Use of Continuous MSMPR Crystallization with Integrated Nanofiltration Membrane Recycle for Enhanced Yield and Purity in API Crystallization

Abstract

If continuous processing is to be employed in pharmaceutical production, it is essential that continuous crystallization techniques can meet the purity and yield achievable in current batch crystallization processes. Recycling of mother liquor in steady state MSMPR crystallizations allows the yield in the equivalent equilibrium batch process to be met or exceeded. However, the extent to which yield can be increased is limited by the buildup of impurities within the system. In this study, an organic solvent nanofiltration membrane was used to preferentially concentrate an API (deferasirox, M.W. = 373 Da) and purge the limiting impurity 4-hydrazinobenzoic acid (MW = 152 Da) from the mother liquor recycle stream in a mixed solvent (THF:ethanol) antisolvent (water) system. Incorporation of the membrane recycle allowed yields of 98.0% and 98.7% to be achieved. This compares to the following: a control MSMPR run without a membrane (70.3%), an equivalent batch process (89.2%), and the current commercial batch process (92%). Comparable product impurity levels were measured for the following: the MSMPR membrane recycle experiments (0.15 ppm and 0.22 ppm), the MSMPR control (0.13 ppm), and batch (0.32 ppm) control experiments. All processes met the regulatory specifications of a maximum of 3 ppm of the impurity 4-hydrainobenzoic acid.

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 …”

Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

“…Continuous crystallisation has been demonstrated on a number of compounds [18][19][20][21] using a range of processing technologies and scales that includes single and multiple stage continuous stirred reactors [22][23][24] and near plug flow reactors, such as oscillatory baffled crystallisers, 25 segmented flow 26 and static mixers. 18 In addition to the general benefits of continuous processing, 9,24,[27][28][29] it offers a means to enhance control of the physical properties of the crystalline product.…”

Design and optimization of a multistage continuous cooling mixed suspension, mixed product removal crystallizer

“…The reasons for investigating these alternative production strategies are to reduce capital and operating costs, improve product quality and increase process safety (Ferguson et al, 2013b;Schaber et al, 2011;Plumb, 2005). The two types of continuous crystallizers encountered in industry are the plug flow crystallizer (PFC) and the mixed suspension, mixed product removal (MSMPR) crystallizer.…”