Solid-State NMR, X-ray Diffraction, and Thermoanalytical Studies Towards the Identification, Isolation, and Structural Characterization of Polymorphs in Natural Bile Acids

Abstract

Combined solid-state NMR, powder, and single crystal X-ray diffraction, as well as thermoanalytical studies were performed towards the identification, isolation, and structural characterization of polymorphs present in commercial samples of six natural bile acids. The 13 C{ 1 H} cross-polarization (CP) magic angle spinning (MAS) NMR technique was used as a primary tool to identify the mixture of polymorphs present in the natural bile acids obtained from commercial sources. A detailed study including selective crystallization of each polymorphic form of the bile acids in different solvents and mixture of solvents was carried out, and their spectral patterns were compared with the mode of packing and number of molecules present in an asymmetric unit. These studies were strongly supported by other complementary techniques such as powder/single crystal X-ray diffraction and differential scanning calorimetric (DSC) experiments. While a few single crystal X-ray structures are solved in order to confirm the correct polymorphic form, most of the powder X-ray diffraction data were compared with the simulated X-ray patterns obtained from previously reported single crystal structures. Detailed analyses using multiple experimental techniques provided useful insights towards the mode of packing which is responsible for unique spectral patterns in the solid state.

Unraveling the packing pattern leading to gelation using SS NMR and X-ray diffraction: direct observation of the evolution of self-assembled fibers

“…Depending on the solvent, cholic acid undergoes crystallization to furnish different polymorphic forms. 33 Samples obtained after crystallization from N, N-dimethylformamide (DMF) resulted in a doublet resonance, where as those from acetone displayed a singlet resonance pattern. However, recrystallization from methanol or ethanol resulted in solvate structures.…”

“…In the case of crystallization from DMF, the doublet resonance nature originates from the two nonequivalent molecules which show a significant difference in the conformation of the side chain and mode of hydrogen bonding patterns of the two molecules present in an asymmetric unit. 33…”

Solvent-Driven Transformation of Zn/Cd2+-Deoxycholate Assemblies

“…However, the size determined from the SAXS data (Figure S4, diameter of 9 Å) is similar to that of a single unassociated molecule, rather than a dimer. Moreover, the size distribution analysis shown in Figure S5 was carried out with a spherical model, and the size distribution is extremely narrow, meaning the DOC molecules are more spherical in a methanol solution than the oblong shape that is observed in every structure we and others − , have published of DOC-acid or metal-DOC complexes. This is also qualitatively evident in the shape of the scattering curves.…”

Facile synthesis of 5β-cholane-sym-triazine conjugates starting from metformin and bile acid methyl esters: Liquid and solid state NMR characterization and single crystal structure of lithocholyl triazine

“…We have found similar behaviour with the naturally occurring bile acids: the crystals containing two molecules per asymmetric unit always have the doublet resonance patterns in their 13 C CP/ MAS spectra. This has been explained to be due to the differences in the side chain as well as in the hydrogen bonding modes of these non-equivalent molecules [10]. In the case of crystals of 4b from DMF-CH 3 CN largest differences in the chemical shift values between the two peaks in the doublet resonances are found in the hydroxyl region which supports the existence of two non-equivalent molecules with different hydrogen bonding systems.…”

“…Studies on the polymorphism of several bile acid derivatives have been reported from our laboratory [9]. Recently we also studied the polymorphic nature of naturally occurring bile acids [10]. Molecular structure and crystal packing of 4a was determined utilizing single crystal X-ray crystallography.…”