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

Abstract

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.

Gelation Phenomenon and Its Regulation Strategy of Tilmicosin Phosphate

“…Although much research has been focused on the formation of gel, the formation mechanism is still not fully understood, making it difficult to identify the key factors of gelation and regulate the gelation process effectively. Besides, several methods have been proposed to avoid the gelation phenomenon in the crystallization process, − including the reverse antisolvent crystallization (RAC) method, oscillating temperature control strategy, seeding-assisted crystallization etc. However, high-quality seeds are generally needed in the seed-assisted method, which limits its application.…”

“…Moreover, the crystal products obtained through gel-mediated crystallization typically have smaller particle sizes and are prone to aggregation, resulting in higher residual impurities. 19 Therefore, gelation should be regulated precisely in the production of drugs. It is found that the gelation phenomenon often occurs in the crystallization process of tilmicosin phosphate, which leads to small particle sizes and easy aggregation.…”

“…Besides, the formed gel would always adhere to the equipment during the production process and subsequent filtration processes, increasing equipment wear and even interrupting the crystallization process. Moreover, the crystal products obtained through gel-mediated crystallization typically have smaller particle sizes and are prone to aggregation, resulting in higher residual impurities . Therefore, gelation should be regulated precisely in the production of drugs.…”