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Fluoxetine hydrochloride, the active pharmaceutical ingredient (API) in the antidepressant Prozac®, can form cocrystals with numerous organic acid coformers. The solvothermal syntheses of cocrystals with (i) fumaric acid, (ii) benzoic acid, and (iii) succinic acid coformers were first reported by Childs et al. in 2004. Herein, we report the novel mechanochemical syntheses of these cocrystals, and their structural characterization using a combination of powder X-ray diffraction (PXRD) and solid-state NMR (SSNMR) spectroscopy. It is demonstrated that high-purity samples of fluoxetine HCl cocrystals can be synthesized using neat grinding or liquid assisted grinding in a fraction of the time required for analogous solvothermal syntheses. 35Cl SSNMR spectroscopy is used as a primary characterization technique of the materials, providing a spectral fingerprint and unique set of 35Cl electric field gradient (EFG) tensor parameters for each system, due to the extreme sensitivity of the 35Cl EFG tensor to unique hydrogen bonding arrangements about the Cl− anions. It is also demonstrated that first-principles quantum chemical calculations conducted using the DFT-D2* method, which introduces two-body semiempirical dispersion corrections, can be applied to obtain better models of the true molecular-level structures of the API salts than is possible through XRD alone, because of the ability to accurately position hydrogen atoms. The combined use of 35Cl SSNMR spectroscopy, PXRD, and DFT-D2* calculations, may find extensive future use in NMR crystallographic refinements of numerous organic HCl salts, including HCl APIs in bulk forms, cocrystals, and dosage formulations. [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]

In this work, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced 35Cl solid-state NMR (SSNMR) spectra at 9.4 T and demonstrate how they can be used to characterize the molecular-level structure of hydrochloride salts of active pharmaceutical ingredients (APIs) in both bulk and low wt% API dosage forms. 35Cl SSNMR central-transition powder patterns of chloride ions are typically tens to hundreds of kHz in breadth, and most cannot be excited uniformly with high-power rectangular pulses or acquired under conditions of magic-angle spinning (MAS). Herein, we demonstrate the combination of DNP and 1H–35Cl broadband adiabatic inversion cross polarization (BRAIN-CP) experiments for the acquisition of high quality wideline spectra of APIs under static sample conditions, and obtain signals up to 50 times greater than in spectra acquired without the use of DNP at 100 K. We report a new protocol, called spinning-on spinning-off (SOSO) acquisition, where MAS is applied during part of the polarization delay to increase the DNP enhancements and then the MAS rotation is stopped so that a wideline 35Cl NMR powder pattern free from the effects of spinning sidebands can be acquired under static conditions. This method provides an additional two-fold signal enhancement compared to DNP-enhanced SSNMR spectra acquired under purely static conditions. DNP-enhanced 35Cl experiments are used to characterize APIs in bulk and dosage forms with Cl contents as low as 0.45 wt%. These results are compared to DNP-enhanced 1H–13C CP/MAS spectra of APIs in dosage forms, which are often hindered by interfering signals arising from the binders, fillers and other excipient materials. [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 new mechanically interlocked molecular linker was prepared by using ring-closing metathesis (Grubbs I) to clip a [24]crown-6 ether wheel around an axle containing both Y-shaped diphenylimidazole and isophthalic acid groups. A metal-organic framework (MOF) material was prepared using this linker and ZnII ions. Single-crystal X-ray diffraction experiments showed that the MOF contains an imidazolium-based rotaxane linked by dimeric [Zn2(NO3)(DEF)] secondary building units (SBUs). Variable-temperature (VT), 2H solid-state NMR spectroscopy was used to characterize the motion of the 'soft' wheel component around the rigid 'hard' lattice of the framework. At higher temperatures (above 150 °C), it was demonstrated that the 24-membered, macrocyclic ring of the MOF undergoes rapid, thermally driven rotation about the axle inside the voids of the lattice. [ABSTRACT FROM AUTHOR]

14N ultra-wideline (UW), 1H{15N} indirectly-detected HETCOR (idHETCOR) and 15N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of 14N EFG tensors, were utilized to characterize a series of nitrogen-containing active pharmaceutical ingredients (APIs), including HCl salts of scopolamine, alprenolol, isoprenaline, acebutolol, dibucaine, nicardipine, and ranitidine. A case study applying these methods for the differentiation of polymorphs of bupivacaine HCl is also presented. All experiments were conducted upon samples with naturally-abundant nitrogen isotopes. For most of the APIs, it was possible to acquire frequency-stepped UW 14N SSNMR spectra of stationary samples, which display powder patterns corresponding to pseudo-tetrahedral (i.e., RR′R′′NH+ and RR′NH2+) or other (i.e., RNH2 and RNO2) nitrogen environments. Directly-excited 14N NMR spectra were acquired using the WURST-CPMG pulse sequence, which incorporates WURST (wideband, uniform rate, and smooth truncation) pulses and a CPMG (Carr-Purcell Meiboom-Gill) refocusing protocol. In certain cases, spectra were acquired using 1H →14N broadband cross-polarization, via the BRAIN-CP (broadband adiabatic inversion – cross polarization) pulse sequence. These spectra provide 14N electric field gradient (EFG) tensor parameters and orientations that are particularly sensitive to variations in local structure and intermolecular hydrogen-bonding interactions. The 1H{15N} idHETCOR spectra, acquired under conditions of fast magic-angle spinning (MAS), used CP transfers to provide 1H–15N chemical shift correlations for all nitrogen environments, except for two sites in acebutolol and nicardipine. One of these two sites (RR′NH2+ in acebutolol) was successfully detected using the DNP-enhanced 15N{1H} CP/MAS measurement, and one (RNO2 in nicardipine) remained elusive due to the absence of nearby protons. This exploratory study suggests that this combination of techniques has great potential for the characterization of solid APIs and numerous other organic, biological, and inorganic systems. [ABSTRACT FROM AUTHOR]