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).

Particle design via spherical agglomeration: A critical review of controlling parameters, rate processes and modelling

“…It has been shown that there is a critical range for the BSR. Below this range, there is no significant agglomeration, and above this range a paste-like product is produced [55,56]. Only within this range is the agglomeration process efficient.…”

Experimental investigation of the effect of scale-up on mixing efficiency in oscillatory flow baffled reactors (OFBR) using principal component based image analysis as a novel noninvasive residence time distribution measurement approach

“…By imposing this oscillatory turbulence, OFBRs do not need to operate at high throughput flow rates like PFRs, meaning smaller tube lengths and holdup volumes. However, several authors have indicated that these oscillations have a significant impact on the RTD of the system, 2,4,5,6 but do not consider system geometry or scale up. Herein, two commercial systems of different geometry and scale will be evaluated under a variety of operating conditions.…”

Development and characterisation of a cascade of moving baffle oscillatory crystallisers (CMBOC)

“…Further flexibility could be achieved by introducing individual motors to control the oscillation conditions in each vessel which may be beneficial for example in controlling the size of agglomerate in spherical agglomeration processing. [68][69][70]…”