Molecular conformations of the polymorphic forms of cimetidine from C-13 solid-state NMR distance and angle measurements

The polymorphic drug compound cimetidine, a histamine H-2 receptor antagoni st, was synthesized containing sites of C-13 enrichment at the imidazolium methine carbon C2 and at the guanidinium methyl carbon C16. The structures of four crystalline forms of double C-13-labeled cimetidine, three anhydrat es (A, B, and C) and a monohydrate (M1), were examined using C-13 cross pol arization magic angle spinning (CPMAS) NMR methods. Rotational resonance ma gnetization exchange curves obtained for forms A and M1 were consistent wit h C2-C16 interatomic distances of 3.78 and 3.82 Angstrom as measured from t heir crystal structures. Exchange curves for forms B and C, for which cryst al structures have not been obtained, indicated that in both cases the C2-C 16 interatomic distance lies between 5.2 and 5.8 Angstrom, suggesting that cimetidine adopts a partially extended conformation in these forms. In addi tion, double quantum heteronuclear local field (2Q-HLF) NMR was used to det ermine the relative orientations of the C-13-H bonds at the two C-13-labele d sites. The experimental data were consistent with the known geometry of f orms A and M1 and, in the case of form C, with a limited number of possible structures. Energetically favorable molecular conformations of form C, whi ch were in agreement with the distance and angle measurements, fell into ju st six distinct clusters. These results demonstrate the feasibility of dete rmining the complete solid-state structures of pharmaceutical compounds, an d other materials not amenable to crystallography, using CP-MAS NMR combine d with a minimal isotope labeling strategy.