Recent Progress in Antisolvent Crystallization of Pharmaceuticals with a Focus on the Membrane-Based Technologies

Continuous crystallization of pharmaceuticals has been in the center of attention during the past two decades, with a more focus on the large-scale production of active pharmaceutical ingredients. The increasing demand for pharmaceuticals requires high-throughput production of drug crystals with different solubilities, stabilities, shapes, habits, polymorphs, and size distributions. With numerous advantages including low cost, ease of scale-up, and superior control over polymorph and size distribution of drug crystals, antisolvent crystallization is one of the most promising crystallization methods recently attempted. However, it fails to deliver the required characteristic where the crystal systems tend to grow and for the preparation of metastable polymorphs. This review focuses on the most recent efforts to tackle these drawbacks by coupling antisolvent crystallization with cooling, supercritical-assisted, microfluidics-assisted, and membrane-assisted crystallization. This systematic review aims to provide a concise summary of each coupled antisolvent technique and their positive and negative aspects. This review can be used as a guideline for pharmacist, biologists, and chemists, who are interested in the crystal engineering of pharmaceuticals to pave the way for further developments in this field.