Silvia Borsacchi

Solid‐State NMR Studies of Pharmaceutical Systems

Abstract High‐and low‐resolution solid‐state nuclear magnetic resonance (SSNMR) applications to the study of pharmaceuticals are reviewed. Examples are shown involving the use of mono‐and bidimensional SSNMR techniques based on different nuclear interactions and the measurement of several nuclear parameters, such as chemical shifts, line widths, and relaxation times (T1, T2, T1ρ). The systems investigated include pure active pharmaceutical ingredients (APIs), substances used as drug excipients, and solid dispersions formed by APIs and excipients, up to final drug formulations. The most important aspects treated concern structural, dynamic, and morphological properties, and, in particular, identification, characterization, and quantitation of polymorphs and related forms, conformational and crystalline packing behavior, amorphous phase properties and stability, effects of drug processing, molecular motions, API‐excipient and excipient‐excipient chemical and physical interactions, and phase mixing in heterophasic systems.

Applications of Solid-State NMR to the Study of Organic/Inorganic Multicomponent Materials

Abstract The characterization of a variety of organic/inorganic multicomponent materials (OIMM) through solid-state NMR (SSNMR) spectroscopy will be reviewed. Many examples of applications to OIMM will be described, based on the observation of different nuclei and the use of various SSNMR methods, such as 1D and 2D techniques, measurements on relaxation and spin diffusion processes. OIMM are a very general category of systems differing, for example, by chemical nature and relative amount of organic and inorganic components, shape and size of the domains, and type of organic-inorganic interface. Some of the most investigated classes of OIMM are organically modified silicates, polymer/clay composites, polymer/inorganic filler systems, polymer electrolytes, stationary chromatographic phases, zeolites, and mesoporous silicas including small organic molecules. The aspects most efficiently investigated by SSNMR and discussed in this review include physical and/or chemical interactions occurring at the organic-inorganic interface, structural and dynamic behavior of the organic components, and dimensions and dispersion of organic and inorganic domains.

Improving compatibility in LDPE–silica dispersions by photo-grafting reaction. Preparation and solid state NMR investigation

A TSPM-modified silica has been prepared and employed as a filler in LDPE films, in which a photo-grafting reaction between polymerizable groups present on the functionalized filler and the polymer has been performed with the aim of obtaining stable composites with improved properties. Besides FT-IR, TGA and SEM characterization, both the TSPM-modified silica and the polymer-filler blends have been extensively investigated by means of solid state NMR, through a combined analysis of several high- and low-resolution experiments, performed on 29Si, 1H and 13C nuclei. This allowed us on one hand to obtain detailed and quantitative information on the silica functionalisation reaction and on the other hand, to get an insight into the change of the dynamic properties of LDPE due to the presence of the filler. The NMR results and several macroscopic properties of the blend LDPE–silica–TSPM, such as Youngs modulus and oxygen permeability, were compared with those of the corresponding blend prepared with unfunctionalized silica.

Dynamics by solid-state NMR: detailed study of ibuprofen Na salt and comparison with ibuprofen.

The various internal rotations and interconformational jumps of the Na-salt form of ibuprofen in the solid state were characterized in detail by means of the simultaneous analysis of a variety of low- and high-resolution NMR experiments aimed at measuring several (13)C and (1)H spectral and relaxation properties at different temperatures and frequencies. The results were first qualitatively analyzed to identify the motions of the different molecular fragments and to assign them to specific frequency regimes (slow, <10(3) Hz; intermediate, 10(3)-10(6) Hz; and fast, >10(6) Hz). Subsequently, a simultaneous fit of the experimental data sets most sensitive to each frequency range was performed by using suitable motional models, thus obtaining, for each motion, correlation times and activation energies. The motions so characterized were: the rotations of the three methyl groups and of the isobutyl group, occurring in the fast regime, and the π-flip of the phenyl ring, belonging to the intermediate motional regime. The results obtained for the Na-salt form were compared with those of the acidic form of ibuprofen, previously obtained from a similar solid-state NMR approach: despite the very similar chemical structure of the two compounds, their dynamic properties in the solid state are noticeably different.

Detailed Characterization of the Dynamics of Ibuprofen in the Solid State by a Multi-Technique NMR Approach

The internal rotations and interconformational jumps of ibuprofen in the solid state are fully characterized by the simultaneous analysis of a variety of low- and high-resolution NMR experiments for the measurement of several (13)C and (1)H spectral and relaxation properties, performed at different temperatures and, in some cases, frequencies. The results are first qualitatively analyzed to identify the motions of the different molecular fragments and to assign them to specific frequency ranges (slow, <10(3) Hz; intermediate, 10(3)-10(6) Hz; and fast, >10(6) Hz). In a second step, a simultaneous fit of the experimental data sets most sensitive to each frequency range is performed by means of suitable motional models to obtain, for each motion, values of correlation times and activation energies. The rotations of the three methyl groups around their ternary symmetry axes, which occur in the fast regime, are characterized by slightly different activation energies. Thanks to the simultaneous analysis of (1)H and (13)C data, the π-flip of the dimeric structure made by the acidic groups is also identified and seen to occur in the fast regime. On the contrary, the π-flip of the phenyl ring is found to occur in the slow motional regime, while the rotations of the isobutyl and propionic groups are frozen. The approach used appears to be of general applicability for studying the dynamics of small organic molecules.

Freezing of Molecular Motions Probed by Cryogenic Magic Angle Spinning NMR.

Cryogenic magic angle spinning makes it possible to obtain the NMR spectra of solids at temperatures low enough to freeze out most molecular motions. We have applied cryogenic magic angle spinning NMR to a crystalline small-molecule solid (ibuprofen sodium salt), which displays a variety of molecular dynamics. Magic angle (13)C NMR spectra are shown for a wide range of temperatures, including in the cryogenic regime down to 20 K. The hydrophobic and hydrophilic regions of the molecular structure display different behavior in the cryogenic regime, with the hydrophilic region remaining well-structured, while the hydrophobic region exhibits a broad frozen conformational distribution.

Thermochromic polyethylene films doped with perylene chromophores: experimental evidence and methods for characterization of their phase behaviour

We report on a thermochromic system suitable for sensing temperature changes in the 30–70 °C regime based on linear low density polyethylene (LLDPE) films doped with N,N′-bis-(1′-phenylethyl)-perylene-3,4,9,10-tetracarboxydiimide (PE-Pery), a fluorescent aggregachromic dye. At low PE-Pery concentration (0.01–0.02 wt%), the dye monomers were well dispersed in the polymer matrix showing their maximum fluorescence intensity at 525 nm. As the dye content was increased, monomers emission quenched whereas dye aggregates prevailed above 0.05 wt% as well as their red fluorescence band at 620–680 nm. Upon heating from 30 to 70 °C, all films displayed a thermochromic response, more evident for the less concentrated samples (<0.05 wt%) in which the emission of the dye as a monomer continuously increased with increasing temperature. This phenomenon promoted effective color changes from a dull red-violet at 30 °C to a bright yellow-green at 70 °C. Combined DSC and variable-temperature Solid State NMR (SSNMR) measurements addressed the thermochromic behavior to the increased amount of the available amorphous phase and to the increased mobility of both the interphase and amorphous components with temperature, which favored PE-Pery dispersion and diffusion, thus recovering their fluorescence. Overall, the present results support the use of PE-Pery-enriched LLDPE films as a chromogenic material suitable for the detection of temperature changes close to the physiological regime.

Understanding the aggregation of bis(benzoxazolyl)stilbene in PLA/PBS blends: a combined spectrofluorimetric, calorimetric and solid state NMR approach

Poly(lactic acid)/poly(butylene succinate) (PLA/PBS) blends, containing a small amount of 4,4′-bis(2-benzoxazolyl)stilbene (BBS) dye, showed a chromogenic response after heating above 80 °C, due to the formation of BBS aggregates. This smart behaviour can be useful for many different applications, such as for the realization of time–temperature optical indicators, and the understanding of the processes lying behind the aggregation of chromophores is fundamental for improving their performances. In this work, the phase transitions occurring in the PLA/PBS polymeric matrix under heating were investigated in detail by combining spectrofluorimetric, DSC, and variable-temperature solid state NMR (SSNMR) measurements on both PLA- (in pellets and film) and PLA/PBS-BBS films. A detailed characterization of the phase behaviour of both PLA and PBS domains was achieved. More specifically, the SSNMR analysis of 1H FID at different temperatures was found to be a very powerful and useful approach to investigate the phase transitions of PLA, complementary to DSC. Different phase and dynamic processes, PBS and PLA cold crystallization and PLA glass transition, seem to concur, at different levels, to promote BBS aggregation. A possible mechanism for the formation of BBS aggregates under heating was proposed.

Synthesis, Characterization, and Solid-State NMR Investigation of Organically Modified Bentonites and Their Composites with LDPE

Polymer/clay nanocomposites show remarkably improved properties (mechanical properties, as well as decreased gas permeability and flammability, etc.) with respect to their microscale counterparts and pristine polymers. Due to the substantially apolar character of most of the organic polymers, natural occurring hydrophilic clays are modified into organophilic clays with consequent increase of the polymer/clay compatibility. Different strategies have been developed for the preparation of nanocomposites with improved properties, especially aimed at achieving the best dispersion of clay platelets in the polymer matrix. In this paper we present the preparation and characterization of polymer/clay nanocomposites composed of low-density polyethylene (LDPE) and natural clay, montmorillonite-containing bentonite. Two different forms of the clay have been considered: the first, a commercial organophilic bentonite (Nanofil 15), obtained by exchanging the natural cations with dimethyldioctadecylammonium (2C18) cations, and the second, obtained by performing a grafting reaction of an alkoxysilane containing a polymerizable group, 3-(trimethoxysilyl)propyl methacrylate (TSPM), onto Nanofil 15. Both the clays and LDPE/clay nanocomposites were characterized by thermal, FT-IR, and X-ray diffraction techniques. The samples were also investigated by means of (29)Si, (13)C, and (1)H solid-state NMR, obtaining information on the structural properties of the modified clays. Moreover, by exploiting the effect of bentonite paramagnetic (Fe(3+)) ions on proton spin-lattice relaxation times (T1s), useful information about the extent of the polymer-clay dispersion and their interfacial interactions could be obtained.

Proton Spin-Lattice Relaxation in Silkworm Cocoons: Physisorbed Water and Serine Side-Chain Motions

The molecular dynamic behavior of silkworm cocoons produced by a single Bombyx mori strain was investigated by means of high- and low-resolution solid-state NMR experiments. Cocoons with different moisture content were prepared to study the effects of physisorbed water on their molecular dynamics in the MHz regime, which was probed through the measurement of (1)H T(1) relaxation times at 25 MHz in the 25-95 degrees C temperature range. The water content of the different samples was determined from the analysis of (1)H free-induction decays. In addition to the rotation of methyl groups, mostly from alanine, and to the reorientation of physisorbed water molecules, already identified in previous works as relaxation sinks, the reorientation of serine side-chains was here found to contribute to (1)H T(1) above room temperature. The analysis of the trends of (1)H T(1) versus temperature was carried out in terms of semiempirical models describing the three main motional processes, and indicated that methyl rotation, water reorientation and serine side-chain motions are the most efficient relaxation mechanisms below 0 degrees C, between 0 and 60 degrees C, and above 60 degrees C, respectively. The activation energies were found to decrease passing from serine to water to methyl motions.