Crystal growth of (+-)-2,4-dichlorophenylacetic acid-BM methanol solvates

摘要

The title compound is a new pharmaceutical product crystallizing as a stable conglomerate. Its resolution by preferential crystallisation was carried out via the Auto-Seeded Programmed Polythermic Preferential Crystallization (AS3PC) process in pure methanol and in the azeotropic mixture methanol/toluene (71/29percent) w/w. However, the results revealed that in both solvents, the entrainment effects were associated to poor enantiomeric excesses, despite the absence of partial solid solution. A crystal growth study of the title compound was performed, and the influence of the solvent, the supersaturation and the counter-enantiomer was interpreted. Some adsorption/desorption of toluene molecules seems to have a great influence on the growth rate that leads to more isometric crystals in azeotropic mixture. A hypothetic adsorption/desorption mechanism of the counter-enantiomer was also simulated by means of molecular modelling, revealing that the adsorption of the counter-enantiomer may have a weak incidence on the strongest intermolecular bonding. These investigations explain partially the modest results of preferential crystallization via the AS3PC process and give another evidence that the existence of a stable conglomerate is not sufficient to guarantee a successful resolution by preferential crystallization. The interactions at crystal-solution interfaces need to be taken in account.