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

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.

Assessing the Detection Limit of a Minority Solid-State Form of a Pharmaceutical by 1H Double-Quantum Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy

“…Cimetidine and cimetidine hydrochloride were purchased from Sigma-Aldrich and used without further purification. The identification of the specific solid-state form was confirmed by PXRD as shown in the studies by Tatton et al 33 and Watts et al 53 Samples containing 10%, 5%, 1%, and 0.5% w/w polymorph A/anhydrous HCl salt were prepared by physically mixing appropriately weighed quantities of the 2 pure solid phases.…”

“…In previous studies, 1-dimensional 13 C CP MAS NMR spectra, as well as the results of various heteronuclear dipolar experiments, have been presented for a free form of cimetidine (polymorph A), 58,59 whereas a 13 C CP MAS spectrum of the anhydrous HCl salt of cimetidine as well as a gauge-including projector-augmented wave (GIPAW) calculation 60,61 of the NMR parameters (for the reported crystal structure following geometry optimization) have been presented recently. 53 Tatton et al 33 have also presented 15 N-1 H spectral-editing and 14 N-1 H and 15 N-1 H correlation spectra for polymorph A of cimetidine, together with GIPAW calculations of the chemical shielding and electric field gradient tensors for the reported crystal structure 62 following geometry optimization. Note that distances stated in this paper are from the geometryoptimized crystal structures on which these GIPAW calculations were carried out (available as Supporting Information in studies by Tatton et al 33 and Watts et al 53 ).…”

“…53 Tatton et al 33 have also presented 15 N-1 H spectral-editing and 14 N-1 H and 15 N-1 H correlation spectra for polymorph A of cimetidine, together with GIPAW calculations of the chemical shielding and electric field gradient tensors for the reported crystal structure 62 following geometry optimization. Note that distances stated in this paper are from the geometryoptimized crystal structures on which these GIPAW calculations were carried out (available as Supporting Information in studies by Tatton et al 33 and Watts et al 53 ).…”

“…19 However, due to the spectral noise associated with the application of 1 H homonuclear decoupling in the CRAMPS approach, it is only possible to conclude that the hydrate form is absent within a detection limit of~5% for the spectra presented in the study by Griffin et al 19 An alternative approach is to use a combination of fast MAS and high magnetic field to give 1 H DQ MAS spectra, where the resolution, although not as good as with the 1 H DQ CRAMPS method, 51 is sufficient to resolve distinct spectral features. For the specific case of the anhydrous HCl salt of cimetidine (the crystal structure of which has been determined recently 53 by a combined PXRD and NMR crystallography strategy) and the free form of cimetidine (anhydrous polymorph A), this article investigates the lower limit of detection of a minority solid-state form of an API, present in a physical mixture with another crystalline phase of the same API, using 1 H DQ MAS NMR spectroscopy.…”

Paenidigyamycin G: 1-Acetyl-2,4-dimethyl-3-phenethyl-1H-imidazol-3-ium

“…The imidazole nucleus represents an important heterocyclic core in several biologically active compounds [15,16] and has been found to exhibit unique medicinal properties such as; excellent tissue penetrability and permeability, high bioavailability and low incidence of adverse toxicity [17]. Imidazole-associated natural products as well as their synthetic derivatives are known to demonstrate a wide spectrum of biological activities including: capravirine (antiviral) [17], metronidazole (antimicrobial) [18], futrimazole (antifungal) [19], losartan (cardiovascular) [20], flumizole (anti-inflammatory) [21], nafimidone (anticonvulsant) [22], cimetidine (anticancer agents) [23], and paenidigyamycin A (antiparasitic) [24]. Many imidazole-based compounds have very useful clinical applications.…”