Crystallization of active pharmaceutical ingredients using microfluidic platforms and meniscus-guided coating

Long lead times and large development cost has led the pharmaceutical industry to evaluate and improve pharmaceutical development and manufacturing procedures. Emphasis has been placed on the connection between drug development and discovery, especially on characterization of candidate drugs earlier in drug development. High throughput screens yield multiple solid forms of candidate drugs that are later characterized and prioritized for further development. Another focus within the pharmaceutical industry has been to improved manufacturing practices with continuous manufacturing and online monitoring for quality control. Additive manufacturing, where drugs are assembled layer-by-layer, is a technique used to improve process development. Microfluidics platforms have been validated for high throughput crystallization of pharmaceutical solid form screening of polymorphs, salts, and cocrystals, however the solid forms obtained are often poor quality crystals that can only be characterized by vibrational spectroscopy (e.g,. infrared or Raman). In this work X-ray compatible microfluidic platforms were develop for on-chip characterization. Crystal growth was controlled by on-chip crystal seeding. This allowed for controlled growth of only one polymorph and growth of large diffraction quality crystals. Diffraction data was collected from crystals residing within the chip and the resulting crystal structure had similar resolution to the previously reported structures. This work validates the use of X-ray characterization on-chip. Solid form screens of two model systems, piroxicam cocrystals and clofazimine salts, were conducted on and off-chip. The goal of this work was to determine (1) if microfluidic platforms would lead to good quality crystals suitable for X-ray diffraction and (2) if microfluidic platforms could facilitate solid form discovery. Concentration and solvent were varied to elucidated different crystal structures. Four solid forms of piroxicam cocrystals were identified via the on-chip screen. Three of the solid forms were good enough crystals for X-ray diffraction, and two of those solid forms had not been identified in off-chip experiments. Four solid forms of clofazimine salts were observed, three were grown in traditional glass vials and one was grown in a microfluidic platform. Three of the solid forms had not been previously reported including the solid form grown in the microfluidic platform. Both works yielded the discovery and crystal structure of solid forms from crystals grown within a microfluidic platform. This work emphasizes the need for multiple crystallization techniques used for high throughput screening of pharmaceuticals, possibly including the use of microfluidic platforms. Meniscus-guided coating was explored as an additive manufacturing technique to make pharmaceutical thin films. Crystalline films were grown on a biocompatible polymer substrate and characterized by polarized optical microscopy to determine the film morphology and X-ray diffraction (powder and grazing incidence) to determine the molecular packing. Process parameters such as concentration of drug in solution and shearing speed were varied resulting in changes in the film morphology, thickness, and polymorph. Aspirin thin films displayed spherulitic and oriented morphology, however the molecular packing was of both morphologies was consistent with the reported crystal structure for aspirin. Films of ellipticine, a model drug, were found to also display multiple morphologies, and again the molecular packing of the different morphologies was the same. However, the ellipticine films did not match the reported crystal structure, the films pack in a second polymorph of ellipticine. Through this work meniscus-guided coating was a useful technique for growing thin pharmaceutical films and controlling the molecular arrangement of the model drugs. Meniscus-guided coating can expand the manufacturing approaches for pharmaceutical additive manufacturing