(686d) Microfluidic Spherical Crystallization and Co-Formulation of Drugs and Excipients – Controlling Morphology and Polymorphism

Authors: 
Somasundar, A., National University of Singapore
Khan, S. A., National University of Singapore

Microfluidic Spherical Crystallization and Co-formulation of drugs and excipients – controlling Morphology and Polymorphism

Eunice W. Q. Yeap, Ambika Somasundar, Denise Z. L. Ng, Yiji Wang, and Saif A. Khan*

Department of Chemical and Biomolecular Engineering,

National University of Singapore, SINGAPORE

There is considerable interest in the creation of “designer” pharmaceutical microparticles with controlled morphology and polymorphism, as drug product intermediates for facile formulations. Emulsion-based crystallization is an attractive route for controlling crystal size in downstream processing of active pharmaceutical intermediates (API), yet crystals formed in batch processes show limited control over key attributes like size and shape.[1] We circumvent these limitations, by coupling capillary microfluidics based emulsion generation, with evaporative crystallization for the production of monodispersed spherical API agglomerates.  This platform has allowed us to produce exquisitely designed spherical agglomerates (of drug or drug mixtures), formed in uniform size, composition, morphology and polymorphism.[2-3] We study how precise control over key attributes of drug or drug-excipient microparticles can be achieved by a combination of process and formulation parameters.

In this work, we demonstrate the co-formulation of model hydrophobic API drugs – ROY and carbamazepine – with excipient, ethyl cellulose (EC). We generate monodisperse emulsion drops containing the API-excipient mixture, and subject these droplets to evaporative crystallization in thin films of continuous phase. We find that the co-formulation of API with EC not only shortens the API crystallization process, but also allows for the direct creation of highly monodisperse spherical microparticles containing API crystals and macromolecular excipient, with nearly complete and tunable control over both morphology and polymorphic outcome. Specifically, we control polymorphic selection of both ROY and CBZ in the API-excipient microparticles, by implementing different film thicknesses for the evaporative crystallization; the film thickness mediates the rate of solvent evaporation from the droplets, controlling the kinetics of nucleation and crystallization. We obtain two completely specific and different polymorphic outcomes for each drug when crystallized in the presence of EC under different film thickness. In summary, our methods pave the way for the synthesis and formulation of novel drug product intermediates that bridge the considerable gap between primary and secondary pharmaceutical manufacturing.

Word Count: 308

CONTACT

*  S. A. Khan, Tel: +65-6516-5133; saifkhan@nus.edu.sg

[1] Chadwick, K.; Davey, R. J.; Mughal, R.; Marziano, I., Org. Process Res. Dev. 2009, 13, 1284 − 1290.

[2] Toldy, A. I.; Badruddoza, A. Z. M.; Zheng, L.; Hatton, T. A.; Gunawan, R.; Rajagopalan, R.; Khan, S. A., Cryst. Growth Des. 2012, 12, 3977 − 3982.

[3] Leon, R. A., Badruddoza, A. Z. M., Zheng, L., Yeap, E. W., Toldy, A. I., Wong, K. Y., Hatton, T. A. Khan, S. A., Cryst. Growth Des., 2015, 15 (1), pp 212–218