High-throughput screening and scale-up of cocrystals using resonant acoustic mixing

This paper explores the effectiveness of resonant acoustic mixing RAM for screening and scale up of cocrystals. 16 cocrystal systems were selected as test cases based on previous literature precedent. A 96 well plate set up in conjunction with zirconia beads was used for cocrystal screening using RAM. A success rate of 80% was obtained in the screen for plates containing solvent or solvent plus Zirconia beads. A proof of concept production of hydrated and anhydrous cocrystals of 1:1 Theophylline Citric acid system at a 400mg scale was demonstrated using solvent and bead assisted RAM. Finally the parameters affecting the scale up of 2:1 Theophylline Oxalic acid cocrystals was explored in a systematic fashion using a Design of Experiments DOE approach. The RAM parameters of acceleration and mixing time were optimized using the DOE approach. A quantitative XRPD method was developed to determine the extent of conversion to the cocrystal when using RAM Mixing time of 2h and an acceleration of 60G were determined to be optimal. The optimized parameters were used to demonstrate scale up of 2:1 Theophylline Oxalic acid cocrystals at an 80 gram scale with a net yield of 94%. RAM is thus established as an environmentally friendly mechanochemical technique for both high throughput screening and scaled up production of cocrystals.