Crystal polymorphs of barbital: news about a classic polymorphic system.

Barbital is a hypnotic agent that has been intensely studied for many decades. The aim of this work was to establish a clear and comprehensible picture of its polymorphic system. Four of the six known solid forms of barbital (denoted I(0), III, IV, and V) were characterized by various analytical techniques, and the thermodynamic relationships between the polymorph phases were established. The obtained data permitted the construction of the first semischematic energy/temperature diagram for the barbital system. The modifications I(0), III, and V are enantiotropically related to one another. Polymorph IV is enantiotropically related to V and monotropically related to the other two forms. The transition points for the pairs I(0)/III, I(0)/V, and III/IV lie below 20 °C, and the transition point for IV/V is above 20 °C. At room temperature, the order of thermodynamic stability is I(0) > III > V > IV. The metastable modification III is present in commercial samples and has a high kinetic stability. The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding). The known correlation between specific N-H···O═C hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph IV.

NMR characterisation of dynamics in solvates and desolvates of formoterol fumarate.

Solid-state NMR is used to characterise dynamics in the ethanol solvate of the pharmaceutical material formoterol fumarate and its associated desolvate. Jump rates and activation barriers for dynamic processes such as phenyl ring rotation and methyl group rotational diffusion are derived from 1D-EXSY and (13)C spin-lattice relaxation times respectively. (2)H and (13)C spin-lattice relaxation times measured under magic-angle spinning conditions are used to show that the fumarate ion in the desolvate is undergoing small-amplitude motion on a frequency scale of 100s of MHz at ambient temperature with an activation parameter of about 32 kJ mol(-1). Exact calculations of relaxation times under MAS provide a simple and robust means to test motional models in cases where relaxation rate maxima are observed, including for systems where the crystal structure of the material is unknown.

NMR characterisation of structure in solvates and polymorphs of formoterol fumarate.

The solid-state structures of two polymorphs and two alcoholates (ethanol and isopropanol) of formoterol fumarate have been investigated by a combination of NMR techniques. First-principles shielding computations are combined with NMR data to successfully relate peaks to their crystallographic positions for the solvates, including atoms that are in equivalent molecular positions. The uncharacterised structure of the asolvate form C is found to contain a single formoterol ion and half a fumarate ion in its asymmetric unit. HETCOR experiments for the ethanolate and form C allow proton chemical shifts to be determined and give improved (13)C resolution for the former compound. Desolvation of the solvates to form C has been monitored under the conditions of the NMR experiment. Differential rates of phenylene ring flipping are observed in the different forms. Carbon-13 relaxation times and (2)H NMR are used to probe dynamics of the fumarate ion.

Computation and NMR crystallography of terbutaline sulfate.

This article addresses, by means of computation and advanced experiments, one of the key challenges of NMR crystallography, namely the assignment of individual resonances to specific sites in a crystal structure. Moreover, it shows how NMR can be used for crystal structure validation. The case examined is form B of terbutaline sulfate. CPMAS (13)C and fast MAS (1)H spectra have been recorded and the peaks assigned as far as possible. Comparison of (13)C chemical shifts computed using the CASTEP program (incorporating the Gauge Including Projector Augmented Wave principle) with those obtained experimentally enable the accuracy of the two distinct single-crystal evaluations of the structure to be compared and an error in one of these is located. The computations have substantially aided in the assignments of both (13)C and (1)H resonances, as has a series of two-dimensional (2D) spectra (HETCOR, DQ-CRAMPS and proton-proton spin diffusion). The 2D spectra have enabled many of the proton chemical shifts to be pinpointed. The relationships of the NMR shifts to the specific nuclear sites in the crystal structure have therefore been established for most (13)C peaks and for some (1)H signals. Emphasis is placed on the effects of hydrogen bonding on the proton chemical shifts.

Natural abundance (25)Mg solid-state NMR of mg oxyanion systems: a combined experimental and computational study.

Solid-state (25)Mg magic angle spinning nuclear magnetic resonance (MAS NMR) data are reported from a range of organic and inorganic magnesium-oxyanion compounds at natural abundance. To constrain the determination of the NMR interaction parameters (delta(iso), chi(Q), eta(Q)) data have been collected at three external magnetic fields (11.7, 14.1 and 18.8 T). Corresponding NMR parameters have also been calculated by using density functional theory (DFT) methods using the GIPAW approach, with good correlations being established between experimental and calculated values of both chi(Q) and delta(iso). These correlations demonstrate that the (25)Mg NMR parameters are very sensitive to the structure, with small changes in the local Mg(2+) environment and the overall hydration state profoundly affecting the observed spectra. The observations suggest that (25)Mg NMR spectroscopy is a potentially potent probe for addressing some key problems in inorganic materials and of metal centres in biologically relevant molecules.

Further conventions for NMR shielding and chemical shifts (IUPAC Recommendations 2008).

IUPAC has published a number of recommendations regarding the reporting of nuclear magnetic resonance (NMR) data, especially chemical shifts. The most recent publication [Pure Appl. Chem. 73, 1795 (2001)] recommended that tetramethylsilane (TMS) serve as a universal reference for reporting the shifts of all nuclides, but it deferred recommendations for several aspects of this subject. This document first examines the extent to which the (1)H shielding in TMS itself is subject to change by variation in temperature, concentration, and solvent. On the basis of recently published results, it has been established that the shielding of TMS in solution [along with that of sodium-3-(trimethylsilyl)propanesulfonate, DSS, often used as a reference for aqueous solutions] varies only slightly with temperature but is subject to solvent perturbations of a few tenths of a part per million (ppm). Recommendations are given for reporting chemical shifts under most routine experimental conditions and for quantifying effects of temperature and solvent variation, including the use of magnetic susceptibility corrections and of magic-angle spinning (MAS). This document provides the first IUPAC recommendations for referencing and reporting chemical shifts in solids, based on high-resolution MAS studies. Procedures are given for relating (13)C NMR chemical shifts in solids to the scales used for high-resolution studies in the liquid phase. The notation and terminology used for describing chemical shift and shielding tensors in solids are reviewed in some detail, and recommendations are given for best practice.

Structural study of polymorphs and solvates of finasteride.

NMR and XRD data are reported for several new forms of finasteride, including the results of complete structure determinations for three solvates. Form III of finasteride, hitherto only mentioned in the patent literature, and a new anhydrous form designated Form X, have been found in mixtures of polymorphs and their (13)C NMR chemical shifts obtained. The results demonstrate that the crystallographic asymmetric units contain three molecules and one molecule, respectively. Attempts to reproduce "Form H1", as described in a patent, resulted in a new IPA solvate hydrate. The previously-reported acetic acid, dioxane, and ethyl acetate solvates have been further characterised, and new THF and diethyl ether solvates prepared and characterised. The crystal structures of the dioxane, IPA, and THF solvates have been determined by single-crystal X-ray diffraction. All the solvates (except the acetic acid case) are found to be hemihydrates, to have a finasteride: solvent molar ratio of 2:1 and to have a common structure. The solvate molecules are highly disordered and sited in channels in the structure. The powder XRD patterns are characteristic of the common structure. These solvates may be distinguished by the characteristic CPMAS (13)C signals from the solvent molecules, but the resonances of the host finasteride structures differ only marginally, and powder XRD patterns are almost indistinguishable. Magic-angle spinning (MAS) proton spectra give sharp lines for the solvent peaks, confirming their high degree of mobility. This is further shown in one case by direct polarisation (13)C spectra. Mobility of the tert-butyl group is also implied. Thermal characteristics have been studied and TGA used (in conjunction with solution-state proton NMR) to estimate molar ratios.

Applications of solid-state NMR to pharmaceutical polymorphism and related matters.

Magic-angle spinning NMR is now making a significant contribution to our understanding of the structure of polymorphs and solvates of pharmaceutical significance. This personal review article discusses a range of applications, with particular emphasis on information about crystallography, for which NMR can address problems that cannot be readily solved by diffraction techniques (such as dynamic disorder and non-stoichiometric hydration). Unlike diffractograms, NMR spectra yield immediate chemical information. Moreover, heterogeneous samples can be investigated and amorphous content provides no significant barrier to studies. Furthermore, NMR can be an effective technique for quantitation (down to the level of ca. 1%). Additional strength is being derived from computation of chemical shifts in solids, using a code that takes account of the spatial repetition inherent in crystalline materials.

Chemical shift computations on a crystallographic basis: some reflections and comments.

Computations for chemical shifts of molecular organic compounds using the gauge-including projector augmented wave method and the NMR-CASTEP code are reviewed. The methods are briefly introduced, and some general aspects involving the sources of uncertainty in the results are explored. The limitations are outlined. Successful applications of the computations to problems of interpretation of NMR results are discussed and the range of areas in which useful information is obtained is illustrated by examples. The particular value of the computations for comparing shifts between resonances where the same chemical site is involved is emphasised. Such cases arise for shifts between different crystallographically independent molecules of the same chemical species, between polymorphs and for shift anisotropies and asymmetries.

Nuclear magnetic resonance investigation of the interaction of water vapor with sildenafil citrate in the solid state.

Solid-state carbon-13 (13C) and nitrogen-15 (15N) nuclear magnetic resonance (NMR) have been used to investigate how water interacts with sildenafil citrate. When the humidity is altered, the water concentration in the solid compound changes in a reversible manner. The proportion of occupied sites depends on the humidity, but the water concentration never reaches a rational (e.g., 1:1) stoichiometric ratio to form a true hydrate. The NMR spectra were obtained under several humidity-controlled conditions to determine what changes occur as the water content is varied and where the water is located in the crystal structure. Only one set of 15N and 13C signals is observed for each humidity level. This shows that water incorporated into the crystal lattice of sildenafil citrate is very mobile and exchanges rapidly on the NMR time scale between various sites. The 13C data are consistent with formation of a hydrogen bond between a water molecule and one carbonyl of the citrate anion. The spectra also show that the water content affects the environment (perhaps influencing the average conformation) of the propyl group. Additionally, 15N dipolar dephasing experiments show that the sildenafil molecule is only protonated in the piperazine ring. The work is supported by solution-state NMR.

Quantification of bambuterol hydrochloride in a formulated product using solid-state NMR.

Carbon-13 NMR spectra of the stable polymorphs of solid bambuterol hydrochloride (BHC) and terbutaline sulfate (TBS) are reported and the resonances assigned with the aid of solution-state spectra. A protocol is presented for quantification of BHC in a formulation in lactose, together with TBS, relative to a reference peak from magnesium stearate. This protocol compares the intensity of an aromatic signal of BHC with that of the main-chain methylene carbons of the stearate. It is shown that the limit of detection (LOD) of BHC in this system under the conditions described is 0.5% with an effective limit of quantification (LOQ) of 1.0%. A calibration plot for the quantification is presented and the various factors affecting the accuracy of the measurements are described. No discernible differences are found in the spectra of physical mixtures of the components, whole tablets, and crushed or ground tablets.

The DIVAM sequence: selective excitation of signals from both rigid and mobile domains in a fluoropolymer.

Simulations have been carried out on z-magnetizations produced by (and hence of the resulting spectra from) the dipolar filter (DF) and the recently suggested "Discrimination Induced by Variable-Amplitude Minipulses" (DIVAM) pulse sequences [S. Ando et al., Polymer 42 (2001) 8137; Magn. Reson. Chem. 40 (2002) 97]. The strengths of dipolar interactions have been modelled by introducing different values for transverse relaxation times. The DF case has been extended by allowing the pulse angles to be smaller than 90 degrees. The pulse intervals have also been used as variables. For the DIVAM case, the variables are similarly the minipulse nutation angles and minipulse intervals. The computations show that DIVAM is superior to DF in terms of selectivity for spectra of heterogeneous materials such as semi-crystalline polymers. The effects of the pulse sequences on 19F spectra of poly(vinylidene fluoride) (PVDF) and of a copolymer of vinylidene fluoride and trifluoroethylene (p(VDF/TrFE)) are presented, together with fits of the experimental results by the simulations.

Efficient 5QMAS NMR of spin-5/2 nuclei: use of fast amplitude-modulated radio-frequency pulses and cogwheel phase cycling.

We report here an efficient multiple-quantum magic-angle spinning (MQMAS) pulse sequence involving fast amplitude-modulated (FAM) radio-frequency pulses for excitation and conversion of five-quantum (5Q) coherences of spin-5/2 nuclei. The use of a FAM-I type pulse train for the conversion of 5Q into 1Q coherences proves to be easier to implement experimentally than the earlier suggested use of a FAM-II type sequence [J. Magn. Reson. 154 (2002) 280], while delivering at least equal signal enhancement. Results of numerical simulations and experimental 27Al 5QMAS spectra of aluminium acetylacetonate for different excitation and conversion schemes are compared to substantiate these claims. We also demonstrate the feasibility of acquiring 5QMAS spectra of spin-5/2 systems using cogwheel phase cycling [J. Magn. Reson. 155 (2002) 300] to select the desired coherence pathways. A cogwheel phase cycle of only 57 steps is shown to be as effective as the minimum conventional nested 77-step phase cycle.

Refinement of hydrogen atomic position in a hydrogen bond using a combination of solid-state NMR and computation.

DFT computations of the proton chemical shift for the intermolecular hydrogen bond in the white form of methylnitroacetanilide, together with the experimental value obtained by high-speed magic-angle spinning NMR, enable the N-H distance to be determined as 1.03 +/- 0.02 A.

The nature of oxygen exchange in ZrW2O8 revealed by two-dimensional solid-state 17O NMR.

17O magic angle spinning (MAS) NMR has been used to determine the nature of oxygen exchange in ZrW(2)O(8). A highly effective isotopic labelling technique has been developed and 1D NMR and 2D exchange spectroscopy (EXSY) experiments have revealed that mutual exchange occurs between all oxygen sites, even at temperatures considerably below the alpha to beta order-disorder phase transition.

Solid-State (199)Hg MAS NMR and Vibrational Spectroscopic Studies of Dimercury(I) Compounds.

The solid-state (199)Hg MAS NMR spectra of Hg(2)X(2) (X = Cl, SCN, NCO, CH(3)CO(2), CF(3)CO(2)) have been measured, and the infrared and Raman spectra of these compounds have been recorded and analyzed to further characterize them and to assist in the interpretation of the NMR data. Spinning-sideband analysis has been used to determine the (199)Hg shielding anisotropy and asymmetry parameters Deltasigma and eta from the solid-state (199)Hg MAS NMR spectra. In contrast to the case of the corresponding mercury(II) compounds, the shielding anisotropy is found to be relatively insensitive to the nature of the X group. This is consistent with the view that the electronic environment of the Hg atom in the mercury(I) compounds is dominated by the Hg-Hg bond. The changes in the (199)Hg shielding parameters from the mercury(II) to the corresponding mercury(I) compounds, as well as the changes in these parameters in the mercury(I) compounds with changes in X, can be interpreted in terms of variations in the local paramagnetic contribution to the shielding tensor.

Quantitative nuclear magnetic resonance analysis of solid formoterol fumarate and its dihydrate.

Carbon-13 cross-polarization magic-angle spinning nuclear magnetic resonance spectra of anhydrous formoterol fumarate and the dihydrate are presented, together with some relaxation time measurements. The latter enabled quantitation of mixtures of the anhydrate and dihydrate to be made. Quantitative nuclear magnetic resonance measurements were then performed on mixtures of the two forms formulated in lactose. Relative amounts of the forms could be assessed at a total formulation level of 2%, whereas the dihydrate on its own in lactose was detectable at the 0.45% level. The optimum experiment involves dipolar dephasing, because that minimizes the intensity of signals from the lactose.

[R,S]-Ethambutol dihydrochloride: variable-temperature studies of a dimorphic system with very similar packing.

The two polymorphs (Forms I and II) of [R,S]-ethambutol dihydrochloride transform enantiotropically and reversibly in a single-crystal-to-single-crystal phase transformation mode. These structurally very similar forms have been characterized and their thermodynamic relationship has been investigated by variable-temperature solid-state carbon-13 nuclear magnetic resonance, variable-temperature powder X-ray diffraction, differential scanning calorimetry, and optical microscopy. The nuclear magnetic resonance results are compared with those for the two polymorphs of the [S,S] diastereomer with known structures.

NMR Nomenclature: Nuclear Spin Properties and Conventions for Chemical Shifts. IUPAC Recommendations 2001.

A unified scale is recommended for reporting the NMR chemical shifts of all nuclei relative to the (1)H resonance of tetramethylsilane. The unified scale is designed to provide a precise ratio, Xi, of the resonance frequency of a given nuclide to that of the primary reference, the (1)H resonance of tetramethylsilane (TMS) in dilute solution (volume fraction, varphi<1%) in chloroform. Referencing procedures are discussed, including matters of practical application of the unified scale. Special attention is paid to recommended reference samples, and values of Xi for secondary references on the unified scale are listed, many of which are the results of new measurements. Some earlier recommendations relating to the reporting of chemical shifts are endorsed. The chemical shift, delta, is redefined to avoid previous ambiguities but to leave practical usage unchanged. Relations between the unified scale and recently published recommendations for referencing in aqueous solutions (for specific use in biochemical work) are discussed, as well as the special effects of working in the solid state with magic-angle spinning. In all, nine new recommendations relating to chemical shifts are made. Standardised nuclear spin data are also presented in tabular form for the stable (and some unstable) isotopes of all elements with non-zero quantum numbers. The information given includes quantum numbers, isotopic abundances, magnetic moments, magnetogyric ratios, and receptivities, together with quadrupole moments and line-width factors (where appropriate).

Micellar solubilization: structural and conformational changes investigated by 1H and 13C liquid-state NMR.

A combination of (1)H self-diffusion measurements and (13)C chemical shift analysis has been used for the study of the solubilization of amphiphilic additives C(n)H(2n+1)X (n=4, 6; X=OH, NH(2)) in cetyltrimethylammonium bromide (CTAB) micelles. This approach, which could be extended to other mixed systems, allows complementary data on structures of micelles and conformations of alkyl chains to be obtained. Previous results on these systems are confirmed and new features emerge. All the additives studied behave as cosurfactants. Their degree of solubilization is determined solely by their alkyl chain length. In the case of cosurfactants with n=6, polar head group differences have been shown to modify micellar structures. This effect has been linked to differences in cosurfactant penetration into micelles. In parallel, the area of CTAB head groups and the length of cetyl chains gradually decrease on average when solubilizing more cosurfactants. Cetyl chain compression is strong in the case of cosurfactants with n=4, whereas it is slightly compensated by an extension below the micellar surface in the case of longer cosurfactants. These conformational changes are related respectively to the formation of smaller spherical micelles and of anisotropic or swollen micelles.