Molecular Conformations of the Polymorphic Forms of Cimetidine from ¹³C Solid-State NMR Distance and Angle Measurements

Abstract

The polymorphic drug compound cimetidine, a histamine H2 receptor antagonist, was synthesized containing sites of 13C enrichment at the imidazolium methine carbon C2 and at the guanidinium methyl carbon C16. The structures of four crystalline forms of double 13C-labeled cimetidine, three anhydrates (A, B, and C) and a monohydrate (M1), were examined using 13C cross polarization magic angle spinning (CP-MAS) NMR methods. Rotational resonance magnetization exchange curves obtained for forms A and M1 were consistent with C2−C16 interatomic distances of 3.78 and 3.82 Å as measured from their crystal structures. Exchange curves for forms B and C, for which crystal structures have not been obtained, indicated that in both cases the C2−C16 interatomic distance lies between 5.2 and 5.8 Å, suggesting that cimetidine adopts a partially extended conformation in these forms. In addition, double quantum heteronuclear local field (2Q-HLF) NMR was used to determine the relative orientations of the 13C−H bonds at the two 13C-labeled sites. The experimental data were consistent with the known geometry of forms A and M1 and, in the case of form C, with a limited number of possible structures. Energetically favorable molecular conformations of form C, which were in agreement with the distance and angle measurements, fell into just six distinct clusters. These results demonstrate the feasibility of determining the complete solid-state structures of pharmaceutical compounds, and other materials not amenable to crystallography, using CP-MAS NMR combined with a minimal isotope labeling strategy.

Crystal Polymorphism of Protein GB1 Examined by Solid-State NMR Spectroscopy and X-ray Diffraction

“…The SSNMR analysis of forms D and E yielded spectra with very few overlapped resonances and narrow linewidths, ~0.2 ppm for 13 C (displayed in Figure 1 and Figure 2) and less than 0.8 ppm for 15 N. In both of these forms, a single resonance was observed for every 13 C and 15 N atom, consistent with a single homologous structure. N(CA)CX spectra of both these forms are displayed in Figure 5 along with the spectrum acquired on form A, highlighting the overall similarities.…”

“…[14][15][16][17][18] One such study by Paulson et al showed that nanocrystalline sample preparations of ubiquitin yielded three different sets of 1 H- 15 N correlation spectra, resulting from three different polymorphs. 10 Subsequently Siedel et al assigned the C', CA and CB chemical shifts for two of these polymorphs.…”

“…11 Both of these studies focused on chemical shift differences among the backbone resonances. Backbone CA shifts report primarily on backbone conformation, [19][20][21][22] whereas 15 N chemical shifts depend upon not only conformation but are especially sensitive to electrostatics and hydrogen bonding. 23,24 Carbonyl chemical shifts also show a dependence on hydrogen bonding, as well as backbone conformation.…”

“…23,24 Carbonyl chemical shifts also show a dependence on hydrogen bonding, as well as backbone conformation. 19,25,26 However, the C', CA and backbone 15 N chemical shifts are not the most prominent reporters on the subtle changes among crystal formulations including intermolecular crystal contacts, protonation state of the ionizable sidechains, aromatic ring interactions and salt bridge geometry. Rather, sidechain residues, especially charged sidechains, are involved in all of these events; 27 therefore these sites are expected to demonstrate the largest changes in chemical shifts upon minor changes in formulation.…”

Low temperature structure and dynamics of β-chloropivalic acid

“…The shape of neopentane (CH 3 ) 4 C can be regarded as a sphere, where as pivalic acid CH 2 Cl(CH 3 ) 2 CCOOH forms dimers and therefore is cigar-like shaped. The surface of these bodys are smooth and the rotation is not sterically hindered.…”