Originally discovered almost a century ago, cocrystals continue to gain interest in the modern day due to their ability to modify the physical properties of solid-state materials, particularly pharmaceuticals. Intensification of cocrystal research efforts has been accompanied by an expansion of the potential applications where cocrystals can offer a benefit. Where once solubility manipulation was seen as the primary driver for cocrystal formation, cocrystals have recently been shown to provide attractive options for taste masking, mechanical property improvement, and intellectual property generation and extension. Cocrystals are becoming a commercial reality with a number of cocrystal products currently on the market and more following in registration and clinical trial phases. Increased commercialization of cocrystals has in turn necessitated additional research on methods to make cocrystals, with particular emphasis placed on emerging technologies that can offer environmentally attractive and efficient options. Methods of producing cocrystals and of harnessing the bespoke physical property adjustment provided by cocrystals are reviewed in this article, with a particular focus on emerging trends in these areas.

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Controlling pharmaceutical polymorphism in crystallization processes represents a major challenge in pharmaceutical science and engineering. For instance, CO 2antisolvent crystallization typically favors the formation of metastable forms of carbamazepine (CBZ), a highly polymorphic drug, with impurities of other forms. This work demonstrates for the first time that a supercritical CO 2antisolvent crystallization process in combination with certain molecular additives allows control of the polymorphic outcome of CBZ. We show herein that in the presence of sodium stearate and Eudragit L-100, needle-shaped crystals of CBZ form II are obtained, while blocky-shaped crystals of CBZ form III are obtained in the presence of Kollidon VA64, sodium dodecyl sulfate, ethyl cellulose, and maltitol. This selectivity for pure forms in this supercritical set up contrasts to the results when the same set of additives where used in a solvent evaporation method that yielded mixtures of form I, II, and III. The type of additive used in the CO 2 -antisolvent crystallization process impacted both the product crystal polymorphic form and size. A detailed molecular-level analysis along with density functional theory calculations allowed us to give a mechanistic insight into the role of sodium stearate and Eudragit L-100 in facilitating nucleation of the metastable form II.

Carbon dioxide has been extensively used as a green solvent medium for the crystallization of active pharmaceutical ingredients (APIs) by replacing harmful organic solvents. This work explores the mechanisms underlying a novel recrystallization methodcocrystallization with supercritical solvent (CSS)which enables APIs cocrystallization by suspending powders in pure CO 2 . Six well-known APIs that form cocrystals with saccharin (SAC) were processed by CSS, namely, theophylline (TPL), indomethacin (IND), carbamazepine (CBZ), caffeine (CAF), sulfamethazine (SFZ), and acetylsalicylic acid (ASA). Pure cocrystals were obtained for TPL, IND, and CBZ (with SAC) after 2 h of CSS processing. Convection was revealed to be a determining parameter for successful cocrystallization with high-yield levels. TPL− SAC was selected as a model system to study the cocrystallization kinetics in the gas, supercritical, and liquid phases under different conditions of pressure (8−20 MPa), temperature (30 to 70°C), and convection regimes. The solubility of each substance in CO 2 was measured at the selected working conditions. TPL−SAC showed a cocrystallization rate of 2.9% min −1 , two times higher than that of IND−SAC, due to the higher solubility of TPL in CO 2 . The cocrystallization kinetics was also improved by increasing the CO 2 density, showing that cocrystallization was limited by the dissolution of cocrystal formers. Overall, the CSS process has a potential for scale-up as a novel, simple, solvent-free batch process whenever the cocrystal phase is formed in the CO 2 media.

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