Application of Solid-State³⁵Cl NMR to the Structural Characterization of Hydrochloride Pharmaceuticals and their Polymorphs

Abstract

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.

Natural abundance 14N and 15N solid-state NMR of pharmaceuticals and their polymorphs

“…39,132,[134][135][136][137][138][139][140] DFT calculations were completed using the CASTEP software package 147 (see Experimental Section for details). Molecular systems involved in strong intermolecular hydrogen-bonding interactions typically require structural optimization prior to calculation of the NMR parameters.…”

“…Furthermore, it has been recently demonstrated that 35 Cl SSNMR can provide important structural information about the chlorine sites in different polymorphic forms in APIs, including the nature of the hydrogen bonding environments and impurity phases, in reduced experimental times compared to conventional pXRD and 13 C SSNMR experiments. 24,32,[39][40][41] For further reading on the use of SSNMR to characterize pharmaceutical compounds, we refer readers to recent reviews by Vogt and Monti et al [42][43][44] Given the ubiquity of nitrogen in functional groups such as amines, amides and numerous heterocycles, and the importance of intermolecular hydrogen-bonding interactions of nitrogen in solid APIs, the naturally occurring NMR-active nitrogen nuclei, 14 [55][56][57][58][59][60][61][62] and pharmaceuticals. 27,63-69 14 N nuclear quadrupole resonance (NQR) spectroscopy has also recently been applied, with some success, to a variety of APIs for purposes of quantification and polymorph differentiation.…”

The molecular structure and vibrational, 1H and 13C NMR spectra of lidocaine hydrochloride monohydrate

“…Studying the structural profile of lidocaine and its salt forms will help in optimizing the formulation and drug delivery method to achieve maximum efficacy and minimal side effects. The interesting pharmaceutical [25][26][27][28][29] and structural [19,30,31] properties of lidocaine hydrochloride have prompted the present study of its conformational profile and vibrational, 1 H and 13 C NMR spectra. The predominant structure of lidocaine hydrochloride monohydrate was characterized by X-ray crystallography as fully hydrogen bonded with adjacent cations linked by water molecules in chains.…”

“…The predominant structure of lidocaine hydrochloride monohydrate was characterized by X-ray crystallography as fully hydrogen bonded with adjacent cations linked by water molecules in chains. The chains are reported to be joined in pairs by chloride ions that bind NH + and H 2 O moieties in different chains [30,31].…”

“…1) can be explained on the basis of the hydrogen bonding in the system suggested by X-ray crystallography [30,31]. If the large chloride ion would be close to the NH + group, then it would block a / 1 À / 9 are the N 1 C 8 C 10 N 12 , C 8 N 1 C 2 C 3 , O 9 C 8 N 1 C 2 , H 11 N 1 C 2 O 9 , C 13 N 12 C 10 C 8 , C 14 N 12 C 10 C 8 , C 15 C 13 N 12 C 10 , C 16 C 13 N 12 C 10 and H 40 N 12 C 10 C 8 torsional angles, respectively (see Fig.…”