Solid-state (35)Cl NMR (SSNMR) spectroscopy is shown to be a useful probe of structure and polymorphism in HCl pharmaceuticals, which constitute ca. 50% of known pharmaceutical salts. Chlorine NMR spectra, single-crystal and powder X-ray diffraction data, and complementary ab initio calculations are presented for a series of HCl local anesthetic (LA) pharmaceuticals and some of their polymorphs. (35)Cl MAS SSNMR spectra acquired at 21.1 T and spectra of stationary samples at 9.4 and 21.1 T allow for extraction of chlorine electric field gradient (EFG) and chemical shift (CS) parameters. The sensitivity of the (35)Cl EFG and CS tensors to subtle changes in the chlorine environments is reflected in the (35)Cl SSNMR powder patterns. The (35)Cl SSNMR spectra are shown to serve as a rapid fingerprint for identifying and distinguishing polymorphs, as well as a useful tool for structural interpretation. First principles calculations of (35)Cl EFG and CS tensor parameters are in good agreement with the experimental values. The sensitivity of the chlorine NMR interaction tensor parameters to the chlorine chemical environment and the potential for modeling these sites with ab initio calculations hold much promise for application to polymorph screening for a wide variety of HCl pharmaceuticals.

A series of HCl salts of active pharmaceutical ingredients (APIs) have been characterized via35Cl solid-state NMR (SSNMR) spectroscopy and first-principles plane-wave DFT calculations of 35Cl NMR interaction tensors.

51V solid-state NMR (SSNMR) studies of a series of non-innocent vanadium(V) catechol complexes have been conducted to evaluate the possibility that 51V NMR observables, quadrupolar and chemical shift anisotropies, and electronic structures of such compounds can be used to characterize these compounds. The vanadium(V) catechol complexes described in these studies have relatively small quadrupolar coupling constants, which cover a surprisingly small range from 3.4 to 4.2 MHz. On the other hand, isotropic 51V NMR chemical shifts cover a wide range from −200 ppm to 400 ppm in solution and from −219 to 530 ppm in the solid state. A linear correlation of 51V NMR isotropic solution and solid-state chemical shifts of complexes containing non-innocent ligands is observed. These experimental results provide the information needed for the application of 51V SSNMR spectroscopy in characterizing the electronic properties of a wide variety of vanadium-containing systems, and in particular those containing non-innocent ligands and that have chemical shifts outside the populated range of −300 ppm to −700 ppm. The studies presented in this report demonstrate that the small quadrupolar couplings covering a narrow range of values reflect the symmetric electronic charge distribution, which is also similar across these complexes. These quadrupolar interaction parameters alone are not sufficient to capture the rich electronic structure of these complexes. In contrast, the chemical shift anisotropy tensor elements accessible from 51V SSNMR experiments are a highly sensitive probe of subtle differences in electronic distribution and orbital occupancy in these compounds. Quantum chemical (DFT) calculations of NMR parameters for [VO(hshed)(Cat)] yield 51V CSA tensor in reasonable agreement with the experimental results, but surprisingly, the calculated quadrupolar coupling constant is significantly greater than the experimental value. The studies demonstrate that substitution of the catechol ligand with electron donating groups results in an increase in the HOMO-LUMO gap and can be directly followed by an upfield shift for the vanadium catechol complex. In contrast, substitution of the catechol ligand with electron withdrawing groups results in a decrease in the HOMO-LUMO gap and can directly be followed by a downfield shift for the complex. The vanadium catechol complexes were used in this work because the 51V is a half-integer quadrupolar nucleus whose NMR observables are highly sensitive to the local environment. However, the results are general and could be extended to other redox active complexes that exhibit similar coordination chemistry as the vanadium catechol complexes.

Herein, we demonstrate the use of 35 Cl 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 13 C 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 35 Cl 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. 35 Cl 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. 35 Cl 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 hydrogenbonding 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.