(23e) Microfluidic Platforms to Screen for Crystallization Conditions of Active Pharmaceutical Ingredients

Screening for polymorphs is critical in the API development process.  Identifying the available solid forms of candidate drugs (CD) as early as possible require intensive screens varying multiple parameters including counter ions, antisolvent and concentration of the CD.

Presently, highly complex robotic systems are used at the macroscale that utilize sample volumes of the order of 5 µl per condition [1,2]. Due to small quantity of the CD available in the early stages, number of conditions that can be screened is limited. Microfluidics have the potential to improve high throughput screening by utilizing reduced sample volumes, allowing improved control over mixing of fluids via free interface diffusion, and increasing the number of conditions that can be screened simultaneously [3]. 

Here we present a microfluidic platform enabling high throughput screening (48 wells on one platform) of antisolvents for polymorphism and crystal habit of APIs utilizing extremely small sample volumes (50nl per well). Several parameters like ratio of volume of API to antisolvent (varied from 1:5 to 5:1), solvent, and API concentration are varied to control supersaturation and are found to influence crystal habit and polymorphism. The microfluidic platform has been modified to enable in-situ Raman spectroscopy for the analysis of crystals and validation of polymorphs crystallized on-chip without need to manually harvest crystals from the chip. To support experimental results, we modeled the effect of geometry of wells on the supersaturation profiles and hence on the nucleation kinetics of the API with antisolvent. We demonstrate the capability of the chip using two model APIs – Indomethacin and Naproxen to generate different polymorphs and crystal morphologies on chip.

References

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

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

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