Development and Scale-Up of Cocrystals Using Resonant Acoustic Mixing

Abstract

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.

Promising CL‐20‐Based Energetic Material by Cocrystallization

“…Similar challenges are encountered in both the pharmaceutical industry as well as the energetic community including scalability.T he use of energeticc ocrystals in field operations is directly restricted by the challenges associated with their production on large scale.T raditional methods of forming cocrystals largely rely on solution-phase crystallizationo rg rinding-assisted methods [14].S olution phase methodsc an be challenging to develop as they are prone to precipitation of the discrete coformers, solvateso f the coformers, other polymorphso ft he discrete coformers, and potentially disordered solids or undesired adducts.A lternatively,g rinding-based methods are restricted due to the sensitivity of energetic materials to stimuli. The effectivenesso fR AM for the preparation of pharmaceutical and energetic cocrystals has recently been demonstrated [15,16].H omogeneous mixing of multiple components with significantly different properties can be achieved throught he application of al ow-frequency acoustic field [17].T his mixing system is designedt ok eep the sample in resonance at 60 Hz with the ability to adjust the mixing intensity to accelerate the material from low intensity,n ear O-g acceleration, to high intensity mixing near 100-g acceleration.T he intimatec oupling of the payload to the mixing container and the continuous adjustment to keep the payload in resonance facilitates the transfer of the potential energy stored in the mixers mechanical system.T he propagation of the low frequency wave creates au niform shear field throughout the mixing vessel. Thus the methodi se fficient, rapid, and environmentally friendly [15,18].U nlike stirred tank vessels,t he mixing provided by resonant acoustics is directly scaleable to multi kilogram scale making it scale-transparent; i.e.…”

“…The effectivenesso fR AM for the preparation of pharmaceutical and energetic cocrystals has recently been demonstrated [15,16].H omogeneous mixing of multiple components with significantly different properties can be achieved throught he application of al ow-frequency acoustic field [17].T his mixing system is designedt ok eep the sample in resonance at 60 Hz with the ability to adjust the mixing intensity to accelerate the material from low intensity,n ear O-g acceleration, to high intensity mixing near 100-g acceleration.T he intimatec oupling of the payload to the mixing container and the continuous adjustment to keep the payload in resonance facilitates the transfer of the potential energy stored in the mixers mechanical system.T he propagation of the low frequency wave creates au niform shear field throughout the mixing vessel. Thus the methodi se fficient, rapid, and environmentally friendly [15,18].U nlike stirred tank vessels,t he mixing provided by resonant acoustics is directly scaleable to multi kilogram scale making it scale-transparent; i.e. the same processc an be used on gram as well as kg scale.…”

Interplay Between Mechanochemistry and Sonochemistry

“…Flow configuration and velocity can be altered by changing the acoustic parameters. The particle aggregation mechanism is herein described in terms of stochastic resonance, which contrasts with the usual approach of maintaining equilibrium conditions during crystallization [47]. Similar analogies can be encountered, within the broad context of mechanochemistry, in granules climbing along a vibrating tube, where the force between the tube and the particles varies periodically thus causing a directional effect [48].…”

Preparation of an Energetic‐Energetic Cocrystal using Resonant Acoustic Mixing

“…We recently demonstrated and published our results for development and scale-up of cocrystals via resonant acoustic mixing (RAM) for non-energetic material [1,2]. Cocrystals comprised of two energetic coformers are now the current focus of our research using RAM methods.…”