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Crystal Engineering of Pharmaceutical Co-crystals: “NMR Crystallography” of Niclosamide Co-crystals
journal contribution
posted on 2016-04-19, 00:00 authored by David Luedeker, Rebecca Gossmann, Klaus Langer, Gunther BrunklausNiclosamide 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.
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Keywords
niclosamideDensity Functional Theory1.4 timesFDAprotein degenerationDrug AdministrationNiclosamideneurodegenerative diseasesmicrocrystalline powder samplesBCSBiopharmaceutics Classification SystemGRASchemical shift computationequilibrium solubilityclass II taeniacidePXRDUnited States FoodDFTNMREAFUScrystal structurecrystal structuresU.Sapplicationcrystal EngineeringNCL
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