Abstract
Cocrystals of biologically active molecular compounds have potential utility in drug products thanks to their effect upon physicochemical properties such as aqueous solubility. The fact that control of cocrystallization can be more challenging than crystallization of single-component crystals means that systematic studies that address the methodology of cocrystal screening, production, and purification are a topical subject. We previously reported a comparison of slow evaporation vs mechanochemistry for a library of 25 molecular cocrystals. Herein, we compare the previously reported mechanochemistry results (solvent-drop grinding (SDG) with eight solvents) with new results obtained from slurrying in five preferred solvents using the same library of 25 cocrystals. Overall, both methods were found to be effective with slurrying and SDG being 94 and 78.5% successful, respectively. Importantly, 96% of the cocrystals formed via slurrying were observed to be free of starting materials (coformers) according to powder X-ray diffraction (PXRD), whereas this was the case for only 72% of the cocrystals prepared by SDG. Slurrying therefore compared favorably with mechanochemistry, which tends to leave small amounts of unreacted coformer(s) as byproducts, and solution crystallization, which often affords crystals of the least soluble coformer because it can be difficult to control the saturation of three or more solids. Perhaps the most interesting and surprising result of this study was that water slurrying proved to be highly effective, even for low-solubility coformers. Indeed, water slurrying was found to be effective for 21 of the 25 cocrystals studied.
Highlights
An excess of the more soluble coformer used in each slurry was used, but this tended to result in isolation of the less soluble coformer as determined by powder X-ray diffraction (PXRD)
The appropriate stoichiometric amount of the second coformer was determined and used. This approach follows that proposed by Zhang and coworkers[52] by promoting nucleation of the cocrystal since; when both coformers are supersaturated, it is more likely that the system is in the appropriate region of ternary phase diagram to favor cocrystallization
An unknown phase was obtained from the water slurry of resorcinol and tetramethylpyrazine, its PXRD pattern being different from polymorphs or hydrates of the cocrystal or the individual coformers archived in the Cambridge Structural Database (CSD; version 5.42, February 2021) (Figure S16)
Summary
Cocrystals have been defined as “solid single-phase crystalline materials made up of two or more different ionic and/or molecular components, generally in a stoichiometric ratio that are neither solvates, nor simple salts”.1 Crystal engineering of cocrystals has grown as a research subject over the last two decades thanks in part to the inherent amenability of most biological molecules to form pharmaceutical cocrystals through hydrogen-bonded interactions[2−8] and the tendency of the resulting cocrystals to alter the physicochemical properties of a molecular compound without affecting its molecular structure.[6,8] Cocrystals have thereby become relevant to the pharmaceutical industry as they can enhance the bioavailability of low-solubility molecular compounds,[9] sometimes dramatically.[10]. With respect to the SDG method, cocrystal 14 formed in the same solvents used for slurry (H2O, MeOH, and EtOAc), DMF, and DMSO.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
