Mechanochemistry: Fundamentals, applications and future

Solvent-free synthesis of pharmaceuticals by twin-screw extrusion Aaron S. McCalmont 1 , Deborah E. Crawford 2 , Stuart L. James 1 , Stefania M. Scalzullo 3 and Hugh Hamilton 3 1 School of Chemistry and Chemical Engineering, Queen’s University Belfast, UK, 2 School of Chemistry and Biosciences, University of Bradford, UK, 3 Johnson Matthey Technology Centre, UK Despite reactive ball milling being capable of facilitating solvent-free chemistry, 1 translation to large scale for industrial implementation can prove problematic, thus requiring an alternative technique. One approach is Twin-Screw Extrusion (TSE), in which reagents are mixed and conveyed along a confined, heatable barrel by two intermeshing, rotating screws. 2 In addition to more conventional applications in material processing 3 and Pharmaceutical formulation, 4 TSE has been demonstrated for the continuous, multi-kg preparation of cocrystals, 5 and the synthesis of both Metal Organic Frameworks (MOFs), 6 and Active Pharmaceutical Ingredients (APIs). 7 In the case of APIs, TSE offered cost, sustainability and operational advantages for the synthesis of nitrofurantoin over the conventional solvent-batch system, by comparing Life Cycle Assessments (LCAs) of the respective processes. 8 Taking these findings as a starting point, we are investigating TSE for the synthesis of pharmaceutically-relevant compounds comprising common functional groups, such as amides, heterocycles and C-C bonds. 9 Initial studies of amide-bond formations have proven successful, enabling the facile synthesis of Paracetamol® under ambient, solvent-free conditions. Furthermore, the potential of TSE to improve drug bioavailability was highlighted by the simultaneous synthesis and co-amorphisation of Paracetamol® with citric acid. References 1. T. Friščić, C. Mottillo and H.M. Titi, Angew. Chem. Int. Ed. , 2020, 59 , 1018-1029. 2. D.E. Crawford and J. Casaban, Adv. Mater. , 2016, 28 , 5747-5754.

3. R. Chokshi and H. Zia, Iran. J. Pharm. Res. , 2004, 3 , 3-16. 4. M. Maniruzzaman, et al. , ISRN Pharm. , 2012, 2012 , 1-9. 5. D. Daurio et al. , Pharmaceutics , 2011, 3 , 582-600. 6. D. Crawford et al. , Chem. Sci. , 2015, 6 , 1645-1649.

7. D.E. Crawford et al. , ACS Sustainable Chem. Eng. , 2020, 8 , 12230-12238. 8. O. Galant et al. , ACS Sustainable Chem. Eng. , 2022, 10 , 1430-1439. 9. J.S. Carey et al. , Org. Biomol. Chem. , 2006, 4 , 2337-2347.

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