(198d) Measuring the Rate of Co-Crystal Nucleation Utilizing Continuous Microfluidic Droplet Generation

Co-crystals provide a unique method for tuning the physical properties of crystalline products such as APIs. Many drugs with poor bioavailability can be made more effective with the addition of a co-crystal former. However large-scale production of co-crystal products requires an understanding of nucleation rate associated with the system. Previously, it has been difficult to directly measure the nucleation rate using macroscopic techniques. However, with the advent of droplet based microfluidic techniques, direct observation of nucleation statistics is possible by treating each droplet as an individual crystallization event. It is desired to observe as many droplets as possible simultaneously to improve the confidence of the gathered statistics. Continuous droplet generation permits the observation of very large droplet counts, without the need for a proportionally larger device or complex microscopy techniques. Our work uses a T-junction droplet generation nozzle connected to a serpentine residence track to demonstrate proof of concept of a continuous co-crystallizing device. We examine nucleation rates for the co-crystal system of caffeine and malic acid, which allows us to test the influence of various parameters including temperature step, ratio of co-formers, and presence of additives on the nucleation rate. The ability to efficiently study co-crystallizing systems allows for the exploration of previously untested compositions, and contributes to the development of new APIs.