Martina Urbanova

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.

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.

Structural and Surface Properties of Novel Polyurethane Films

In this work, novel polycarbonatediol- and polybutadienediol-based polyurethanes (PU) with promising properties were prepared and compared with an analogous polypropyleneglycol-based product. Hexamethylenediisocyanate was used as isocyanate (NCO) component. All three PU systems were subsequently modified by the incorporation of two different nanofillers (Montmorillonite clays): “Cloisite 15A” and “Bentonite for organic systems.” The PUs were prepared in form of film coatings and characterized by atomic force microscopy (AFM), transmission electron microscopy (TEM), and wide angle X-ray scattering (WAXS). Their chemical microstructure was checked by 13C-NMR spectroscopy.

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.

Location of Framework Al Atoms in the Channels of ZSM‐5: Effect of the (Hydrothermal) Synthesis

(27) Al 3Q MAS NMR and UV/Vis spectroscopy with bare Co(II) ions as probes of Al pairs in the zeolite framework were employed to analyze the location of framework Al atoms in the channel system of zeolite ZSM-5. Furthermore, the effect of Na(+) ions together with tetrapropylammonium cation (TPA(+)) in the ZSM-5 synthesis gel on the location of Al in the channel system was investigated. Zeolites prepared using exclusively TPA(+) as a structure-directing agent (i.e., in the absence of Na(+) ions) led to 55-90% of Al atoms located at the channel intersection, regardless the presence or absence of Al pairs [Al-O-(Si-O)2 -Al sequences in one ring] in the zeolite framework. The presence of Na(+) ions in the synthesis gel did not modify the Al location at the channel intersection (55-95% of Al atoms) and led only to changes in i) the distribution of framework Al atoms between Al pairs (decrease) and single isolated Al atoms (increase), and ii) the siting of Al in distinguishable framework tetrahedral sites.

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.

Structural insight into the physical stability of amorphous Simvastatin dispersed in pHPMA: Enhanced dynamics and local clustering as evidenced by solid-state NMR and Raman spectroscopy

New drug formulations are sought for poorly water-soluble substances because there is a risk of compromised bioavailability if such substances are administered orally. Such active pharmaceutical ingredients can be reformulated as solid dispersions with suitable water-soluble polymers. In this contribution, formulation of a novel and physically stable dispersion of Simvastatin in poly(2-hydroxypropyl) methacrylamide (pHPMA) is demonstrated. Due to the limited water sorption of pHPMA and a high Tg, the prepared dispersion is more suited for oral administration and storage compared with neat amorphous Simvastatin. Surprisingly, the rate of global reorientation and the internal motion of Simvastatin molecules were enhanced and exhibited dynamical heterogeneities when incorporated into the pHPMA matrix. As revealed by solid-state nuclear magnetic resonance combined with Raman spectroscopy exploiting the fluorescence phenomenon the mobility of the ester and lactone components increased considerably, whereas the naphthalene ring remained rigid. Furthermore, the solid dispersion was found to be nano-heterogeneous with nanometer-sized Simvastatin domains. The presence of these clusters had no impact on the dynamics of the rigid pHPMA chains. Thus, the diffusion of Simvastatin molecules through the glassy pHPMA walls and the subsequent transformation of the clusters into larger crystallites were prevented. No crystallization was detected for more than two years.

Biaxial Q-shearing of 27Al 3QMAS NMR spectra: insight into the structural disorder of framework aluminosilicates.

In this contribution, we present the application potentiality of biaxial Q-shearing of (27)Al 3QMAS NMR spectra in the analysis of structural defects of aluminium units in aluminosilicates. This study demonstrates that the combination of various shearing transformations of the recorded (27)Al 3QMAS NMR spectra enables an understanding of the broadening processes of the correlation signals of disordered framework aluminosilicates, for which a wide distribution of (27)Al MAS NMR chemical shifts and quadrupolar parameters (i.e., second-order quadrupolar splitting and quadrupole-induced chemical shifts) can be expected. By combining the suitably selected shearing transformation procedures, the mechanisms of the formation of local defects in aluminosilicate frameworks, including Al/Si substitution effects in the next-nearest neighbouring T-sites, variations in bond angles, and/or variations in the physicochemical nature of charge-balancing counter-ions, can be identified. The proposed procedure has been extensively tested on a range of model aluminosilicate materials (kyanite, γ-alumina, metakaolin, analcime, chabazite, natrolite, phillipsite, mordenite, zeolite A, and zeolite Y).