Enhancing pharmaceutical crystallization in a flow crystallizer with ultrasound: Anti-solvent crystallization

Abstract

Continuous crystallization is a fast growing application domain in the pharmaceutical industry. Application of ultrasound has been proven to have positive effects like reduction in induction time and Metastable Zone Width (MSZW) in both batch and flow systems. Further understanding of flow-based sonocrystallization is required to achieve industrial level scale up. This work investigates the sonocrystallization of pharmaceutical compounds in a tubular flow crystallizer. Acetyl Salicylic Acid (ASA-Aspirin) is used as a model compound with ethanol and water as solvent and anti-solvent, respectively. Experiments were conducted in silent and sonicated conditions to study the MSZW. Ultrasound made it possible to achieve crystallization within the crystallizer which was not possible in silent conditions, under the tested conditions. Continuous crystallization was achieved at as low as 48 wt% of anti-solvent and crystallization was already seen at a supersaturation of 1.02. In some experiments, temperature rise with ultrasound caused the crystals to re-dissolve within the channels. Better crystallization - no re-dissolution - was achieved by using low ultrasonic power without any loss in the yield. Particle sizes of product crystals were in the range of 4-46 mu m. In conclusion, ultrasound was highly effective in enabling anti-solvent crystallization of a pharmaceutical compound in a tubular flow crystallizer.