Gelation Mechanism and Oscillatory Temperature Control Strategy in Perindopril Erbumine Solution Crystallization

The gelation phenomenon often occurs in the solution crystallization process, which would seriously affect the process robustness and product quality. In this paper, the gelation phenomenon during the solution crystallization of perindopril erbumine (PDP) was systematically studied by spectroscopy and microscopy techniques. The results suggest that the PDP gel does not have the characteristic diffraction peak of the PDP crystal and the infrared spectrum has changed significantly compared with that of the crystal product. Accordingly, the mechanism of the gelation phenomenon of PDP was inferred to follow the status of aggregates, amorphous, crystalline fibers, and jelly-like phases during the gelation process development. Based on the proposed gelation mechanism, three controlling strategies, namely, direct cooling crystallization, seeding-assisted crystallization, and oscillatory temperature crystallization, were carried out to evaluate the effectiveness of process optimization. Inspired by direct nucleation control theory, through controlling the seed crystal number before the cooling step, the oscillatory temperature crystallization strategy effectively avoided the gelation problem, and the crystal product has good filtration properties and powder properties, which provides a feasible process method for practical production, avoiding the gelation phenomenon and important changes of the production line.