Nutraceuticals in Bulk and Dosage Forms: Analysis by ³⁵Cl and ¹⁴N Solid-State NMR and DFT Calculations

Abstract

This study uses 35 Cl and 14 N solid-state NMR (SSNMR) spectroscopy and dispersion-corrected plane-wave density functional theory (DFT) calculations for the structural characterization of chloride salts of nutraceuticals in their bulk and dosage forms. For eight nutraceuticals, we measure the 35 Cl EFG tensor parameters of the chloride ions and use plane-wave DFT calculations to elucidate relationships between NMR parameters and molecular-level structure, which provide rapid NMR crystallographic assessments of structural features. We employ both 35 Cl direct excitation and 1 H→ 35 Cl cross-polarization methods to characterize a dosage form containing α-Dglucosamine HCl, observe possible impurity and/or adulterant phases, and quantify the weight percent of the active ingredient. To complement this, we also investigate 14 N SSNMR spectroscopy and DFT calculations to characterize nitrogen atoms in the nutraceuticals. This includes a discussion of targeted acquisition experimental protocols (i.e., acquiring a select region of the overall pattern that features key discontinuities) that allow ultrawideline spectra to be acquired rapidly, even for unreceptive samples (i.e., those with long values of T 1 ( 14 N), short values of T 2 eff ( 14 N), or very broad patterns). It is hoped that these experimental and computational protocols will be useful for the characterization of various solid forms of nutraceuticals (i.e., salts, polymorphs, hydrates, solvates, cocrystals, amorphous solid dispersions, etc.), help detect impurity and counterfeit solid phases in dosage forms, and serve as a foundation for future NMR crystallographic studies of nutraceutical solid forms, including studies using ab initio crystal structure prediction algorithms.

Multi-component crystals containing urea: mechanochemical synthesis and characterization by 35Cl solid-state NMR spectroscopy and DFT calculations

“…The DFT-D2* calculations result in better agreement between calculation and experiment, since the RMS EFG distance is Γ RMS = 0.53 MHz for the XRD-derived models, and much lower, Γ RMS = 0.21 MHz, for the DFT-D2* models (ESI † S2), which is consistent with our previous work. 58,63 The structural models with atomic coordinates refined at the DFT-D2* level indicate that each chloride ion features between four and six H⋯Cl − contacts with urea and/or water molecules (Table 2) that are all greater than ca. 2.2 Å, which is consistent with the small magnitudes of C Q .…”

“…As such, it is desirable to develop NMR crystallographic techniques that use quadrupolar parameters for crystal structure prediction, refinement, and validation. 46,[51][52][53][54][55][56][57][58][59][60][61][62] Of the commonly occurring quadrupolar nuclei in organic solids, 35 Cl (I = 3/2) is the most widely explored from the perspective of structural refinements based on the measurement and computation of EFG tensors; 45,47,56,59,[63][64][65][66][67][68][69] this is due to both the preponderance of hydrochloride (HCl) salts of organic solids (such as APIs) and the relative ease of measurement of 35 Cl SSNMR spectra of chloride ions. 35 Cl SSNMR spectra feature central transition (CT, +½ ↔ −½) powder patterns that are influenced by the second-order quadrupolar interaction (SOQI) and chemical shift anisotropy (CSA).…”

“…Slight differences in the hydrogen bonding environments of chloride ions have dramatic impacts on their 35 Cl EFG tensors, resulting in distinct sets of quadrupolar parameters (i.e., the quadrupolar coupling constant, C Q , and the asymmetry parameter, η Q ) for even very small differences or changes in structure; as such, 35 Cl SSNMR spectra often yield unique spectral fingerprints, making them useful for the differentiation of polymorphs, hydrates, solvates, and other solid forms of organic HCl salts, as well as the detection of impurity phases. 42,45,47,56,59,[63][64][65][66][67][68] In order to design an NMR crystallography protocol that can be used for solving crystal structures of MCCs involving cationic and/or ionic species, including PCCs, a series of simple candidate systems is required that meet the following criteria: (i) elementary chemical structures; (ii) small numbers of atoms in the asymmetric units; and (iii) abundance of useful NMR handles. One family of MCCs that meets these criteria is urea MCCs (i.e., MCCs comprised of urea molecules and other elementary ionic species).…”

“…, the quadrupolar coupling constant, C Q , and the asymmetry parameter, η Q ) for even very small differences or changes in structure; as such, 35 Cl SSNMR spectra often yield unique spectral fingerprints, making them useful for the differentiation of polymorphs, hydrates, solvates, and other solid forms of organic HCl salts, as well as the detection of impurity phases. 42,45,47,56,59,63–68…”

Rapid Quantification of Pharmaceuticals via 1H Solid-State NMR Spectroscopy

“…Furthermore, by judiciously choosing which nuclei to examine, API signals can be selectively detected. This has been demonstrated using nuclei such as 35 Cl and 19 F, where spectra of APIs were obtained without interferences from excipients. ,,− In contrast to many analytical techniques, SSNMR spectroscopy is inherently quantitative since the peak area is directly proportional to the number of spins. Thus, for some SSNMR experiments, quantification can be performed without calibration. ,,,,− …”