Jiri Brus

Heating of samples induced by fast magic-angle spinning

Intense sample heating through high-speed magic-angle spinning (MAS; up to 58 K temperature difference) is demonstrated. The role of probehead and spinner design, as well as that of the temperature of the bearing air on the heating of a rotating sample, is examined. MAS-induced heating can affect the accurate determination of the isotropic value of the chemical shift as well as the principal values, asymmetry and anisotropy parameters of the chemical shift tensor. In some cases, a very large temperature gradient (12 K) within the fast rotating sample was found, which may limit the resolution of high-speed 1H MAS nuclear magnetic resonance (NMR) spectra.

New perspectives of 19F MAS NMR in the characterization of amorphous forms of atorvastatin in dosage formulations

Despite recent advances in solid-state NMR spectroscopy, the structural characterization of amorphous active pharmaceutical ingredients (APIs) in solid dosage forms continues to be a monumental challenge. To circumvent complications following from low concentrations of APIs in tablet formulations, we propose a new time-saving procedure based on chemometric approach: factor analysis of (19)F MAS NMR spectra. Capability of the proposed method is demonstrated on atorvastatin--a typical representative of fluorinated pharmaceutical substances exhibiting extensive polymorphism. Applying the factor analysis on the recorded (19)F MAS NMR spectra, unique parameters for every sample were derived. In this way every solid form of atorvastatin was characterized and clearly distinguishable even among various amorphous and disordered forms. The proposed method was also found to be suitable for both qualitative and quantitative analysis of mixtures of various forms of atorvastatin. Reliability of the proposed method was extensively examined by comparing the obtained results with other experimental techniques such as (13)C CP/MAS NMR, FTIR and XRPD. As highly linear correlations between the sets of parameters obtained from different experimental data were found, the perspectives of the applied comparative factor analysis to obtain detail structural view on variability of amorphous forms of atorvastatin are also discussed. Although the reported method was tested on atorvastatin, authors expect wider application for any fluorinated compound to give the routine, fast and reliable characterization of amorphous forms of APIs in drug products even at low concentrations (1-5%). Bear in mind that 20-25% of currently developed pharmaceuticals contain at least one fluorine atom in the molecule.

13C Chemical Shift Tensors in Hypoxanthine and 6-Mercaptopurine: Effects of Substitution, Tautomerism, and Intermolecular Interactions

Principal values of the (13)C chemical shift tensor (CST) are measured for two biologically interesting and structurally related compounds, hypoxanthine and 6-mercaptopurine, and differences in the values are discussed with an attempt to reveal chemical shifts sensitive to substitution and prototropic tautomerism in the purine ring. Furthermore, methods of density-functional theory (DFT) are used to calculate principal values of the (13)C chemical shift tensor and orientations of the principal components. Values calculated for isolated molecules are compared to those for several supramolecular clusters and then to experimental data to investigate the degree of modulation of the (13)C CSTs by molecular packing. Focusing on the protonated carbons, C2 and C8, which are crucial for relaxation measurements, we show that neglecting intermolecular interactions can lead to errors as large as 30 ppm in the delta(22) principal component. This has significant implications for the studies of molecular dynamics, employing spin relaxation, in large fragments of nucleic acids at high magnetic fields.

Structural Diversity of Solid Dispersions of Acetylsalicylic Acid As Seen by Solid-State NMR

Solid dispersions of active pharmaceutical ingredients are of increasing interest due to their versatile use. In the present study polyvinylpyrrolidone (PVP), poly[N-(2-hydroxypropyl)-metacrylamide] (pHPMA), poly(2-ethyl-2-oxazoline) (PEOx), and polyethylene glycol (PEG), each in three Mw, were used to demonstrate structural diversity of solid dispersions. Acetylsalicylic acid (ASA) was used as a model drug. Four distinct types of the solid dispersions of ASA were created using a freeze-drying method: (i) crystalline solid dispersions containing nanocrystalline ASA in a crystalline PEG matrix; (ii) amorphous glass suspensions with large ASA crystallites embedded in amorphous pHPMA; (iii) solid solutions with molecularly dispersed ASA in rigid amorphous PVP; and (iv) nanoheterogeneous solid solutions/suspensions containing nanosized ASA clusters dispersed in a semiflexible matrix of PEOx. The obtained structural data confirmed that the type of solid dispersion can be primarily controlled by the chemical constitutions of the applied polymers, while the molecular weight of the polymers had no detectable impact. The molecular structure of the prepared dispersions was characterized using solid-state NMR, wide-angle X-ray scattering (WAXS), and differential scanning calorimetry (DSC). By applying various (1)H-(13)C and (1)H-(1)H correlation experiments combined with T1((1)H) and T1ρ((1)H) relaxation data, the extent of the molecular mixing was determined over a wide range of distances, from intimate intermolecular contacts (0.1-0.5 nm) up to the phase-separated nanodomains reaching ca. 500 nm. Hydrogen-bond interactions between ASA and polymers were probed by the analysis of (13)C and (15)N CP/MAS NMR spectra combined with the measurements of (1)H-(15)N dipolar profiles. Overall potentialities and limitations of individual experimental techniques were thoroughly evaluated.

Characterization of solid polymer dispersions of active pharmaceutical ingredients by 19F MAS NMR and factor analysis

In this contribution the ability of (19)F MAS NMR spectroscopy to probe structural variability of poorly water-soluble drugs formulated as solid dispersions in polymer matrices is discussed. The application potentiality of the proposed approach is demonstrated on a moderately sized active pharmaceutical ingredient (API, Atorvastatin) exhibiting extensive polymorphism. In this respect, a range of model systems with the API incorporated in the matrix of polvinylpyrrolidone (PVP) was prepared. The extent of mixing of both components was determined by T(1)((1)H) and T(1ρ)((1)H) relaxation experiments, and it was found that the API forms nanosized domains. Subsequently it was found out that the polymer matrix induces two kinds of changes in (19)F MAS NMR spectra. At first, this is a high-frequency shift reaching 2-3 ppm which is independent on molecular structure of the API and which results from the long-range polarization of the electron cloud around (19)F nucleus induced by electrostatic fields of the polymer matrix. At second, this is broadening of the signals and formation of shoulders reflecting changes in molecular arrangement of the API. To avoid misleading in the interpretation of the recorded (19)F MAS NMR spectra, because both the contributions act simultaneously, we applied chemometric approach based on multivariate analysis. It is demonstrated that factor analysis of the recorded spectra can separate both these spectral contributions, and the subtle structural differences in the molecular arrangement of the API in the nanosized domains can be traced. In this way (19)F MAS NMR spectra of both pure APIs and APIs in solid dispersions can be directly compared. The proposed strategy thus provides a powerful tool for the analysis of new formulations of fluorinated pharmaceutical substances in polymer matrices.

Characterizing Crystal Disorder of Trospium Chloride: A Comprehensive,13C CP/MAS NMR, DSC, FTIR, and XRPD Study

Analysis of C cross-polarization magic angle spinning (CP/MAS) nuclear magnetic resonance (NMR), differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and X-ray powder diffraction data of trospium chloride (TCl) products crystallized from different mixtures of water-ethanol [φ(EtOH) = 0.5-1.0] at various temperatures (0°C, 20°C) and initial concentrations (saturated solution, 30%-50% excess of solvent) revealed extensive structural variability of TCl. Although (13) C CP/MAS NMR spectra indicated broad variety of structural phases arising from molecular disorder, temperature-modulated DSC identified presence of two distinct components in the products. FTIR spectra revealed alterations in the hydrogen bonding network (ionic hydrogen bond formation), whereas the X-ray diffraction reflected unchanged unit cell parameters. These results were explained by a two-component character of TCl products in which a dominant polymorphic form is accompanied by partly separated nanocrystalline domains of a secondary phase that does not provide clear Bragg reflections. These phases slightly differ in the degree of molecular disorder, in the quality of crystal lattice and hydrogen bonding network. It is also demonstrated that, for the quality control of such complex products, (13) C CP/MAS NMR spectroscopy combined with factor analysis (FA) can satisfactorily be used for categorizing the individual samples: FA of (13) C CP/MAS NMR spectra found clear relationships between the extent of molecular disorder and crystallization conditions.

Potential and Limitations of 2D 1H-1H Spin-Exchange CRAMPS Experiments to Characterize Structures of Organic Solids

Summary. A brief overview of our recent results concerning the application of 2D CRAMPS experiments to investigate a wide range of materials is presented. The abilities of the 2D 1H–1H spin-exchange technique to characterize the structure of organic solids as well as the limitations resulting from segmental mobility and from undesired coherence transfer are discussed. Basic principles of 1H NMR line-narrowing and procedures for analysis of the spin-exchange process are introduced. We focused to the qualitative and quantitative analysis of complex spin-exchange process leading to the determination of domain sizes and morphology in heterogeneous multicomponent systems as well as the characterization of clustering of surface hydroxyl groups in polysiloxane networks. Particular attention is devoted to the determination of the 1H–1H interatomic distances in the presence of local molecular motion. Finally we discuss limitations of the 13C–13C correlation mediated by 1H–1H spin exchange to obtain structural constraints. The application of Lee-Goldburg cross-polarization to suppress undesired coherence transfer is proposed.

6Li MAS NMR Study of Lithium Insertion into Hydrothermally Prepared Li-Ti-O Spinel

Open-circuit measurements and 6 Li magic-angle spinning (MAS) NMR spectroscopy were used to study Li coordination in partly reduced Li 1 . 1 Ti 1 . 9 O 4 + δ spinels prepared by hydrothermal reaction. The reduced spinels show four different Li sites. Signals at -0.2 and 0.3 ppm correspond to Li in 16d and 8a positions. The signal at 0.9 ppm corresponds to a tetrahedrally coordinated Li and represents the primary site for the inserted lithium. The signal at -0.7 ppm appears simultaneously with a decrease of the population of Li in 8a position and indicates a local phase transition connected with ordering of Li into 16c positions.

Factor analysis of 27Al MAS NMR spectra for identifying nanocrystalline phases in amorphous geopolymers.

Nanostructured materials offer enhanced physicochemical properties because of the large interfacial area. Typically, geopolymers with specifically synthesized nanosized zeolites are a promising material for the sorption of pollutants. The structural characterization of these aluminosilicates, however, continues to be a challenge. To circumvent complications resulting from the amorphous character of the aluminosilicate matrix and from the low concentrations of nanosized crystallites, we have proposed a procedure based on factor analysis of 27Al MAS NMR spectra. The capability of the proposed method was tested on geopolymers that exhibited various tendencies to crystallize (i) completely amorphous systems, (ii) X‐ray amorphous systems with nanocrystalline phases, and (iii) highly crystalline systems. Although the recorded 27Al MAS NMR spectra did not show visible differences between the amorphous systems (i) and the geopolymers with the nanocrystalline phase (ii), the applied factor analysis unambiguously distinguished these materials. The samples were separated into the well‐defined clusters, and the systems with the evolving crystalline phase were identified even before any crystalline fraction was detected by X‐ray powder diffraction. Reliability of the proposed procedure was verified by comparing it with 29Si MAS NMR spectra. Factor analysis of 27Al MAS NMR spectra thus has the ability to reveal spectroscopic features corresponding to the nanocrystalline phases. Because the measurement time of 27Al MAS NMR spectra is significantly shorter than that of 29Si MAS NMR data, the proposed procedure is particularly suitable for the analysis of large sets of specifically synthesized geopolymers in which the formation of the limited fractions of nanocrystalline phases is desired. Copyright

Interface Induced Growth and Transformation of Polymer-Conjugated Proto-Crystalline Phases in Aluminosilicate Hybrids: A Multiple-Quantum 23Na–23Na MAS NMR Correlation Spectroscopy Study.

Nanostructured materials typically offer enhanced physicochemical properties because of their large interfacial area. In this contribution, we present a comprehensive structural characterization of aluminosilicate hybrids with polymer-conjugated nanosized zeolites specifically grown at the organic-inorganic interface. The inorganic amorphous Al-O-Si framework is formed by alkali-activated low-temperature transformation of metakaoline, whereas simultaneous copolymerization of organic comonomers creates a secondary epoxide network covalently bound to the aluminosilicate matrix. This secondary epoxide phase not only enhances the mechanical integrity of the resulting hybrids but also introduces additional binding sites accessible for compensating negative charge on the aluminosilicate framework. This way, the polymer network initiates growth and subsequent transformation of protocrystalline short-range ordered zeolite domains that are located at the organic-inorganic interface. By applying an experimental approach based on 2D (23)Na-(23)Na double-quantum (DQ) MAS NMR spectroscopy, we discovered multiple sodium binding sites in these protocrystalline domains, in which immobilized Na(+) ions form pairs or small clusters. It is further demonstrated that these sites, the local geometry of which allows for the pairing of sodium ions, are preferentially occupied by Pb(2+) ions during the ion exchange. The proposed synthesis protocol thus allows for the preparation of a novel type of geopolymer hybrids with polymer-conjugated zeolite phases suitable for capturing and storage of metal cations. The demonstrated (23)Na-(23)Na DQ MAS NMR combined with DFT calculations represents a suitable approach for understanding the role of Na(+) ions in aluminositicate solids and related inorganic-organic hybrids, particularly their specific arrangement and clustering at interfacial areas.