Combining the Advantages of Powder X-ray Diffraction and NMR Crystallography in Structure Determination of the Pharmaceutical Material Cimetidine Hydrochloride

Abigail E. Watts,Colan E. Hughes,Keisuke Maruyoshi,Steven P. Brown,Kenneth D. M. Harris

doi:10.1021/acs.cgd.6b00016

Abstract

We report the crystal structure of the anhydrous phase of cimetidine hydrochloride, determined directly from powder X-ray diffraction data. The material was prepared by dehydration of the readily obtained monohydrate form of cimetidine hydrochloride, the only form for which a crystal structure has previously been reported. As such, solid-state dehydration processes typically yield the product phase as a microcrystalline powder, and structure determination was carried out directly from powder X-ray diffraction data, using the direct-space genetic algorithm technique for structure solution followed by Rietveld refinement. The structure determined from powder X-ray diffraction was further validated by calculating solid-state 13C NMR data for the crystal structure (using first-principles periodic DFT techniques within the GIPAW approach) and assessing the quality of agreement with the corresponding experimental solid-state 13C CPMAS NMR data. This strategy provides a robust vindication of the correctness of the crystal structure by assessing the quality of agreement of the structure both with experimental powder X-ray diffraction data and with experimental solid-state 13C NMR data.

Highlights

Powder X-ray diffraction (XRD) and solid-state NMR spectroscopy are two of the most powerful techniques for characterizing structural properties of polycrystalline samples of organic materials
Within the context of crystal structure determination, the prospects for combining the complementary information provided by these two techniques has the potential to yield more detailed insights than may be obtained from the use of just one of these techniques alone
Following determination of the crystal structure of the anhydrous phase of cimetidine hydrochloride from powder XRD data in the present work, first-principles DFT calculations within the GIPAW approach were used to calculate the solidstate 13C NMR data corresponding to the structure, followed by careful scrutiny of the agreement between the calculated and experimental solid-state 13C NMR data

Summary

■ INTRODUCTION

Powder X-ray diffraction (XRD) and solid-state NMR spectroscopy are two of the most powerful techniques for characterizing structural properties of polycrystalline samples of organic materials. We exploit powder XRD, combined with analysis of solid-state NMR data, to determine the crystal structure of the anhydrous phase of cimetidine hydrochloride. Following determination of the crystal structure of the anhydrous phase of cimetidine hydrochloride from powder XRD data in the present work, first-principles DFT calculations within the GIPAW approach were used to calculate the solidstate 13C NMR data corresponding to the structure, followed by careful scrutiny of the agreement between the calculated and experimental solid-state 13C NMR data. The final Rietveld refinement was carried out using the data set recorded over the 2θ range 6−70°, with cimetidine hydrochloride monohydrate included as a second phase in the refinement. The results from these calculations confirm that the sample analyzed in our experimental solid-state 13C NMR study was the anhydrous form of cimetidine hydrochloride

■ RESULTS AND DISCUSSION

■ ACKNOWLEDGMENTS

■ REFERENCES