(466c) Design and Scale-Up of the Continuous Reactive Crystallization of An API

Polster, C. S. - Presenter, Eli Lilly and Company

Design and Scale-Up of the Continuous Reactive Crystallization of an API

Christopher S. Polster

Eli Lilly and Company, Small Molecule Design and Development


A continuous reactive crystallization of an active pharmaceutical ingredient (API) was designed to increase process throughput and product consistency.  The process uses high shear mixing elbow injectors in order to enable a process to grow crystals in a controlled fashion, allowing for direct control of product particle size and powder physical properties.  The work described in this presentation includes the analysis of crystallization kinetics, the use of kinetics to enable modeling for process scale up and optimization as well as the correlation of several measurable characteristics of API which correlate directly to drug product blend flow.  Crystallization kinetics are elucidated through the usage of gCRYSTAL software; both growth and nucleation kinetics are modeled.  The kinetics obtained are used to compare rates of nucleation, growth and liquid/liquid mixing phenomena, establishing limits on processing parameters.  Equipment capable of 10 kilograms of throughput over 72 hours in a 2.5 L crystallizer volume is described.