Development and Scale-Up of Cocrystals Using Resonant Acoustic Mixing

In the present work resonance acoustic mixing was applied to afford a practical and environmentally friendly approach to produce and scale up cocrystals. Scale-up options for producing cocrystals are limited. Solution-phase cocrystallizations, although amenable to scale-up in stirred tanks, may be limited due to multiple solubility constraints on both coformers and the product cocrystals, resulting in challenges to find feasible processing conditions. While mechanochemical methods such as liquid-assisted grinding (LAG), solid drop grinding (SDG), and ball-milling have been shown to be more general than solution-phase methods, they are also more difficult and impractical to scale up. In the present work a resonant acoustic mixer was used to intimately mix active pharmaceutical ingredient (API) compound and coformer at high frequency, in the presence of a small amount of solvent, to induce conversion to cocrystals with no grinding media required. Carbamazepine (CBZ) and nicotinamide (NCT) were used as a model system for successfully producing CBZ:NCT cocrystals. Thus, it was shown that resonant acoustic mixing provides the mixing intensity required of lab-scale mechanochemical methods, such as liquid-assisted grinding, but now on a platform more amenable to larger-scale manufacture. Resonant acoustic mixing in general has been demonstrated to be scalable to volumes greater than 200 L and thus affords a potential new platform for cocrystallization processes.