Understanding the mechanochemical effects of SpeedMixing through the lens of pharmaceutical cocrystals Yong Teoh 1 , Ghada Ayoub 1 , Igor Huskić 1 , Hatem M. Titi 1 , Christopher W. Nickels 2 , Brad Herrmann 3 and Tomislav Friščic 1 1 Mcgill University, Canada, 2 Form-Tech Scientific, Canada, 3 Flaktek, USA Mechanochemistry, the use of grinding or milling methods to synthesize chemicals or materials, is an increasingly popular method to manufacture cocrystals. The solvent free nature of mechanochemistry makes cocrystal synthesis not only greener, but it also bypasses solubility concerns, allowing highly soluble cocrystals to be discovered and synthesized from poorly soluble components. 1 This is particularly applicable to pharmaceuticals, which utilises cocrystals to alter physical and biological chemical properties of the drug without altering the chemical structure of the active pharmaceutical ingredient. 2 Whereas conventional ball milling or twin-screw extrusion equipment is currently highly popular for this purpose, such methodologies rely on the use grinding media that can be a cause of contamination. In order to resolve these challenges of mechanochemical synthesis, we have recently explored the use of a FlackTek SpeedMixer as a mechanochemical tool capable of inducing mechanochemical transformations without milling media, by rapid spinning (SpeedMixing) at rates as high as 3500 rpm to mix the components down to the molecular level (figure 1). Through the addition of liquid additives known, as well as previously not reported, cocrystal forms were synthesized and scaled up with ease.
Figure 1. The spinning motion of speedmixing. In this study, we deepen our understanding of the mechanism of SpeedMixing cocrystallization by looking at the kinetics, intermediates, and the various parameters of the process. The data is compared with ball milling and other methods of cocrystal synthesis and screening, such as slurrying 3 or vapor assisted tumbling, 4,5 to better understand the place of SpeedMixing in the mechanochemical spectrum. References 1. Chadha, K.; Karan, M.; Bhalla, Y.; Chadha, R.; Khullar, S.; Mandal, S.; Vasisht, K. Cocrystals of Hesperetin: Structural, Pharmacokinetic, and Pharmacodynamic Evaluation. Cryst. Growth Des. 2017 , 17, 2386−2405. 2. Tan, D.; Loots, L.; Friščić, T. Towards medicinal mechanochemistry: evolution of milling from pharmaceutical solid form screening to the synthesis of active pharmaceutical ingredients (APIs). Chem. Commun. 2016, 52 , 7760-7781. 3. Haskins, M. M.; Zaworotko M. J. Screening and Preparation of Cocrystals: A Comparative Study of Mechanochemistry vs Slurry Methods. Cryst. Growth Des. 2021 , 21, 7, 4141–4150. 4. Stirk, A. J.; Souza, F.E.S.; Gerster, J.; Mir, F.M.; Karadeoliana, A.; Reya, A.W. Formation of pharmaceutical salts and cocrystals via vapour-assisted tumbling (VAT) – a solvent efficient process. Green Chem. , 2022 . DOI: 10.1039/D1GC03683 5. A. Huskić, I.; Christopherson, J.; Užarević, k.; Friščić, T.; Chem. Commun ., 2016 , 52, 5120-5123.
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