(310d) Continuous Cocrystallization of Benzoic Acid and Isonicotinamide By Mixing-Induced Supersaturation: Exploring Opportunities between Reactive and Antisolvent Crystallization Concepts

Multicomponent crystalline materials are composed of more than one molecule in its crystal lattice. This includes cocrystals, solid solutions, solvates, and salts. The interest in multicomponent systems is a growing trend within the pharmaceutical industry due to their ability to tailor physical and pharmaceutical properties of active pharmaceutical ingredients (APIs) such as solubility, bioavailability, stability, and the processability of the solid powder within industrial manufacturing processes[1]. They can also be utilized to expand IP portfolios. However, co-crystallization is inherently more complex than single component crystallization as it involves an additional component with additional solid phases. Having additional components and related process variables makes navigating the phase diagram and crystallization process more challenging.

Antisolvent and reactive crystallization approaches can be combined in order to design a process where supersaturation is induced by mixing and is determined by the position in a quaternary phase diagram involving two crystal coformers and two solvents. Depending on the shape of the phase diagram, which often shows a highly unsymmetrical nature[2], the co-crystal would be the thermodynamically most stable phase under some conditions. However, sometimes it may not be readily crystallized due to kinetic limitations (slow nucleation or growth) even if thermodynamically favored. Mixed solvents have previously been used in controlling solid phase outcomes in cooling cocrystallization[3]. Solvent selection, a key design choice in crystallization, becomes more challenging in multicomponent systems. The key parameter of co-crystallization process design is the supersaturation with respect to the co-crystal phase, rather than the supersaturations of the individual co-formers. While having four components increases the complexity of mapping the phase diagram, it also allows for more options how to access solid phase regions which might not be easily accessible at a fixed solvent composition. For example, it may be possible to start with a solution of both coformers undersaturated in one solvent and add a second solvent to induce supersaturation, as in antisolvent crystallization. Alternatively, one can start with one co-former undersaturated in a given solvent mixture, and the other co-former undersaturated in the same solvent mixture and generate supersaturation by mixing these two solutions together, as in reactive crystallization. These decisions will be driven by the shape of the phase diagram and the nature of the target solid phase.

This study[4] combines reactive and antisolvent crystallization concepts to demonstrate a wider range of options for solvent system selection in multicomponent crystallization. This approach was applied to investigate continuous crystallization of 1:1 and 1:2 cocrystals of benzoic acid and isonicotinamide[5]. Mixing induced crystallization allows for rapid targeting of a specific region in the phase diagram as well as easy scale-up through continuous manufacturing. With four components in the crystallization system, Design of Experiments (DoE) with vial screening was used to determine crystallization conditions instead of mapping the entire quaternary phase diagram. Design of Experiments approach was used to identify conditions where pure solid phase is obtained for each cocrystal form as well as conditions suitable for crystallization in continuous flow. Based on this, the continuous mixing-induced co-crystallization process was implemented to selectively produce either 1:1 or 2:1 co-crystals.

Control of cocrystal phase was achieved using two types of mixers in continuous at several throughputs with consistent results. A concentric capillary mixer was used for majority of continuous runs with a comparison run using the Ehrfeld Modular Micro-reactor System. Both setups utilized gear pumps with Coriolis flowmeters to maintain outlet composition. The solid product was characterized for solid phase using XRPD with DSC, IR and NMR for validation. Particle size and shape were measured using Malvern Morphologi G3 by microscopy with image analysis. Conditions for producing pure 2:1 and 1:1 cocrystals were identified. Mixing conditions were found to influence the solid yield and particle size distribution of crystal produced although not the solid form.

The combined antisolvent and reactive crystallization approach can be a useful tool for reaching solid phases that are otherwise difficult to access through mixing-induced supersaturation. Under conditions of thermodynamic control, it may be possible to reach certain regions of phase diagrams that would be not accessible by other approaches due to non-ideal shapes of some phase diagrams. Under conditions of kinetic control, it may be possible to influence nucleation kinetics through the initial mixing of two solutions which would depend on compositions of both solutions as well as mixing conditions applied.

(1) Elder, D. P.; Holm, R.; Diego, H. L. de. Int. J. Pharm. 2013, 453(1), 88–100.

(2) Leyssens, T.; Springuel, G.; Montis, R.; Candoni, N.; Veesler, S. Cryst. Growth Des. 2012, 12(3), 1520–1530.

(3) Munshi, T.; Redha, B.; Feeder, N.; Meenan, P.; Blagden, N. Cryst. Growth Des. 2016, 16(4), 1817–1823.

(4) Svoboda, V.; MacFhionnghaile, P.; McGinty, J.; Connor, L. E.; Oswald, I. D. H.; Sefcik, J. Cryst. Growth Des. 2017, 17 (4), 1902–1909.

(5) Seaton, C. C.; Parkin, A.; Wilson, C. C.; Blagden, N. Cryst. Growth Des. 2008, 9 (1), 47–56.