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

Abstract

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-HA 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.

A13C solid-state NMR investigation of four cocrystals of caffeine and theophylline

“…As such, cocrystals provide an especially attractive set of comparison compounds, wherein the systematic substitution of one of the coformers enables 'control' comparisons of chemical shifts to isolate contributions to the chemical shift. While there is an extensive literature on the application of solid-state NMR for the investigation of organic solids, the technique has only recently gained momentum in the study of cocrystals (Vogt et al, 2009;Chierotti & Gobetto, 2013;Dudenko et al, 2013b;Mandala et al, 2014;Fernandez et al, 2015;Kerr et al, 2016;Luedeker et al, 2016). We report here a 13 C solid-state NMR study of a controlled set of four cocrystals of two API mimics (theophylline and caffeine) and two diacid coformers (malonic acid and glutaric acid).…”

Single-crystal X-ray diffraction and NMR crystallography of a 1:1 cocrystal of dithianon and pyrimethanil

“…The computational analysis is complemented by the recording of 1D (one-dimensional) and 2D (two-dimensional) experimental 1 H and 13 C MAS NMR spectra. Building upon studies of pharmaceutical cocrystals by such an NMR crystallography investigation (Tatton et al, 2013;Dudenko et al, 2013;Stevens et al, 2014;Kerr et al, 2015;Sardo et al, 2015;Luedeker et al, 2016), we present here the application of this approach to an agrochemical cocrystal.…”

Characterization of Pharmaceutical Cocrystals and Salts by Dynamic Nuclear Polarization-Enhanced Solid-State NMR Spectroscopy

“…20,26,[32][33][34] Brunklaus and co-workers have used 1 H and 13 C solid-state NMR experiments in combination with DFT calculations and powder X-ray diffraction (P-XRD) to solve the crystal structures of multicomponent solids. 33,35 A variety of 6 15 N solid-state NMR experiments have also been applied to understand nitrogen protonation states in organic solids and materials [36][37][38][39][40][41] and biological systems. 24,42,43 Unfortunately, the sensitivity of solid-state NMR spectroscopy is intrinsically poor and many of the aforementioned experiments require extremely long experiment times when samples have 15 NMR experiments on natural abundance samples typically require many hours or even days of signal averaging obtain spectra with adequate signal-to-noise ratio (SNR).…”