(170d) Solvent Compatible Microfluidic Platforms for Solid Form Screening of Pharmaceutical Parent Compounds

We present solvent compatible microfluidic platforms for solid form (salts, co-crystals, and polymorphs) screening of pharmaceutical parent compounds (PC). Success in finding a crystalline solid form of a PC with optimized CMC properties using conventional screening procedures is limited due to the limited experimental conditions that can be investigated while utilizing small quantities of PCs available (≈ 10 mg) in the early stages of drug development. Microfluidics enable screening with reduced sample volumes of PC solutions [1] and thereby can allow screening of multiple conditions using the limited amount of PC.  This will help reduce the time and money invested in the solid form development of PCs by enabling early identification of all possible solid forms of PCs. 

Previously, we had reported on hybrid polymer based microfluidic platforms that permitted combinatorial mixing of PC and precipitants (salt or cocrystal formers or antisolvents) solutions on-chip in arrays of 24/48, 50 to 200 nL wells, which is a drastic reduction in the volume of PC needed per condition compared to traditional approaches (~5 to 100 ul per condition [2]).  The platforms were designed, fabricated, and validated to screen for solid forms employing different modes of crystallization – free interface diffusion mixing, antisolvent addition, and solvent evaporation.  The developed platforms enabled on-chip solid form identification via Raman spectroscopy.  These platforms were compatible with mild organic solvents such as alcohols, acetonitrile, and water.  However, they were incompatible with a variety of strong organic solvents employed in pharmaceutical crystallization.

Here, we present microfluidic platforms with enhanced solvent compatibility thereby enabling investigation of a much wider range of conditions on-chip. These platforms enable enhanced control over the rates of solvent evaporation compared to previously reported platforms and thereby, high propensity to form crystals on-chip [2].   In this presentation, the design, fabrication, and application of the solvent compatible platforms to solid form screening will be covered. Model compounds such as theophylline and piroxicam have been used to validate the platform’s ability to screen for salts, cocrystals, and polymorphs.  On-chip Raman analysis was employed to identify the salts and cocrystals.

References

[1] C. Hansen, E. Skordalakes, J. Berger, S. Quake, Proc. Nat'l Acad. Sci., 2002, 99, 16531-6.

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