(707a) Microfluidic Platform for Cocrystal Screening and Characterization

Microfluidic Platform for Cocrystal Screening and Characterization

Elizabeth Horstman,¹ Geoff G. Z. Zhang,² Yuchuan Gong,² and Paul J. A. Kenis¹

¹Department of Chemical & Biomolecular Engineering, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801,USA.

²Materials Science, Global Pharmaceutical R & D, AbbVie Laboratories, 1401 Sheridan Road, NCR13-317B, North Chicago, Illinois 60064, USA.

In pharmaceutical drug discovery, thousands of compounds are screened to determine if the active pharmaceutical ingredients (APIs) have appropriate physical and chemical properties.  Most APIs on the market are crystalline so in depth solid form screening is done to determine the experimental conditions needed to produce the desired solid form (polymoph, cocrystal, or salt) of the API.  Unfortunately, at the early stages of drug discovery only small quantities of APIs are available for testing, limiting the number of screening conditions.  To address this challenge, we have developed microfluidic platforms for crystallization of pharmaceutical solid forms.^1-2  Utilizing a microfluidic platform allows the quantity of API needed per condition to be reduced from 5 mg to 5 μg per condition.  Additionally, microfluidic platforms can be designed to be compatible with solid form analysis instruments used to differentiate solid forms such as Raman spectroscopy or X-ray diffraction.³

An increasing number of APIs in the pipeline have low aqueous solubility. To address this issue, APIs can be crystallized with other small molecules to produce a cocrystal.  We developed a simple array based microfluidic platform comprised of single isolated microwells for high throughput screening.  In this work, we present the discovery and characterization of cocrystals of piroxicam (PRX) and 2,5-dihydroxybenzoic acid (HBA). Two cocrystals were identified via solvent evaporation and subsequently characterized with X-ray diffraction.  One was a 1:1 molar raito of PRX-HBA and the other was a solvated cocrystals containing acetone in a 1:1:1 molar ratio, PRX-HBA-ACT.  The inclusion of acetone was unexpected since acetone was not used in the crystallization experiment and not identified until the structure of the cocrystal was determine. To further characterize the thermal properties of the cocrystals slurry crysalliztion was used to make bulk quantities (gram scale) of the cocrystals.  Thermogravimetric analysis and differential scanning calorimetry were used to determine the desolvation temperature of PRX-HBA-ACT and the melting temperatures of the cocrystals.  Powder X-ray diffraction data was taken as a function of temperature to determine the phase behavior of PRX-HBA-ACT during desolvation.  Overall this work points to the importance of structure determination of pharmaceutical solid forms and the importance on impurities.⁴

References
1.  M.R. Thorson, P.J.A. Kenis, et al. Lab Chip, 2011, 11, 3829-3837

2.  M.R. Thorson, P.J.A. Kenis, et al.  CrystEngComm, 2012, 14, 2404-2412

3.  E.M. Horstman, P.J.A. Kenis, et al. Cryst. Growth Des., 2015, 15 , 1201–1209  

4.  E.M. Horstman, P.J.A. Kenis, et al. CrystEngComm, 2015, DOI: 10.1039/c5ce00355e