Marco Geppi

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.

PREPARATION, CHARACTERISATION AND PHOTOSENSITIVITY STUDIES OF SOLID DISPERSIONS OF DIFLUNISAL AND EUDRAGIT RS100 AND RL100

Solid dispersions of diflunisal (DIF) with Eudragit RS100 (RS) and RL100 (RL) with different drug-to-polymer ratios were prepared by a solvent method (coevaporates) and were characterised in the solid state in comparison with the corresponding physical mixtures. The work was aimed at characterising the interactions occurring between DIF and RS or RL polymers, along with their influence on the in-vitro drug-dissolution pattern. The findings suggest that the drug did not change its crystalline form within the polymer network. Drug dispersion in the polymer matrix strongly influences its dissolution rate, which appears slower and more gradual while increasing the polymer ratios. Moreover, DIF is known to be a photosensitive compound, and its photoproduct has been found to be a toxic agent. This can be evidenced by testing red blood cell membranes for their resistance to the osmotic shock induced by UVA irradiation in the presence of DIF. The presence of some DIF/RS coevaporates was shown to reduce significantly the drug photosensitization process towards cell membranes. This suggests the possibility of combining the design of a drug delivery system with a photoprotective strategy.

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.

Structural and Dynamic Properties of Amorphous Solid Dispersions: The Role of Solid-State Nuclear Magnetic Resonance Spectroscopy and Relaxometry

Amorphous solid dispersions (ASDs) are one of the frontier strategies to improve solubility and dissolution rate of poorly soluble drugs and hence tackling the growing challenges in oral bioavailability. Pharmaceutical performance, physicochemical stability, and downstream processability of ASD largely rely on the physical structure of the product. This necessitates in-depth characterization of ASD microstructure. Solid-state nuclear magnetic resonance (SS-NMR) techniques bear the ultimate analytical capabilities to provide the molecular level information on the dynamics and phase compositions of amorphous dispersions. SS-NMR spectroscopy/relaxometry, as a single and nondestructive technique, can reveal diverse and critical structural information of complex ASD formulations that are barely amenable from any other existing technique. The purpose of the current article is to review the recent most important studies on various sophisticated and information-rich one-dimensional and two-dimensional SS-NMR spectroscopy/relaxometry for the analysis of molecular mobility, miscibility, drug-carrier interactions, crystallinity, and crystallization in ASD. Some specific examples on microstructural elucidations of challenging ASD using multidimensional and multinuclear SS-NMR are presented. Additionally, some relevant examples on the utility of solution-NMR and NMR-imaging techniques for the investigation of the dissolution behavior of ASD are gathered.

Magic-angle spinning NMR of cold samples.

Magic-angle-spinning solid-state NMR provides site-resolved structural and chemical information about molecules that complements many other physical techniques. Recent technical advances have made it possible to perform magic-angle-spinning NMR experiments at low temperatures, allowing researchers to trap reaction intermediates and to perform site-resolved studies of low-temperature physical phenomena such as quantum rotations, quantum tunneling, ortho-para conversion between spin isomers, and superconductivity. In examining biological molecules, the improved sensitivity provided by cryogenic NMR facilitates the study of protein assembly or membrane proteins. The combination of low-temperatures with dynamic nuclear polarization has the potential to boost sensitivity even further. Many research groups, including ours, have addressed the technical challenges and developed hardware for magic-angle-spinning of samples cooled down to a few tens of degrees Kelvin. In this Account, we briefly describe these hardware developments and review several recent activities of our group which involve low-temperature magic-angle-spinning NMR. Low-temperature operation allows us to trap intermediates that cannot be studied under ambient conditions by NMR because of their short lifetime. We have used low-temperature NMR to study the electronic structure of bathorhodopsin, the primary photoproduct of the light-sensitive membrane protein, rhodopsin. This project used a custom-built NMR probe that allows low-temperature NMR in the presence of illumination (the image shows the illuminated spinner module). We have also used this technique to study the behavior of molecules within a restricted environment. Small-molecule endofullerenes are interesting molecular systems in which molecular rotors are confined to a well-insulated, well-defined, and highly symmetric environment. We discuss how cryogenic solid state NMR can give information on the dynamics of ortho-water confined in a fullerene cage. Molecular motions are often connected with fundamental chemical properties; therefore, an understanding of molecular dynamics can be important in fields ranging from material science to biochemistry. We present the case of ibuprofen sodium salt which exhibits different degrees of conformational freedom in different parts of the same molecule, leading to a range of line broadening and line narrowing phenomena as a function of temperature.

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.

Molecular properties of flurbiprofen and its solid dispersions with Eudragit RL100 studied by high- and low-resolution solid-state nuclear magnetic resonance.

PurposeInvestigation of the conformational and molecular dynamic properties of the acidic and sodium salt forms of Flurbiprofen and their solid dispersions with Eudragit® RL100, obtained by two different preparation methods (physical mixtures and coevaporates), and of the mixing degree between the two components in the dispersions.Materials and Methods1H and 13C high-resolution solid state NMR techniques, including Single Pulse Excitation-MAS, CP-MAS, FSLG-HETCOR; low-resolution 1H FID analysis; 1H spin-lattice relaxation time measurements.ResultsConformational, molecular packing and dynamic differences were observed between the two pure forms of flurbiprofen, as well as between the pure drugs and the corresponding coevaporates. In the coevaporates of the two flurbiprofen forms, drug and polymer appear intimately mixed; their chemical interactions were detected and characterized.ConclusionsA combined analysis of several 13C and 1H high- and low-resolution solid state NMR experiments allowed the investigation of the conformational 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 compared to the in vitro drug release profiles given by these solid dispersions.

Orientational Order of Difluorinated Liquid Crystals : A Comparative 13C-NMR, Optical, and Dielectric Study in Nematic and Smectic B Phases

Structural and orientational order properties of 3Cy2CyBF2 and of 5CyCy2BF2 have been investigated by means of (13)C-NMR, optical, and dielectric spectroscopy methods. In the case of NMR, order parameters have been independently obtained from the analysis of either (13)C-(19)F dipolar couplings or (13)C chemical shift anisotropies, both measured from (13)C-{(1)H} NMR static spectra. The assignment of the (13)C resonances has been carried out thanks to the comparison with solution state spectra and DFT calculations, and the relevant geometrical parameters and (13)C chemical shift tensors needed to derive orientational order parameters have been calculated by DFT methods. In the analysis of (13)C-(19)F dipolar couplings, empirical corrections for vibrations and anisotropic scalar couplings have been included. Dielectric measurements have been performed over a broad frequency range for two orientations of the nematic director with respect to the measuring field. At low frequencies (static case) a positive dielectric anisotropy has been determined, which has enabled the calculation of the order parameters according to a well-tested procedure. At high frequencies the dielectric anisotropy changes its sign, a property which can be useful in designing a dual addressing display. The nematic order parameter determined from optical, dielectric, and NMR methods have been compared: their trends with temperature are very similar, apart from some slight shifts, and were analyzed by Haller and Chirtoc models. The differences among the results obtained by the four methods have been discussed in detail, also with reference to the assumptions and approximations used in each case, and to the results recently reported for similar fluorinated nematogens. The presence of a non-negligible order biaxiality has been related to the presence of a CH2CH2 bridging group, linking one cyclohexylic unit with either the other cyclohexyl or the phenyl ring.