Control of Polymorphism in Continuous Crystallization via Mixed Suspension Mixed Product Removal Systems Cascade Design

Abstract

Control of polymorphism of the enantiotropic p-aminobenzoic acid at either the α or β polymorph while maintaining high yield was achieved by mixed suspension mixed product removal (MSMPR) cascade design. A systematic approach was developed to identify the operational window of the process variables, stage temperature and residence time, in which the stringent polymorph purity criterion (>95 wt %) and high yield were met. The comprehensive understanding of the polymorphism of the model compound, p-aminobenzoic acid, was the key for the identification of the operational window. On the basis of single-stage MSMPR experiments, three temperature regimes thermodynamic control, energy barrier control, and kinetic competitionwere identified, and the interplay between the crystallization kinetics and the thermodynamics in each regime was elucidated. Experimental studies also demonstrated the first polymorph specific MSMPR for enantiotropic systems. Single-stage MSMPRs at low temperature, e.g., 5°C, were found to be β polymorph-specific at steady states across multiple operating conditions. Two-stage MSMPR was designed to alter the polymorphism at the 5°C stage from β polymorph-specific to α polymorph-specific. The first stage temperature was selected in the thermodynamic control regime (30°C) at which the steady state polymorphism was α-specific. Feeding continuously to the second stage, the α crystals generated at the first stage increased the total surface area and thereby the secondary nucleation and mass deposition rates of the α polymorph in the 5°C stage. This in turn increased the α polymorph from 0 wt % to at least 75 wt %, proving that it is feasible to control the polymorphism via design of the MSMPR cascade.

Diastereomeric salt crystallization of chiral molecules via sequential coupled‐Batch operation

“…Traditionally, this may have been difficult to implement industrially in the pharmaceutical industry which has almost exclusively utilized standard batch equipment. However, the past decade has seen a significant uptake of crystallizer technologies for use in next generation continuous pharmaceutical platforms with ability to separate enantiomers in a continuous manner as well as access to a wider ranges of particle sizes, improved polymorph control, and increased purity …”

Continuous protein crystallisation platform and process: Case of lysozyme

“…Many research on continuous crystallizers have been investigated in mixed-suspension, mixed-product removal (MSMPR) crystallizer (Su et al, 2015;Yang et al, 2017), i.e. continuous stirred tank reactors (CSTRs) (Lai et al, 2015), plug flow reactor (PFR) (Neugebauer and Khinast, 2015), continuous (baffled) oscillatory flow reactor/crystalliser (OBR)/(COFC) (Chew et al, 2004;Jian and Ni, 2005;Yang et al, 2016).…”

Equipment and Separation Units for Flow Chemistry Applications and Process Development

“…In general, continuous crystallization is performed in two basic apparatuses, namely, on the one hand in the continuously stirred tank (CST), especially the mixed-suspension, mixedproduct-removal (MSPMR) [26][27][28][29][30], and on the other hand in the plug flow (PF) [31][32][33][34][35][36][37][38]. There are many variants of both types, which are described in literature [39,40].…”