Process Intensification through Continuous Spherical Crystallization Using a Two-Stage Mixed Suspension Mixed Product Removal (MSMPR) System

Abstract

Of utmost importance in the crystallization of active pharmaceutical ingredients (APIs) in the pharmaceutical industry is to produce crystals of good physical, processing, and biopharmaceutical properties. The definition of good physical properties depends on what the end goal and the drug formulation that the crystals will be a part of, but often processing and biopharmaceutical properties are competing interests. In most cases, the crystallization process is tailored to improve downstream process efficiency rather than improve drug molecule efficacy in the human body. Herein a novel concept and method to help satisfy both processing and biopharmaceutical interests is proposed, which is based on performing crystallization and spherical agglomeration in a two-stage continuous mixed suspension mixed product removal (MSMPR) system. With the suitable operating mode, the system enables to decouple the nucleation and growth from the agglomeration mechanisms, while performing efficient continuous manufacturing of particles with desired properties. Decoupling will offer more degrees of freedom for the control of each mechanism. This in turn provides the means by which properties in the nucleation/growth stage can be tailored to those of most biopharmaceutical benefit and efficacy (e.g., bioavailability, dissolution, morphology) while allowing the agglomeration stage to be tailored to produce spherical agglomerates of the most processing efficiency (e.g., filtering, drying, friability).