(451e) Application of Microfluidics in the Solid Form Screening of Pharmaceutical Parent Compounds

We present on the application of solvent resistant microfluidic platforms to screen solid form (salts, co-crystals, and polymorphs) 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. Microfluidic technology capable of screening with reduced sample volumes of PC and precipitants (salt or cocrystal formers or antisolvents) solutions [1] can enable screening of multiple conditions using the limited amount of PC.  This will enable early identification of all possible solid forms of PCs and help reduce the time and money invested in the solid form development. 

To date, we have reported on hybrid polymer-based microfluidic platforms that permit combinatorial mixing of PC and precipitants solutions on-chip in arrays of 24/48, 50 to 200 nL wells [3-6], which is a drastic reduction in the volume of PC needed per condition compared to traditional approaches (~5 to 100 ul per condition [2]).  These platforms were compatible with mild organic solvents and water, and enabled identification of the solid form crystallized on-chip via on-chip Raman spectroscopy. We screened for solid forms of PCs employing free interface diffusion (FID) mixing [3,5], antisolvent addition (AS) [4], and solvent evaporation [6] modes of crystallization employing the polymer-based platforms. 

In this work, we present on the application of the aforementioned solvent compatible platforms to grow single, isolated crystals of PC solid forms (esp. cocrystals) that are hard to distinguish via Raman spectroscopy, employing on-chip seeding methodology followed by solid form identification via in-situ single crystal X-ray diffraction.  In addition, we present the design, fabrication, and application of newly developed solvent resistant microfluidic platforms for solid form screening of PCs.  These hybrid polymer-based microfluidic platforms are compatible with a much wider range of solvents including chloroform, toluene, and hexanes, and thereby enable investigation of a much wider range of conditions on-chip as well as allow a better control on the supersaturation levels attained on-chip.  We employed these platforms to screen for solid forms of model compounds including theophylline, piroxicam, and carbamazepine.  On-chip Raman and X-ray analysis was employed to identify and distinguish different solid forms crystallized on-chip.  These microfluidic platforms have the potential to enable solid form development at the early stages of drug development.

References

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

[2] S. Talreja, P.J.A. Kenis, et al. J. Appl. Crystallography, 2005, 38, 988-995.

[3] M.R. Thorson, S. Goyal, P.J.A. Kenis, et al. Lab Chip, 2011, 11, 3829-3837

[4] M.R. Thorson, S. Goyal, P.J.A. Kenis, et al.  CrystEngComm, 2012, 14, 2404-2412

[5] S. Goyal, P.J.A. Kenis, et al. Crystal Growth & Design, 2012, 12 (12), 6023-6034

[6] S. Goyal, P.J.A. Kenis, et al. Lab Chip, 2013, 13, 1708-1723