C–H▪▪▪S Hydrogen Bonds in Ampicillin and Amoxicillin Crystals Investigated by Sulfur K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy and Single-Crystal X-Ray Structure Analysis

Abstract

Sulfur K-edge X-ray absorption near-edge structure (XANES) spectroscopy was evaluated for its ability to detect non-conventional C-H▪▪▪S hydrogen bonds in crystals of the sulfur-containing penam antibiotics ampicillin and amoxicillin. The XANES spectra of the nearly isomorphous crystals of ampicillin trihydrate and amoxicillin trihydrate were very similar, whereas that of ampicillin anhydrate displayed unique features. Single-crystal X-ray structure analyses revealed that the C-H▪▪▪S hydrogen bond geometries and the chemical types of the hydrogen donors differed between the isomorphous trihydrate crystals and ampicillin anhydrate crystal. These observations demonstrate that the shapes of the sulfur K-edge XANES spectra are dependent on the nature of the C-H▪▪▪S hydrogen bonds. Sulfur K-edge XANES spectroscopy shows promise for use in the detection and analysis of non-covalent interactions, including hydrogen bonds to sulfur atoms, within active pharmaceutical ingredients.

Characterization of Ambroxol and Its Hydrochloride Salt Crystals by Bromine K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy and X-Ray Crystal Structure Analysis

“…Although these non-conventional interactions were weak, they may have affected bromine electronic states in these crystals, which were detected as shape variations in the XANES spectra. The differences in the bromine K-edge XANES spectra caused by these interactions were not as prominent as those observed for chlorine 10,11) and sulfur, 12,13) which had absorption-edge energies of approximately 2822 and 2472 eV, respectively. This a) Close interaction relating N-H…π-interaction.…”

“…3a), considering the high reproducibility of this method. 9,11,16) Each spectrum had four peaks in this region. The peak heights of forms A and I were comparable, while the heights of the first and second peaks of form II were higher than those of forms A and I.…”

“…9) XANES is sensitive to weak interatomic interactions, such as hydrogen bonds and halogen bonds, and can be used to characterize API crystal polymorphs. [10][11][12][13][14][15] XANES spectroscopy is an element-specific method and is useful for evaluating the APIs containing a specific element in the pharmaceutical formulations. It was also used to differentiate polymorphs of bromhexine hydrochloride crystals in tablets, even when the tablets were packed in pressthrough sheets.…”

Frontiers of molecular crystal structure prediction for pharmaceuticals and functional organic materials

“…295 Fig. 12 Overlay of the ampicillin crystal structures determined from Xray diffraction experiments 285 (blue) and the direct NMR crystallography solution (red) which employed a combination of DFTB energies and ShiftML chemical shifts. 261 Early force-eld predictions demonstrated the ability to compute elastic constants within ∼40-50% of experiment, 304 with the neglect of thermal expansion of the crystal being a signicant source of error.…”

Characterization of Bisphosphonate Hydrate Crystals by Phosphorus K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy

“…10,11) Another advantageous characteristic of XANES spectroscopy is that it can be used to analyze not only solid state materials including crystals and amorphous structures, 3,10) but also liquids and even gases. Our previous study applied XANES spectroscopy to discriminate the crystal polymorphs and amorphous forms of various APIs containing phosphorus, 3,4) chlorine, 10,12,13) bromine 11,14,15) and sulfur. 16,17) In addition, the study about the phosphorus K-edge XANES spectra of organophosphorus compounds in aqueous solution has been reported.…”