of supersaturation, reaction volume and agitation rate. The combined polythermal and antisolvent addition approach was applied to determine MSZWs and, subsequently, the kinetic parameters were estimated based on both linearized integral and 3D nucleation models. It was demonstrated how the derived parameters complemented with accurate solubility data are required to guide solvent selection for bottom-up generation of nanosuspensions. The findings were validated by conducting batch and continuous LASC of intermediate A. Particle size distributions derived from electron scanning microscopy obtained at similar driving forces confirmed the solvents selection order based on their nucleation tendency of dissolved intermediate A. These results serve as an example for applying a nucleation kinetics-based fundamental approach for solvent selection in the development of LASC process for generation of long-acting injectable suspensions.