(651b) Toward Equant Shaped Crystal Habit through a 3-Stage Cyclic Process: Design and Applications

Crystallization is a fundamental unit operation in many chemical processes where a product in solid form is obtained, and several parameters are of interest when assessing the quality of a crystalline powder. The size and the shape of the crystals are certainly among their most important physical attributes, and contribute to determining properties such as the flowability, filterability, and, in the case of an active pharmaceutical ingredient (API), its bioavailability.

Multiple ways to modify the crystal size and shape have been investigated and are applied at the industrial scale, e.g. temperature cycles, dry milling, wet milling, micronization [1-2]. A 3-stage process [3], consisting of cycles of crystallization, milling, and dissolution, has been recently proposed to efficiently reduce the aspect ratio of needle-like crystals, so as to facilitate downstream processing, while avoiding common problems such as amorphization and formation of sub-micron particles.

In this contribution, we elucidate the link between compound-dependent, yet general features of the crystals, namely the ratios of growth and dissolution rates along their width and length, and the attainable regions through the 3-stage process in terms of average sizes. The process variables spanning the attainable regions are the number of temperature cycles performed and the rotor speed of the wet milling device. Depending on the aforementioned ratios, for the same combinations of process variables, the amplitude of the regions was observed to vary significantly, thus strongly affecting the effectiveness of the process. [4]

Further attention was dedicated to the dissolution step, which aims at reducing the number of fines, and is commonly applied to dissolve a given mass ratio of the solids in suspension. In the frame of the 3-stage process, we show alternative procedures of performing the dissolution step, which aim at removing the fine particles while extending the attainable regions.

The presented results combine experimental work in a laboratory-scale setup and modeling based on two-dimensional PBEs for needle-like particles, and are given in the perspective of performing a robust and quick process design.

[1] Lovette, M. A.; Muratore, M.; Doherty M. F. AIChE J., 2012, 58, 1465–1474.

[2] Rasenack, N.; Mueller, B. W. Pharm. Dev. Technol., 2004, 9, 1–13.

[3] Salvatori, F.; Mazzotti, M. Ind. Eng. Chem. Res., 2017, 56, 9188–9201.

[4] Salvatori, F.; Binel, P; Mazzotti, M. Chem. Eng. Sci. X, 2019, 1, 100004.