Search

Mechanochemical synthesis provides new pathways for the rational design of multi-component crystals (MCCs) involving anionic or cationic components that offer molecular-level architectures unavailable to MCCs comprising strictly neutral components. Structural characterization of the products of mechanochemical syntheses is essential for divining clear relationships between the nature of coformers, milling conditions, reaction mechanisms, and intermolecular bonding. Notably, when powder X-ray diffraction and solid-state NMR (SSNMR) are combined with plane-wave density functional theory (DFT) calculations, they offer opportunities for NMR crystallographic solutions and structural refinements. Herein, we report mechanochemical syntheses of five urea-containing MCCs of the form NR4Cl:xUrea·yH2O (R = H, Et, n-Pr; x = 1, 2, 3; y = 0, 2), which can be made in high yields (> ca. 99%) and great rapidity (<40 minutes). We demonstrate the utility of 35Cl SSNMR for providing distinct fingerprints for each urea MCC and detecting chlorine-containing impurities. Dispersion-corrected plane-wave DFT-D2* calculations are used for structural refinement and relating 35Cl electric field gradient (EFG) tensors and chloride ion hydrogen bonding environments. Finally, ab initio molecular dynamics calculations are used to study the impact of molecular motions on 35Cl EFG tensors, and their concomitant use for site assignment and NMR crystallography. Together, these techniques show great promise for future development of crystal structure prediction protocols using NMR of quadrupolar nuclei. [ABSTRACT FROM AUTHOR]

Herein, we demonstrate the use of 35Cl solid-state NMR (SSNMR) at moderate (9.4 T) and high (21.1 T) magnetic field strengths for the structural fingerprinting of hydrochloride (HCl) salts of active pharmaceutical ingredients (APIs) and several polymorphs, in both bulk and dosage forms. These include salts of metformin, diphenhydramine, nicardipine, isoxsuprine and mexiletine (the crystal structure of a mexiletine polymorph is reported herein). Signal-enhancing pulse sequences utilizing frequency-swept pulses and broadband cross polarization were employed to significantly decrease experimental times. In most cases, powder X-ray diffraction (pXRD) patterns and 13C SSNMR spectra are not useful for characterizing the APIs in dosage forms, due to interfering signals from the excipients (e.g., fillers and binders). However, it is demonstrated that 35Cl SSNMR can be used independently to fingerprint individual APIs and to detect the nature of the solid phases in the dosage forms without interference from the excipient. 35Cl SSNMR experiments were also conducted on systems with multiple polymorphs (i.e., isoxsuprine HCl and mexiletine HCl), and the solid phases of these APIs in their dosage forms are identified. 35Cl EFG tensors obtained from plane-wave DFT calculations on model systems are also presented and discussed in the context of their relationship to the local hydrogen-bonding environments of the chloride ions. This methodology shows great promise for identification of solid phases and detection of polymorphs and impurities, which are matters of importance for quality assurance in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Herein, we demonstrate the use of 35Cl solid-state NMR (SSNMR) at moderate (9.4 T) and high (21.1 T) magnetic field strengths for the structural fingerprinting of hydrochloride (HCl) salts of active pharmaceutical ingredients (APIs) and several polymorphs, in both bulk and dosage forms. These include salts of metformin, diphenhydramine, nicardipine, isoxsuprine and mexiletine (the crystal structure of a mexiletine polymorph is reported herein). Signal-enhancing pulse sequences utilizing frequency-swept pulses and broadband cross polarization were employed to significantly decrease experimental times. In most cases, powder X-ray diffraction (pXRD) patterns and 13C SSNMR spectra are not useful for characterizing the APIs in dosage forms, due to interfering signals from the excipients (e.g., fillers and binders). However, it is demonstrated that 35Cl SSNMR can be used independently to fingerprint individual APIs and to detect the nature of the solid phases in the dosage forms without interference from the excipient. 35Cl SSNMR experiments were also conducted on systems with multiple polymorphs (i.e., isoxsuprine HCl and mexiletine HCl), and the solid phases of these APIs in their dosage forms are identified. 35Cl EFG tensors obtained from plane-wave DFT calculations on model systems are also presented and discussed in the context of their relationship to the local hydrogen-bonding environments of the chloride ions. This methodology shows great promise for identification of solid phases and detection of polymorphs and impurities, which are matters of importance for quality assurance in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

A series of dichlorophenyl dithiadiazolyls (DCP-DTDA) have been prepared and structurally characterized by X-ray diffraction (1 = 2,3-DCP-DTDA; 2 = 2,4-DCP-DTDA; 3 = 2,5-DCP-DTDA, 4 = 3,4-DCP-DTDA and 5 = 3,5-DCP-DTDA). All the radicals adopt -cofacial π*-π* dimers with intra-dimer S...S contacts in the range 3.119(8)--3.300(5) Å. The propensity for chloro-aromatics to adopt a β-sheet structure assists formation of lamellar structures in 1-5 with intra-stack Cl⋯Cl contacts in the range 3.44(1)-3.82(1) Å. Perpendicular to the stacking direction, the packing is dominated by formation of intermolecular S⋯Cl contacts. Variable-temperature magnetic susceptibility measurements on 1-5 in the range 5-300 K reveal the onset of paramagnetism around 200 K. Solid-state EPR studies reveal that this paramagnetism is associated with thermal population of a triplet excited state. A good fit to the Bleaney-Bowers model determined the exchange interactions (2 ) between the radicals in the dimers to be in the range -904 to -1529 cm-1. Computational studies of the dimerisation process indicate that at intra-dimer S⋯S distances in excess of 3.2 Å the closed-shell singlet becomes destabilized with respect to both the open-shell singlet and triplet state configurations. [ABSTRACT FROM AUTHOR]