(4bj) Design of Pharmaceutical Crystallizers Using Dual-Impinging-Jet Mixers, Multi-Phase Flow, and Controlled Dynamic Operations

Jiang, M., Massachusetts Institute of Technology

Crystallization is a key unit operation in the pharmaceutical industry. The crystal size distribution (CSD) can affect the efficacy of drug products (such as the amount of drug reaching the lungs from a nasal spray) as well as the efficiency of downstream processes such as filtration and milling. CSD control can be challenging when the crystallization simultaneously includes many phenomena, such as growth, particle attrition and breakage, agglomeration, and primary and secondary heterogeneous nucleation. This poster describes new crystallizer designs that greatly enhance the control of the crystal size distribution. One strategy is to exploit dual-impinging-jet mixers and/or multiphase flow to decouple nucleation and growth so that these phenomena can be individually controlled. Another strategy is to increase the degrees of freedom in the dynamic operation of the crystallizer. Experimental validation confirmed that the designs suppressed secondary nucleation, attrition, and aggregation/agglomeration—phenomena that worsen the ability to control the CSD but are dominant in most existing crystallizer designs.

The last portion of the poster will propose some new design strategies for the crystallization of biopharmaceuticals, especially proteins, which constitute a growing proportion of new therapeutic compounds. Strategies are proposed both for the generation of single protein crystals for use in determining the protein structure for use in drug design, and for the generation of large quantities of protein crystals as a route towards inexpensive purification, extended shelf-life, or alternative modes of drug delivery.