Antisolvent crystallization in porous hollow fiber devices

Abstract

This paper examines antisolvent crystallization under a new perspective and in the unique environment offered by porous hollow fiber membrane devices. The latter are compact, extremely efficient on a volumetric basis, easy to scale up and control. Their inherent characteristics promote the creation of homogeneous concentration conditions on a scale considerably smaller than existing industrial crystallizers without the necessity of a large energy input, properties that are desirable but rarely achieved in industrial crystallizers. Mixing studies were performed to examine the maximum achievable supersaturation in porous hollow fiber devices. It was shown that they are able to offer the supersaturation levels necessary to perform antisolvent crystallization. Moreover, supersaturation is created uniformly due to the large number of feed introduction points, the membrane pores. In addition, radial mixing is substantial in contrast with traditional tubular devices and the characteristic time involved in this process is comparable to the device residence time. Porous hollow fiber antisolvent crystallization of aqueous L-asparagine monohydrate systems proved successful. Mean crystal sizes up to two times smaller compared to batch stirred crystallizers were obtained in standalone membrane hollow fiber crystallizers (MHFC) and their combinations with completely stirred tanks. The CSD was confined below 165 μ m for the former and 75 μ m for the latter, levels that are sufficient for most pharmaceutical crystalline products, for which bioavailability and formulation concerns dictate the desired CSD. In addition, porous hollow fiber devices achieved comparable or slightly higher nucleation rates with respect to batch stirred crystallizers and similar values compared to tubular precipitators. Considerable improvements can be obtained by carefully designing membrane hollow fiber crystallizers.