³⁵Cl solid-state NMR spectroscopy of HCl pharmaceuticals and their polymorphs in bulk and dosage forms

Abstract

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.

DNP‐enhanced solid‐state NMR spectroscopy of active pharmaceutical ingredients

“…Usually, the API will be the only component within a formulation that contains chloride anions that can give rise to observable 35 Cl solid‐state NMR signals. Therefore, 35 Cl solid‐state NMR spectra of the tablets are free of interfering excipient signals and allow APIs to be directly interrogated . For example, the DNP‐enhanced static 35 Cl solid‐state NMR spectra of pure crystalline diphenhydramine HCl and of a commercial tablet were identical in appearance, which confirmed that the form of the API was identical in both pure and dosage forms (Figure ) .…”

“…Hydrochloride salts in both pure and dosage forms can be studied with 35 Cl solid‐state NMR spectroscopy . 35 Cl solid‐state NMR has previously been applied to differentiate the polymorphs of APIs and detect APIs within formulations . 35 Cl is a highly abundant (natural abundance (NA) = 75.5%) half‐integer quadrupolar nucleus ( I = 3/2).…”

“…The availability of high‐field NMR systems and specialized pulse sequences has enabled solid‐state NMR experiments on APIs with quadrupolar nuclei such as 7 Li, 14 N, 17 O, 23 Na, and 35 Cl . For example, Schurko and coworkers have demonstrated that 35 Cl solid‐state NMR spectroscopy can be applied to hydrochloride salts of APIs to differentiate polymorphs and detect APIs within dosage forms . Wu and coworkers have previously applied 17 O solid‐state NMR spectroscopy to study 17 O‐labeled pharmaceuticals such as acetylsalicylic acid (aspirin) and warfarin .…”

87Sr, 119Sn, 127I Single and {1H/19F}‐Double Resonance Solid‐State NMR Experiments: Application to Inorganic Materials and Nanobuilding Blocks

“…In this contribution, we extend the BRAIN CP approach to the study of half‐integer nuclei such as 87 Sr (I=9/2) (one notes that very recently, Schurko et al . used also this approach to study pharmaceutical derivatives and their polymorphs by 35 Cl NMR, I=3/2).…”

Exploring Systematic Discrepancies in DFT Calculations of Chlorine Nuclear Quadrupole Couplings

“…For example, it has been used as a technique for polymorph distinction and in the screening of hydrochloride (HCl)-containing APIs [25][26][27][28] as well as their dosage forms with excipients, which is difficult for other techniques. [29][30] Chlorine SS-NMR has also been used for the characterization of a chloride ion receptor, 21 alkaline earth chlorides (including hydrates) 24,31 and has been used to comment on halogen bonding [32][33][34] and ion dynamics in solids. [35][36] Chlorine SS-NMR has also found applications in the study of materials such as sodalities 37 However, the optimal choice of the cluster for C Q calculations may not be obvious.…”