(410f) Polymorph and Crystal Habit Screening On a Microfluidic Platform

Identification and control of polymorphism and crystal habit of pharmaceutical parent compounds (PC) has become a focal point of research in the pharmaceutical industry for the last century.  Polymorphism is a critical parameter as it influences drugs’ packing, thermodynamic, kinetic, surface and mechanical properties [1].  These properties affect a PC’s likelihood to reach the market.  Identification of all polymorphs allows for the selection of the solid form with the best available physical properties.    Additionally, polymorph identification is critical for securing patents, and for prevention of drugs being pulled from the market.  Identification and control of crystal habit is an equally important factor affecting attriction of PCs.  Crystal habit affects both drug processing and dissolution.  Here, we present a microfluidic approach to assist in crystal habit and polymorphism identification.

Polymorph and crystal habit identification requires extensive screening [2,3,4].  Microfluidics provides an ideal platform for polymorph screening due to its ability to screen many conditions with minimal material.  We utilize multilayer, very-large-scale-integrated, solvent compatibility technologies to develop a microfluidic platform for the screening of PCs using common pharmaceutical solvents.

Here we present a microfluidic chip designed for polymorph and crystal habit screening of APIs via antisolvent crystallization.  Using minimal material, we screen for the crystal habit and polymorphism of two pharmaceutical drugs, Indomethacin and Naproxen, by varying both the solvents employed, and the antisolvent to PC volumetric ratios.  In-situ raman spectroscopy is used to identify polymorphs on-chip.  The solvents, concentrations, and volumetric ratios were found to influence both polymorphism and crystal habit. 

References

[1] Liberski, A. R., Tizzard, G. J., Diaz-Mochon, J. J., Hursthouse, M. B., Milnes, P., Bradley, M., Journal of Combinatorial Chemistry, 2008, 10, 24.

[2] P. Desrosiers, Modern Drug Discovery, 2004, 40.

[3] S. Talreja, D.Y. Kim, A.Y. Mirarefi, C.F. Zukoski, P.J.A. Kenis, J. Appl. Crystallography, 2005, 38, 988-995.

[4] Lee, A. L.,  Lee, I. S., Dette, S. S., Boerner, J., Myerson, A. S., J. Am. Chem. Soc., 2005, 127 14982.