Crystal Engineering of Pharmaceutical Co-crystals: “NMR Crystallography” of Niclosamide Co-crystals

Niclosamide is a Biopharmaceutics Classification System (BCS) class II taeniacide currently reconsidered for new promising applications including treatment of rheumatoid arthritis, prevention of protein degeneration in neurodegenerative diseases, or even multi-targeted therapy of cancer and cancer stem cells. Its efficacy in medical treatments, however, is currently limited by its insufficient solubility or bioavailability. Thus, we have further explored the potential of hydrogen-bond-mediated co-crystal formation of niclosamide with suitable co-formers selected from either the “Generally Regarded as Safe” (GRAS) or United States Food and Drug Administration (U.S. FDA) “Everything Added to Food in the United States” (EAFUS) list, respectively. Solvent-assisted solid grinding and/or slow solvent evaporation yielded four new co-crystals: (i) niclosamide–2-aminothiazole (NCL-AT), (ii) niclosamide–benzamide (NCL-BA), (iii) niclosamide–isoniazide (NCL-IN), and (iv) niclosamide–acetamide I and II (NCL-AA-I/NCL-AA-II). The crystal structures of NCL-AA-I/II, NCL-AT were solved from white microcrystalline powder samples on the basis of the combined application of powder X-ray diffraction (PXRD), solid-state NMR, and Density Functional Theory (DFT) chemical shift computation. In addition, the crystal structure of the monohydrate NCL-H<sub>A</sub> was reconsidered for comparison. Finally an improvement of the equilibrium solubility of the 1:1 co-crystal NCL-AT could be determined (2.8 times that of pristine NCL and 1.4 times that of NCL-UREA co-crystal), suggesting NCL-AT as a candidate for future medical treatment.