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.

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.

Scandium(III) trifluoromethanesulfonate [Sc(OTf)3] is extensively used in organic synthesis to catalyze a wide variety of carbon–carbon bond-forming reactions in aqueous media. It has previously been demonstrated that it is possible to immobilize Sc(OTf)3 in polystyrene (PS) to form the heterogeneous catalysts, microencapsulated (ME) Sc(OTf)3. The ME catalysts are recoverable, reusable, often reduce metal leaching, and have activity similar to that of their homogeneous counterparts. Aside from preliminary scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) imaging studies and solution 45Sc NMR studies, there is little information available about the molecular and bulk structure of the ME catalyst. In this regard, we have conducted a 45Sc solid-state NMR investigation of the Sc environments in the crystalline and ME forms of anhydrous Sc(OTf)3 and hydrated Sc(OTf)3·8H2O. Additional solid-state 1H, 19F, and 13C NMR and powder X-ray diffraction experiments provide information that is complementary to that obtained from the 45Sc NMR spectra, allowing for structural models of ME complexes to be proposed. The principal findings are that Sc(OTf)3 is hydrated upon microencapsulation to form Sc(OTf)3·8H2O. 1H–45Sc TRAPDOR and 1H–19F CP SSNMR experiments and powder X-ray diffraction experiments suggest that Sc is dispersed throughout the polymer within nanocrystalline domains of Sc(OTf)3·8H2O. The approach outlined here should be applicable for the characterization of many other polymer-supported metal-based catalysts.

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