Carlo Alberto Veracini

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.

Synthesis and 13C NMR characterization of some π-excessive heteropolyaromatic compounds

Abstract Several π-excessive heteropolyaromatic compounds, which contain furan and thiophen ring and are possible antifungal agents, have been synthesized in good yields according to two general methods. The first method has been used to prepare compounds possessing thiophens linked by their 2- and 5-positions, such as the ter-aryls 2b , 2d and 2a . Two precursors of these compounds have been obtained either by the Glaser reaction, or using a novel Pd-mediated reaction. The second method,which consists of the Ni-or Pd-catalyzed heteroarylation of heteroarene halides via cross-coupling with heteroaryl Grignard reagents or zinc halides,has been used to prepare the bi-aryls 1a-e , which contain two heteroaromatic units, and the ter-aryl 2c . Compound 1e has been also prepared starting from 2-(2-thienyl) furan ( 1c ) by selective lithiation, followed by bromination. The 13C NMR signals of 1a-e and 2a-d have been assigned on the basis of the literature data and by relaxation measurements. Relaxation data have been also used to obtain qualitative informations on the conformational equilibria of the bi-aryls 1a , 1c and the ter-aryls 2a-d .

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.

Molecular Properties of Ibuprofen and Its Solid Dispersions with Eudragit RL100 Studied by Solid-State Nuclear Magnetic Resonance

PurposeThe aim of this study was to investigate, at a molecular level, the structural and dynamic properties of the acidic and sodium salt forms of ibuprofen and their solid dispersions with Eudragit RL-100, obtained by two different preparation methods (physical mixtures and coevaporates), which may affect the release properties of these drugs in their dispersed forms.Methods1H and 13C high-resolution solid-state nuclear magnetic resonance techniques, including single-pulse excitation magic-angle spinning, cross-polarization magic-angle spinning, and other selective 1D spectra, as well as more advanced 2D techniques Frequency Switched Lee-Goldburg HETeronuclear CORrelation (FSLG-HETCOR) and Magic Angle Spinning -J- Heteronuclear Multiple-Quantum Coherence (MAS-J-HMQC) and relaxation time measurements were used.ResultsA full assignment of 13C resonances and precise 1H chemical shift values were achieved for the first time for the two forms of ibuprofen that showed very different interconformational dynamic behavior; drug–polymer interactions were observed and characterized in the coevaporates of the two forms but were much stronger for the acidic form.ConclusionsA combined analysis of several high-resolution solid-state nuclear magnetic resonance experiments allowed the investigation of the structural and dynamic properties of the pure drugs and of the solid dispersions with the polymer, as well as of the degree of mixing between drug and polymer and of the chemical nature of their interaction. Such information could be related to the in vitro drug release profiles observed for the tested coevaporates.

A maximum‐entropy analysis of the problem of the rotameric distribution for substituted biphenyls studied by 1H nuclear magnetic resonance spectroscopy in nematic liquid crystals

The statistical principle of maximum entropy is applied to the analysis of dipolar couplings from 1H NMR of nonrigid molecules dissolved in liquid‐crystalline phases. A distribution function for the orientational and inter‐ring angles is so obtained. The most probable internal angle φ is determined for 4,4’‐dichlorobiphenyl (φ=34°) in the nematic phase of I52, 4‐pentyl‐4’‐cyanobiphenyl (φ=32°) and 4’‐Br‐4‐Cl‐2,6‐difluorobiphenyl (φ=42°) in EBBA. The physical reliability of the distributions determined is discussed. The maximum‐entropy treatment seems to indicate a limit for the information on the internal motion obtainable from the experimental data.

Insect pheromone components: Use of 13C NMR spectroscopy for assigning the configuration of CC double bonds of monoenic or dienic pheromone components and for quantitative determination of Z/E mixtures

Abstract Several insect sex pheromone components and structural analogues have been characterized by 13C NMR spectroscopy. The evaluation of the difference between the chemical shift values of the allytic carbons present in the diunsaturated pheromone components and those of the carbons having the same position on the n-alkane chain of the corresponding saturaated compounds was used to assign the configuration of the CC double bonds present into such dienic compounds. The technique avoids the need to use the nuclear Overhausser effect; it allows quantitative evaluation, with good accuracy, of the stereoisomeric composition of mixtures of synthetic monoenic or dienic pheromone components such as (Z)- and (E)-9-tetraceden-1-yl acetate and (Z)- and (E)-9,11-dodecadien-1-yl acetate.

An internal order approach to the investigation of intramolecular rotations in liquid crystals by NMR: 3-Phenyl-thiophene in PCH and phase IV

Abstract The internal order parameter formalism is used to analyze the proton NMR spectrum of 3-phenyl-thiophene in two nematic phases: PCH and phase IV. Using a maximum-entropy approach we have obtained from the experimental dipolar couplings purely orientational order parameters for the two rings as well as an approximate rotamer distribution. The distribution in PCH peaks at 27° with a much smaller hump at 90° while the distribution in phase IV again peaks at 27° but is much broader, suggesting a noticeable solvent effect.

How do banana-shaped molecules get oriented (if they do) in the magnetic field?

In this work the orientation of banana-shaped molecules in the magnetic field is investigated. A new and original hypothesis of the peculiar aggregation of banana-shaped molecules in the nematic phase in the presence of a magnetic field is here reported. Deuterium NMR measurements on two selectively deuterium labelled mesogens and preliminary calculations of the magnetic susceptibility anisotropy of the aromatic core of these bent molecules are reported and discussed to support our hypothesis.

Structure determination of clay/methyl methacrylate copolymer interlayer complexes by means of 13C solid state n.m.r.

Abstract The interlayer complexes of several methyl methacrylate (MMA)/2-( N -methyl- N,N -diethylammonium iodide) ethyl acrylate (MDEA) copolymers with two smectite clays (bentonite and hectorite), synthesized in two different ways, were studied by means of solid state 13 C n.m.r. techniques. Given the relatively high content of paramagnetic centres in bentonite, which is approximately 50 times more paramagnetic than hectorite, the s.p.e./m.a.s. and c.p./m.a.s. spectra of the different complexes with bentonite show differences according to the proximity of the different copolymer moieties to the clay surface. The dynamics of the organic macromolecules in the inorganic interlayers has been investigated by measuring various relaxation times ( 13 C T 1 , 13 C T 1 ρ and 1 H T 1 ρ ). The paramagnetism of the clay, where relevant, strongly influences the relaxation times measured, whereas in the other cases the different relaxation times allow one to discern differences in the structural organization and mobility of the organic macromolecules dependinding on the complex preparation. Useful indications on the structure of the different complexes have been obtained by combining the above results with X-ray measurements of the interlayer distance for all the samples investigated.

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.