(466d) Use of Continuous Msmpr Crystallization With Integrated Nanofiltration Membrane Recycle for Enhanced Yield and Purity in API Crystallization

Ferguson, S. T., Massachusetts Institute of Technology
Ortner, F., TU Munich
Quon, J., Massachusetts Institute of Technology
Peeva, L. G., Imperial College London
Livingston, A., Imperial College London
Myerson, A. S., Massachusetts Institute of Technology
Trout, B. L., Massachusetts Institute of Technology

 Crystallization is the most widely used separation and purification technique in the pharmaceutical industry. Therefore, it is essential that continuous crystallization techniques are available to meet or exceed the purity and yield achievable in current batch crystallization processes if they are to be widely utilized in pharmaceutical production. Continuous tank based MSMPR crystallizers operate at steady state at a fixed position on the phase diagram for a given crystallization. This means that the process can operate at a set of conditions (temperature, solvent composition, supersaturation etc.) that are kinetically favorable for a given crystallization. In cases where these kinetically favorable conditions require a higher liquid phase solute concentration than the alternate batch crystallization (at final isolation conditions), there would be an associated loss in yield. Any such loss in yield can be eliminated by recycling concentrated mother liquor back into the MSMPR.  An evaporation based mother liquor recycle strategy enabled improved crystallization performance in terms purity for the API cyclosporin compared with the current commercial batch process. [1]

 Evaporation based concentration and recycling of mother liquor recycle has two major limitations that can be mitigated by the use of a nanofiltration membrane module in its place. Firstly, evaporation will change the solvent composition in mixed solvent and solvent anti-solvent systems, thus limiting this techniques applicability. This is not an issue for nanofiltration concentration as it works through selective molecular sieving. In this case, API molecules are preferentially retained by the membrane relative to the smaller solvent molecules. The concentrated retentate stream from the membrane is then recycled back to the crystallizer. In this work a nanofiltration module is successfully used to concentrate the recycle stream for the MSMPR crystallization of an API from a mixed solvent system (THF:Ethanol) using combined cooling anti-solvent (Water) approach to generate supersaturation.

 In both the evaporative concentration and the nanofiltration module, the limiting factor on yield is the purification requirements for the API in question. For this reason API containing solution must be purged at a rate that prevents the build up of impurities in the system, thus reducing the process yield. However, nanofiltration can also allow preferential removal and purging of impurities that have a reasonable large deviation in structure or molecular weight compared to a given API. [2] This was the case for the crystallization of the API in this study (MW=373 g/mol) where the most significant impurity had a lower molecular weight of 152 g/mol. Through screening experiments, a membrane that allowed preferential permeation of impurity was found and incorporated into the MSMPR recycle process. This negated the need for the use of a purge stream to reduce impurity concentration, resulting in significantly higher yield and comparable or improved purity than would be attainable in batch or standard MSMPR crystallizations.

 [1]          Wong, S.Y., Tatusko, A.P., Trout, B.L., Myerson, A.S. (2012). Development of Continuous Crystallization Processes. Using a Single-Stage, Mixed-Suspension, Mixed-Product Removal Crystallizer with Recycle. Cryst. Growth & Des. 12(11), 5701-5707.

[2]          Sereewatthanawut, I., Lim ,W., Bhole, Y.S., Ormerod, D., Horvath, A., Boam, A.T., Livingston, A.G. (2010). Demonstratio of Molecular Purification in Polar Aprotic Solvents by Organic Solvent Nanofiltration. Org. Proc. Res & Des. 14, 600-611.