Microfluidic Approach to Cocrystal Screening of Pharmaceutical Parent Compounds

Abstract

We describe a microfluidic approach to screen for the formation of cocrystalline solid forms of pharmaceutical parent compounds (PCs). Saturated solutions of PCs and of cocrystal formers dissolved in a variety of solvents are precisely metered in arrays of 48 wells to enable the combinatorial mixing of all possible combinations. Key characteristics of the microfluidic approach, including small quantities (∼240 μg/48 conditions), the ability to generate and screen 48 unique conditions per chip, and the ability to identify solid forms on-chip via Raman spectroscopy, enable solid form screening very early in the drug development process. In contrast, current approaches require on the order of ∼240 mg for 48 conditions, thus delaying solid form screening to later stages of the drug development. Sequential screening experiments using caffeine as the model compound were conducted to validate the on-chip approach reported here. Preliminary screens were executed to identify conditions with the highest propensity for crystallization and to identify the cocrystal formers (CCFs) resulting in formation of cocrystals via on-chip Raman spectroscopy. Next, the identified, promising conditions were replicated to confirm reproducibility and consistency of the on-chip outcomes. Nine cocrystals of caffeine were identified in this way.

Using flow technologies to direct the synthesis and assembly of materials in solution

“…Flow technologies are particularly well suited to high-throughput optimisation applications; using small volumes of materials to investigate a wide range of parameters such as co-former [42], concentration [34] and reaction time [38]. Ismagilov and co-workers have developed an array of microfluidic devices for high-throughput optimisation of crystallisation conditions [43, 44].…”

Vibrational Spectroscopy for Cocrystals Screening. A Comparative Study

“…Some examples on cocrystal screening involve mechanochemical grinding [9,10], solvent, and solvent drop sonication in 96-well plates [8,11,12]. Development of miniaturized systems based on microfluidics for cocrystal screening has been increasing [13,14,15].…”

Kinetics of co-crystal formation with caffeine and citric acid via liquid-assisted grinding analyzed using the distinct element method

“…Co-crystallization can also enhance the physical properties of compounds, such as solubility, stability, and compressibility (Steed, 2013;Goyal et al, 2012;Wouters and Quéré, 2011), without disrupting intrinsic structures (Qiao et al, 2011). Co-crystals have been applied in wide range of areas, such as the production of energy materials (Lee et al, 2013), electronics (Yamamura et al, 2012), and pharmaceuticals (Lemmerer et al, 2010).…”