Crystallization Optimization of Pharmaceutical Solid Forms with X‑ray Compatible Microfluidic Platforms

We describe a microfluidic approach
to optimize crystallization
of active pharmaceutical ingredients (APIs) and their solid forms
(cocrystals) via crystal seeding. Subsequent on-chip X-ray diffraction
is used to verify the crystal from. The microfluidic platform comprises
an 8 × 9 well array that enables screening of seeding conditions
(dilutions) by metering of API solution or API/cocrystal former solution
and seed solution in ratios of 1:4 to 4:1, respectively, across each
row. Slow solvent evaporation leads to seed growth and results in
isolated diffraction quality crystals. To validate this microfluidic
crystal seeding approach, three APIs (piroxicam, piracetam, and carbamazepine)
and a cocrystal (carbamazepine/4-hydroxybenzoic acid) were used as
model compounds. X-ray diffraction data was collected on-chip at room
temperature to determine the crystal structure of the model compounds
for comparison to published structural data. This on-chip seeding
approach aided in crystallization of a desired solid form (e.g., a
specific polymorph) over a mixture of solid forms. Easy handling,
automated seeding and dilution, high throughput screening using small
quantities of API (about 5 μg/well), and on-chip X-ray analysis
of multiple crystals makes this platform attractive for solid form
identification and characterization.