Search

We describe a new quadrupolar NMR crystallography guided crystal structure prediction (QNMRX-CSP) protocol for the prediction and refinement of crystal structures, including its design, benchmarking, and application to seven organic HCl salts. Five HCl salts with a limited number of low-energy conformations were chosen as model systems for benchmarking: betaine HCl, glycine HCl, D -alanine HCl, guanidine HCl, and aminoguanidine HCl; two were chosen for blind tests: N,N′-dimethylglycine HCl and metformin HCl. The QNMRX-CSP protocol uses experimental 35Cl solid-state NMR (SSNMR) spectra and X-ray diffraction (XRD) data in tandem with Monte Carlo simulated annealing and dispersion-corrected plane-wave density functional theory (DFT-D2*) calculations. The protocol comprises three modules: (i) the assignment of motion groups, (ii) a Monte Carlo simulated annealing algorithm for generating tens of thousands of candidate structures, and (iii) DFT-D2* geometry optimizations of structural models and concomitant computation of 35Cl EFG tensors. Key benchmarked metrics are used for retaining the best candidate structures, including unit cell parameters, static lattice energies, and EFG distances (ΓEFG). The protocol is shown to generate structural models that are excellent matches with experimental crystal structures that have been DFT-D2* geometry optimized, as validated by crystallographic R-factors (R) and root-mean squared distances (RMSDs) of atomic positions that are well below 10% and 0.2 Å, respectively. Finally, consideration is given to the use of the QNMRX-CSP protocol as a standalone technique or in concert with other NMRX methods and Rietveld refinements, and possible applications employing other quadrupolar nuclei (i.e., 14N and 17O). [ABSTRACT FROM AUTHOR]

This study describes the discovery of a unique ionic cocrystal of the active pharmaceutical ingredient (API) ponatinib hydrochloride (pon·HCl), and characterization using single-crystal X-ray diffraction (SCXRD) and solid-state NMR (SSNMR) spectroscopy. Pon·HCl is a multicomponent crystal that features an unusual stoichiometry, with an asymmetric unit containing both monocations and dications of the ponatinib molecule, three water molecules, and three chloride ions. Structural features include (i) a charged imidazopyridazine moiety that forms a hydrogen bond between the ponatinib monocations and dications and (ii) a chloride ion that does not feature hydrogen bonds involving any organic moiety, instead being situated in a "square" arrangement with three water molecules. Multinuclear SSNMR, featuring high and ultra-high fields up to 35.2 T, provides the groundwork for structural interpretation of complex multicomponent crystals in the absence of diffraction data. A 13C CP/MAS spectrum confirms the presence of two crystallographically distinct ponatinib molecules, whereas 1D 1H and 2D 1H–1H DQ–SQ spectra identify and assign the unusually deshielded imidazopyridazine proton. 1D 35Cl spectra obtained at multiple fields confirm the presence of three distinct chloride ions, with density functional theory calculations providing key relationships between the SSNMR spectra and H⋯Cl− hydrogen bonding arrangements. A 2D 35Cl → 1H D-RINEPT spectrum confirms the spatial proximities between the chloride ions, water molecules, and amine moieties. This all suggests future application of multinuclear SSNMR at high and ultra-high fields to the study of complex API solid forms for which SCXRD data are unavailable, with potential application to heterogeneous mixtures or amorphous solid dispersions. [ABSTRACT FROM AUTHOR]

Correction for 'Quadrupolar NMR crystallography guided crystal structure prediction (QNMRX-CSP)' by Austin A. Peach et al., CrystEngComm, 2024, 26, 4782–4803, https://doi.org/10.1039/D3CE01306E. [ABSTRACT FROM AUTHOR]

There are currently no methods for the acquisition of ultra-wideline (UW) solid-state NMR spectra under static conditions that enable reliable separation and resolution of overlapping powder patterns arising from magnetically distinct nuclei. This stands in contrast to the variety of techniques available for spin-1/2 or half-integer quadrupolar nuclei with narrow central transition patterns under magic-angle spinning (MAS). Resolution of overlapping signals is routinely achieved in MRI and solution-state NMR by exploiting relaxation differences between nonequivalent sites. Preliminary studies of relaxation assisted separation (RAS) for separating overlapping UWNMR patterns using pseudo-inverse Laplace Transforms have reported two-dimensional spectra featuring relaxation rates correlated to NMR interaction frequencies. However, RAS methods are inherently sensitive to experimental noise, and require that relaxation rates associated with overlapped patterns be significantly different from one another. Herein, principal component analysis (PCA) denoising is implemented to increase the signal-to-noise ratios of the relaxation datasets and RAS routines are stabilized with truncated singular value decomposition (TSVD) and elastic net (EN) regularization to resolve overlapped patterns with a larger tolerance for differences in relaxation rates. We extend these methods for improved pattern resolution by utilizing 3D frequency-R1–R2 correlation spectra. Synthetic and experimental datasets, including 35Cl (I = 3/2), 2H (I = 1), and 14N (I = 1) NMR of organic and biological compounds, are explored with both regularized 2D RAS and 3D RAS; comparison of these data reveal improved resolution in the latter case. These methods have great potential for separating overlapping powder patterns under both static and MAS conditions. [ABSTRACT FROM AUTHOR]

Mechanochemical synthesis provides new pathways for the rational design of multi-component crystals (MCCs) involving anionic or cationic components that offer molecular-level architectures unavailable to MCCs comprising strictly neutral components. Structural characterization of the products of mechanochemical syntheses is essential for divining clear relationships between the nature of coformers, milling conditions, reaction mechanisms, and intermolecular bonding. Notably, when powder X-ray diffraction and solid-state NMR (SSNMR) are combined with plane-wave density functional theory (DFT) calculations, they offer opportunities for NMR crystallographic solutions and structural refinements. Herein, we report mechanochemical syntheses of five urea-containing MCCs of the form NR4Cl:xUrea·yH2O (R = H, Et, n-Pr; x = 1, 2, 3; y = 0, 2), which can be made in high yields (> ca. 99%) and great rapidity (<40 minutes). We demonstrate the utility of 35Cl SSNMR for providing distinct fingerprints for each urea MCC and detecting chlorine-containing impurities. Dispersion-corrected plane-wave DFT-D2* calculations are used for structural refinement and relating 35Cl electric field gradient (EFG) tensors and chloride ion hydrogen bonding environments. Finally, ab initio molecular dynamics calculations are used to study the impact of molecular motions on 35Cl EFG tensors, and their concomitant use for site assignment and NMR crystallography. Together, these techniques show great promise for future development of crystal structure prediction protocols using NMR of quadrupolar nuclei. [ABSTRACT FROM AUTHOR]

An H-shaped [2]rotaxane comprising a bis(benzimidazole) axle and a 24-membered crown ether wheel appended with four trityl groups forms a highly crystalline material with enough free volume to allow large amplitude motion of the interlocked macrocycle. Variable-temperature (VT) 2H solid-state nuclear magnetic resonance (SSNMR) was used to characterize the dynamics of the [2]rotaxane wheel in this material. [ABSTRACT FROM AUTHOR]

Zr(IV) metal–organic frameworks (MOFs) UiO-68 and PCN-57, containing triphenylene dicarboxylate (TPDC) and tetramethyl-triphenylene dicarboxylate (TTDC) linkers, respectively, were doped with an H-shaped tetracarboxylate linker that contains a [2]rotaxane molecular shuttle. The new MOFs, UWDM-8 and UWDM-9, contain a [2]rotaxane crossbar spanning the tetrahedral cavities of the fcu topology while the octahedral cavities remain empty. 13C solid-state NMR (SSNMR) spectra and solution 1H NMR spectra verified that the [2]rotaxanes were included as designed. Variable-temperature (VT) cross polarization (CP) magic-angle spinning (MAS) 13C SSNMR was used to explore the translational motion of the macrocyclic ring in both MOFs. The SSNMR results clearly show that the structure of the linker (TPDCvs.TTDC) affects the shuttling rate of the macrocyclic ring, although questions remain as to how rotation of the central phenylene unit of the strut might also affect the motion of the macrocycle. [ABSTRACT FROM AUTHOR]

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]

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]

Nitrogen-14 solid-state NMR (SSNMR) is utilized to differentiate three polymorphic forms and a hydrochloride (HCl) salt of the amino acid glycine. Frequency-swept Wideband, Uniform Rate, Smooth Truncated (WURST) pulses were used in conjunction with Carr-Purcell Meiboom-Gill refocusing, in the form of the WURST-CPMG pulse sequence, for all spectral acquisitions. The 14N quadrupolar interaction is shown to be very sensitive to variations in the local electric field gradients (EFGs) about the 14N nucleus; hence, differentiation of the samples is accomplished through determination of the quadrupolar parameters CQ and ηQ, which are obtained from analytical simulations of the 14N SSNMR powder patterns of stationary samples (i.e., static NMR spectra). Additionally, differentiation of the polymorphs is also possible via the measurement of 14N effective transverse relaxation time constants, TSTACKABOVEeff/ABOVEBELOW2/BELOW/STACK(14N). Plane-wave density functional theory (DFT) calculations, which exploit the periodicity of crystal lattices, are utilized to confirm the experimentally determined quadrupolar parameters as well as to determine the orientation of the 14N EFG tensors in the molecular frames. Several signal-enhancement techniques are also discussed to help improve the sensitivity of the 14N SSNMR acquisition method, including the use of selective deuteration, the application of the BRoadband Adiabatic INversion Cross-Polarization (BRAIN-CP) technique, and the use of variable-temperature (VT) experiments. Finally, we examine several cases where 14N VT experiments employing Carr-Purcell-Meiboom-Gill (CPMG) refocusing are used to approximate the rotational energy barriers for RNH3+ groups. [ABSTRACT FROM AUTHOR]

A series of HCl salts of active pharmaceutical ingredients (APIs) have been characterized via 35Cl solid-state NMR (SSNMR) spectroscopy and first-principles plane-wave density functional theory (DFT) calculations of 35Cl NMR interaction tensors. 35Cl NMR spectra have been acquired at both standard (9.4 T) and high (21.1 T)magnetic field strengths, on stationary samples and under conditions of magic-angle spinning (MAS). The 35Cl electric field gradient (EFG) and chemical shift (CS) tensor parameters are readily extracted from analytical simulations of these spectra. These parameters are distinct for each sample, indicating that these spectra can be used as fingerprints for identifying unique solid phases. It is possible to correlate the 35Cl EFG parameters (the quadrupolar coupling constant, CQ, and the asymmetry parameter, ηQ) to the hydrogen- bonding environments of each chlorine anion, and several simple trends are observed. 35Cl EFG tensors obtained from plane-wave DFT calculations are found to be in good agreement with experiment, and unique structural insights are gained by considering the predicted EFG tensor orientations and the signs of the quadrupolar coupling constants. 35Cl SSNMR can be easily applied for the differentiation of polymorphs of HCl APIs, since the spectra are sensitive to even the subtlest changes in the chlorine anion environments. We discuss the application of this combination of techniques as both standalone and complementary NMR crystallography methodologies for structural characterization and potential high-throughput screening of polymorphs ofHCl APIs. [ABSTRACT FROM AUTHOR]

Coordination complexes of (2,6-Me2C6H3S)2Pb (1) with flexible bidentate ligands have been prepared to explore new bonding environments for Pb(ii) thiolates. The reaction of 1 with a series of ethylenediamine and ethylenediphosphine ligands resulted in isolation of the adducts [(2,6-Me2C6H3S)2Pb]2(tmeda) (9), [(2,6-Me2C6H3S)2Pb]3(dmpe) (10) and [(2,6-Me2C6H3S)2Pb]2(dppe) (11) [tmeda = N,N,N′,N′-tetramethylethylenediamine; dmpe = bis(dimethylphosphino)ethane; dppe = bis(diphenylphosphino)ethane]. The X-ray crystal structure of 9 shows a dinuclear species in which tmeda is chelating a φ-trigonal bipyramidal S2N2 Pb centre via axial and equatorial sites. The structure of 10 displays a trinuclear structural unit in which dmpe is chelating a φ-trigonal bipyramidal S2P2 Pb centre via equatorial sites. Compounds 9 and 10 also contain a second unique metal centre with φ-tetrahedral S3Pb bonding motifs. The structure of 11 shows the dppe ligand bridging two Pb φ-tetrahedral S2P metal bonding environments. Static 207Pb solid-state NMR (SSNMR) spectra of 9–11 and [Ph4As][(PhS)3Pb] (12) were acquired with cross polarization (CP)-CPMG and frequency swept pulse (WURST)-CPMG pulse sequences, and the efficiencies of these pulse sequences are compared. The 207Pb SSNMR spectra reveal that the lead chemical shift anisotropies (CSA) vary greatly between the different Pb sites, and are generally large in magnitude. DFT calculations are utilized to relate the orientations of the 207Pb nuclear magnetic shielding tensors to the molecular structures, and to aid in spectral assignment where multiple Pb centres are present. The combination of X-ray diffraction, 207Pb SSNMR and DFT is shown to be invaluable for the structural characterization of these important structural motifs, and should find wide-ranging application to numerous lead coordination compounds. [ABSTRACT FROM AUTHOR]

The recently reported direct enhancement of integer spin magnetization (DEISM) methodology for signal enhancement in solid-state NMR of integer spins has been used to obtain static 14N powder patterns from α-glycine, l-leucine and l-proline in relatively short experimental times at 9.4 T, allowing accurate determination of the quadrupolar parameters. Proton decoupling and deuteration of the nitrogen sites were used to reduce the 1H–14N dipolar contribution to the transverse relaxation time allowing more echoes to be acquired per scan. In addition, ab initiocalculations using molecular clusters (Gaussian 03) and the full crystal lattice (CASTEP) have been employed to confirm these results, to obtain the orientation of the electric field gradient (EFG) tensors in the molecular frame, and also to correctly assign the two sets of parameters for l-leucine. The 14N EFG tensor is shown to be highly sensitive to the surrounding environment, particularly to nearby hydrogen bonding. [ABSTRACT FROM AUTHOR]

This study demonstrates the application of 103 Rh solid-state NMR (SSNMR) spectroscopy to inorganic and organometallic coordination compounds, in combination with relativistic density functional theory (DFT) calculations of 103 Rh chemical shift tensors and their analysis with natural bond orbital (NBO) and natural localized molecular orbital (NLMO) protocols, to develop correlations between 103 Rh chemical shift tensors, molecular structure, and Rh-ligand bonding. 103 Rh is one of the least receptive NMR nuclides, and consequently, there are very few reports in the literature. We introduce robust 103 Rh SSNMR protocols for stationary samples, which use the broadband adiabatic inversion-cross polarization (BRAIN-CP) pulse sequence and wideband uniform-rate smooth-truncation (WURST) pulses for excitation, refocusing, and polarization transfer, and demonstrate the acquisition of 103 Rh SSNMR spectra of unprecedented signal-to-noise and uniformity. The 103 Rh chemical shift tensors determined from these spectra are complemented by NBO/NLMO analyses of contributions of individual orbitals to the 103 Rh magnetic shielding tensors to understand their relationship to structure and bonding. Finally, we discuss the potential for these experimental and theoretical protocols for investigating a wide range of materials containing the platinum group elements., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In this work, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced 35 Cl 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. 35 Cl 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 1 H- 35 Cl 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 35 Cl 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 35 Cl 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 1 H- 13 C CP/MAS spectra of APIs in dosage forms, which are often hindered by interfering signals arising from the binders, fillers and other excipient materials.

(14)N ultra-wideline (UW), (1)H{(15)N} indirectly-detected HETCOR (idHETCOR) and (15)N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of (14)N 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 (14)N 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 (14)N 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 (1)H → (14)N broadband cross-polarization, via the BRAIN-CP (broadband adiabatic inversion - cross polarization) pulse sequence. These spectra provide (14)N electric field gradient (EFG) tensor parameters and orientations that are particularly sensitive to variations in local structure and intermolecular hydrogen-bonding interactions. The (1)H{(15)N} idHETCOR spectra, acquired under conditions of fast magic-angle spinning (MAS), used CP transfers to provide (1)H-(15)N 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 (15)N{(1)H} 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.

Coordination complexes of (2,6-Me2C6H3S)2Pb (1) with flexible bidentate ligands have been prepared to explore new bonding environments for Pb(II) thiolates. The reaction of 1 with a series of ethylenediamine and ethylenediphosphine ligands resulted in isolation of the adducts [(2,6-Me2C6H3S)2Pb]2(tmeda) (9), [(2,6-Me2C6H3S)2Pb]3(dmpe) (10) and [(2,6-Me2C6H3S)2Pb]2(dppe) (11) [tmeda = N,N,N',N'-tetramethylethylenediamine; dmpe = bis(dimethylphosphino)ethane; dppe = bis(diphenylphosphino)ethane]. The X-ray crystal structure of 9 shows a dinuclear species in which tmeda is chelating a ψ-trigonal bipyramidal S2N2 Pb centre via axial and equatorial sites. The structure of 10 displays a trinuclear structural unit in which dmpe is chelating a ψ-trigonal bipyramidal S2P2 Pb centre via equatorial sites. Compounds 9 and 10 also contain a second unique metal centre with ψ-tetrahedral S3Pb bonding motifs. The structure of 11 shows the dppe ligand bridging two Pb ψ-tetrahedral S2P metal bonding environments. Static (207)Pb solid-state NMR (SSNMR) spectra of 9-11 and [Ph4As][(PhS)3Pb] (12) were acquired with cross polarization (CP)-CPMG and frequency swept pulse (WURST)-CPMG pulse sequences, and the efficiencies of these pulse sequences are compared. The (207)Pb SSNMR spectra reveal that the lead chemical shift anisotropies (CSA) vary greatly between the different Pb sites, and are generally large in magnitude. DFT calculations are utilized to relate the orientations of the (207)Pb nuclear magnetic shielding tensors to the molecular structures, and to aid in spectral assignment where multiple Pb centres are present. The combination of X-ray diffraction, (207)Pb SSNMR and DFT is shown to be invaluable for the structural characterization of these important structural motifs, and should find wide-ranging application to numerous lead coordination compounds.

Hexadentate ligands cis,cis-C(6)H(9)(N[double bond, length as m-dash]CHC(6)H(4)(PPh(2)))(3) () and cis,cis-C(6)H(9)(NHCH(2)C(6)H(4)(PPh(2)))(3) () were synthesized starting from cis,cis-1,3,5-triaminocyclohexane, and characterized using NMR spectroscopy and single-crystal X-ray diffraction. These ligands can bind both Pt(0) and Pt(II) metal centers using either or both of the soft phosphine moieties and the hard amine/imine moieties. In many cases the resulting complexes are negligibly soluble; hence, (31)P and (195)Pt solid-state NMR (SSNMR) spectroscopy was applied to analyse the bonding modes of the hexadentate ligands. The (195)Pt SSNMR spectroscopy of these complexes is particularly challenging, since (1)H-(195)Pt cross polarization is extremely inefficient, the (195)Pt longitudinal relaxation times are extremely long and the (195)Pt powder patterns are expected to be quite broad due to platinum chemical shift anisotropy. It is demonstrated that the ultra-wideline (195)Pt SSNMR spectra can be efficiently acquired with a combination of frequency-stepped piecewise acquisitions and cross-polarization/Carr-Purcell Meiboom-Gill (CP/CPMG) NMR experiments. The (195)Pt and (31)P SSNMR data are correlated to important structural features in both Pt(0) and Pt(II) species.

The recently reported direct enhancement of integer spin magnetization (DEISM) methodology for signal enhancement in solid-state NMR of integer spins has been used to obtain static (14)N powder patterns from alpha-glycine, L-leucine and L-proline in relatively short experimental times at 9.4 T, allowing accurate determination of the quadrupolar parameters. Proton decoupling and deuteration of the nitrogen sites were used to reduce the (1)H-(14)N dipolar contribution to the transverse relaxation time allowing more echoes to be acquired per scan. In addition, ab initio calculations using molecular clusters (Gaussian 03) and the full crystal lattice (CASTEP) have been employed to confirm these results, to obtain the orientation of the electric field gradient (EFG) tensors in the molecular frame, and also to correctly assign the two sets of parameters for L-leucine. The (14)N EFG tensor is shown to be highly sensitive to the surrounding environment, particularly to nearby hydrogen bonding.

The synthesis and comprehensive characterisation of a series of 1,2,5-selenadiazolium salts, which were generated from the direct reaction between the neutral bidentate ligand tert-butyl-DAB and a variety of heavy chalcogen halides, are reported. The formation of the cationic heterocycle from the reaction of SeX4 (X = Cl, Br) and the ligand results in a two electron redox process where the chalcogen undergoes a two electron reduction concomitant with the elimination of X2, the oxidation by-product. A reaction pathway for this chemistry has been proposed necessitating several key intermediates. These species have been synthesized and used in a stepwise series of transformations that strongly supports this very unusual reactivity for the chalcogens. In contrast, the reaction between tert-butyl DAB and TeX4 (X = Cl, Br, I), does not result in redox, rather an octahedral Te(iv) x DAB complex is formed or no reaction was observed.