Physical or chemical interactions between drug product (DP) components can occur during manufacturing and/or upon storage; and may alter DP shelf life and performance. In this work a new Powder X-ray Diffraction (PXRD) peak was observed in DP under accelerated storage conditions. Due to the complex drug product matrix (including API, polymer, fillers, super disintegrant and lubricant), it was challenging to pinpoint the component(s) responsible for the new peak. In addition to PXRD, other orthogonal techniques including Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), Solid State Nuclear Magnetic Resonance (SSNMR) and Infrared (IR) spectroscopy were employed in this investigation to understand the root cause mechanistically. Specifically, multi nuclei SSNMR (1H, 23Na, 13C) was instrumental in delineating the components of the matrix. We identified the root cause to be an acid base reaction occurring in the DP, whereby sodium ion in sodium stearyl fumarate (SSF) is replaced by proton leading to SSF form conversion. We also identified commercially available SSF to be a hydrate that can dehydrate to an anhydrous form upon heating. In general, the same techniques can be used to investigate interactions of any multi component solid dosage forms.

A crystalline phase of the pharmaceutical compound ronacaleret hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) spectroscopy and single-crystal X-ray diffraction. The crystal structure is determined to contain two independent cationic molecules and chloride anions in the asymmetric unit, which combine with the covalent structure of the molecule to yield complex SSNMR spectra. Experimental approaches based on dipolar correlation, chemical shift tensor analysis, and quadrupolar interaction analysis are employed to obtain detailed information about this phase. Density functional theory (DFT) calculations are used to predict chemical shielding and electric field gradient (EFG) parameters for comparison with experiment. (1)H SSNMR experiments performed at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling provide information about hydrogen bonding and molecular connectivity that can be related to the crystal structure. (19)F and (13)C assignments for the Z' = 2 structure are obtained using DFT calculations, (19)F homonuclear dipolar correlation, and (13)C-(19)F heteronuclear dipolar correlation experiments. (35)Cl MAS experiments at 16.4 T observe two chlorine sites that are assigned using calculated chemical shielding and EFG parameters. SSNMR dipolar correlation experiments are used to extract (1)H-(13)C, (1)H-(15)N, (1)H-(19)F, (13)C-(19)F, and (1)H-(35)Cl through-space connectivity information for many positions of interest. The results allow for the evaluation of the performance of a suite of SSNMR experiments and computational approaches as applied to a complex but typical pharmaceutical solid phase.

Chemical imaging using confocal Raman microscopy is a useful analytical tool in drug development because of its ability to spatially image active ingredients and excipients in dosage forms and relate their distribution to product performance. While Raman spectra are highly specific for individual components of a formulation, most Raman microscopic mapping experiments require extensive experimental time. Laser wavelengths in the near-infrared range are used to suppress fluorescence but reduce sensitivity because of the inverse quadratic dependence of Raman scattering on laser wavelength. Compact, simple ultraviolet (UV) laser designs now allow for confocal UV Raman microscopy to be performed using a versatile instrument also capable of conventional Raman microscopy and epifluorescence imaging analyses. This study presents the results of UV Raman microscopy analyses using 266 nm laser irradiation of four pharmaceutical compositions of interest, including two types of tablets containing low doses of active ingredients (in the 0.2% w/w range), an amorphous dispersion containing 1% w/w of a small molecule drug, and an enteric coated layered peptide formulation. Resonance Raman enhancements are observed for four of the active ingredients studied in these formulations. The spectroscopic properties of the materials used in this study are also assessed by diffuse reflectance UV-visible spectroscopy, fluorescence spectroscopy, and conventional bulk Fourier transform Raman spectroscopy using 1064 nm laser irradiation. Confocal UV Raman microscopy was found to offer good sensitivity and allowed for rapid microscopic mapping of drugs and excipients at low concentrations in pharmaceutical formulations.

The solubility of drug molecules can often be improved through preparation and delivery of cyclodextrin (CD) inclusion complexes. These drug-oligosaccharide complexes can be prepared in solution and converted to the solid state via methods such as lyophilization and spray-drying, or they can be prepared directly from solids by a variety of methods. The development of drug-CD complexes as solids allows for potential advantages in dosage form design, such as the preparation of layered formulations, and it also can yield improvements in chemical and physical stability. 2D solid-state NMR (SSNMR) methods provide a direct way to probe drug-CD interactions in solid complexes through dipolar interactions between nuclei within the drug and CD molecules. In this study, 2D heteronuclear and homonuclear correlation SSNMR experiments involving (1)H, (13)C, (19)F, and (31)P nuclei are used to demonstrate the inclusion of drug within the CD cavity in a variety of powder samples. To illustrate the general applicability of the SSNMR approach presented, examples are shown for the drugs diflunisal, adefovir dipivoxil, voriconazole, dexamethasone, and prednisolone in complexes with α-CD, β-CD, and sulfobutylether-substituted β-CD. The quantitative analysis of included and free drug fractions in a solid drug-CD complex using SSNMR is also demonstrated. On the basis of these results, general approaches to the characterization of these materials using SSNMR are proposed.

Solid-state (13)C, (19)F, and (15)N magic angle spinning NMR studies of Form I of atorvastatin calcium are reported, including chemical shift tensors of all resolvable carbon sites and fluorine sites. The complete (13)C and (19)F chemical shift assignments are given based on an extensive analysis of (13)C-(1)H HETCOR and (13)C-(19)F HETCOR results. The solid-state NMR data indicate that the asymmetric unit of this material contains two atorvastatin molecules. A possible structure of Form I of atorvastatin calcium (ATC-I), derived from solid-state NMR data and density functional theory calculations of various structures, is proposed for this important active pharmaceutical ingredient (API).

AbstractSolid‐state NMR (SSNMR) spectroscopy has been found to be very useful technique for pharmaceutical development. This technique is currently applied for the study of pharmaceutical solids, ranging from detailed structural studies of active pharmaceutical ingredients (APIs) forms to analysis of complex drug products and formulations. The study suggests that solid‐state structure of a pharmaceutical product can influence its properties, manufacturability, and stability. It is essential to regulate and control over solid‐state structure and subsequent properties. The studies show that SSNMR is closely related to the widely used technique of solution‐state NMR and possesses many of the same features. Further the study concludes that field of pharmaceutical SSNMR continues to advance at a rapid rate and will develop new molecular classes and new formulations and delivery modes in near future.

AbstractA practical procedure for the enantioselective reaction between α,β‐unsaturated ketones and glycine imines is described using a FOXAP‐type ferrocene as optimal ligand.

Solid-state NMR (SSNMR) can provide detailed structural information about amorphous solid dispersions of pharmaceutical small molecules. In this study, the ability of SSNMR experiments based on dipolar correlation, spin diffusion, and relaxation measurements to characterize the structure of solid dispersions is explored. Observation of spin diffusion effects using the 2D (1)H-(13)C cross-polarization heteronuclear correlation (CP-HETCOR) experiment is shown to be a useful probe of association between the amorphous drug and polymer that is capable of directly proving glass solution formation. Dispersions of acetaminophen and indomethacin in different polymers are examined using this approach, as well as (1)H double-quantum correlation experiments to probe additional structural features. (1)H-(19)F CP-HETCOR serves a similar role for fluorinated drug molecules such as diflunisal in dispersions, providing a rapid means to prove the formation of a glass solution. Phase separation is detected using (13)C, (19)F, and (23)Na-detected (1)H T(1) experiments in crystalline and amorphous solid dispersions that contain small domains. (1)H T(1) measurements of amorphous nanosuspensions of trehalose and dextran illustrate the ability of SSNMR to detect domain size effects in dispersions that are not glass solutions via spin diffusion effects. Two previously unreported amorphous solid dispersions involving up to three components and containing voriconazole and telithromycin are analyzed using these experiments to demonstrate the general applicability of the approach.

4,7-Dihydro-1H-tricyclopenta[def,jkl,pqr]triphenylene (sumanene) and indeno[1,2,3-cd]fluoranthene (indenofluoranthene) are structural moieties related to Buckminsterfullerene (C(60)). As such, understanding their structural characteristics is of great interest because of the insight they shed upon C(60). Hence, solid-state NMR (ssNMR) and ab initio quantum mechanical calculations with Gaussian03 are used in order to understand and to better characterize the molecular conformation and properties of sumanene and indenofluoranthene. Sumanene has bowl shaped curvature in its natural conformation and indenofluoranthene is planar in its natural conformation, which led us to examine how altering the curvature affects the chemical shifts in relation to those of C(60). Using X-ray structures of both sumanene and indenofluoranthene as our starting model, we calculate the energy and chemical shielding tensors and compare these data with those collected utilizing the (13)C ssNMR FIREMAT experiment. We define curvature of sumanene and indenofluoranthene using the pi-orbital axis vector (POAV) pyramidalization angle (theta(p)). We calculate the energy of varying conformations of indenofluoranthene versus their theta(p) associated with each deformed conformation.

Solid-state analysis with powder X-ray diffraction (PXRD), solid-state NMR (SSNMR), and other spectroscopic and physical methods can provide detailed structural information about organic and pharmaceutical cocrystals. In this study, a range of solid-state analysis methods are used to characterize co-crystallized solid solutions of 5-fluorouracil and thymine. 1H, 13C and 19F SSNMR and PXRD methods are used to study the structure and disorder present in a solid solution previously prepared by solution evaporation methods; here the solid solution is prepared over a wider stoichiometric range by solvent-drop grinding techniques. Long-range perturbations of key chemical shifts are detectable by SSNMR, indicating that the solid solution is not random. Cross-polarization and heteronuclear correlation SSNMR experiments between 1H, 13C, and 19F nuclei offer insight into the structure of this solid solution, and density functional theory (DFT) methods are applied to calculate lattice energies and NMR properties in order to understand the population of the two primary disordered sites in the crystal structure. In addition, a second solid solution of 5-fluorouracil and thymine is reported and analyzed. This solid solution, which was produced by solvent-drop grinding experiments and characterized by SSNMR and powder X-ray diffraction methods, is determined to be an isostructural phase to that of anhydrous thymine with the inclusion of 5-fluorouracil defects. A similar effect does not occur under excess 5-fluorouracil conditions; instead, phase-separated Form 1 of 5-fluorouracil and anhydrous thymine are obtained. DFT calculations are applied to offer a possible explanation for this disparity.

Solid-state NMR (SSNMR) is capable of providing detailed structural information about organic and pharmaceutical cocrystals and complexes. SSNMR nondestructively analyzes small amounts of powdered material and generally yields data with higher information content than vibrational spectroscopy and powder X-ray diffraction methods. These advantages can be utilized in the analysis of pharmaceutical cocrystals, which are often initially produced using solvent drop grinding techniques that do not lend themselves to single crystal growth for X-ray diffraction studies. In this work, several molecular complexes and cocrystals are examined to understand the capabilities of the SSNMR techniques, particularly their ability to prove or disprove molecular association and observe structural features such as hydrogen bonding. Dipolar correlation experiments between spin pairs such as (1)H-(1)H, (1)H-(13)C, and (19)F-(13)C are applied to study hydrogen bonding, intermolecular contacts, and spin diffusion to link individual molecules together in a crystal structure and quickly prove molecular association. Analysis of the principal components of chemical shift tensors is also utilized where relevant, as these are more sensitive to structural effects than the isotropic chemical shift alone. In addition, (1)H T(1) relaxation measurements are also demonstrated as a means to prove phase separation of components. On the basis of these results, a general experimental approach to cocrystal analysis by SSNMR is suggested.

The 1H–13C solid-state NMR heteronuclear correlation (HETCOR) experiment is demonstrated to provide shift assignments in certain powders that have two or more structurally independent molecules in the unit cell (i.e. multiple molecules per asymmetric unit). Although this class of solids is often difficult to characterize using other methods, HETCOR provides both the conventional assignment of shifts to molecular positions and associates many resonances with specific molecules in the asymmetric unit. Such assignments facilitate conformational characterization of the individual molecules of the asymmetric unit and the first such characterization solely from solid-state NMR data is described. HETCOR offers advantages in sensitivity over prior methods that assign resonances in the asymmetric unit by 13C–13C correlations and therefore allows shorter average analysis times in natural abundance materials. The 1H–13C analysis is demonstrated first on materials with known shift assignments from INADEQUATE data (santonin and Ca(OAc)2 phase I) to verify the technique and subsequently is extended to a pair of unknown solids: (+)-catechin and Ca(OAc)2 phase II. Sufficient sensitivity and resolution is achieved in the spectra to provide assignments to one of the specific molecules of the asymmetric unit at over 54% of the sites.

A detailed, quantitative description of the unfolded states of proteins at atomic resolution has been elusive due to enormous experimental and theoretical problems resulting from the huge number of degrees of freedom of an unfolded structural ensemble. In particular, direct long-range information has been extremely sparse. Here we show that such long-range information can be obtained by NMR with high sensitivity and precision from H-N-H-N residual dipolar couplings (RDCs) and hydrogen bond (Hbonds) scalar couplings for an unfolded, perdeuterated (amide protonated) protein (urea-denatured ubiquitin at pH 2.5). Besides numerous sequential contacts, the RDCs reveal the persistence of nativelike structure in ubiquitin's first beta-hairpin. This native-like structure is confirmed by the direct detection of H-bonds via (h3)J(NC') H-bond scalar couplings as well as by chemical shifts, (3)J(HNHA) couplings, and relaxation rates. A quantitative analysis suggests that despite 25% native backbone torsion angles indicated by the chemical shifts, the H-bonds of the hairpin are formed to a much lesser degree in urea.

Angewandte Chemie International EditionVolume 45, Issue 32 p. 5322-5326 Communication The Structure of Fractionally Charged Tetracyanobenzenen− Present in [TCNB]32−† Joshua D. Bagnato Dr., Joshua D. Bagnato Dr. Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorWilliam W. Shum, William W. Shum Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorMark Strohmeier Dr., Mark Strohmeier Dr. Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorDavid M. Grant Prof., David M. Grant Prof. Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorAtta M. Arif Dr., Atta M. Arif Dr. Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorJoel S. Miller Prof., Joel S. Miller Prof. jsmiller@chem.utah.edu Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this author Joshua D. Bagnato Dr., Joshua D. Bagnato Dr. Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorWilliam W. Shum, William W. Shum Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorMark Strohmeier Dr., Mark Strohmeier Dr. Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorDavid M. Grant Prof., David M. Grant Prof. Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorAtta M. Arif Dr., Atta M. Arif Dr. Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this authorJoel S. Miller Prof., Joel S. Miller Prof. jsmiller@chem.utah.edu Department of Chemistry, University of Utah, Salt Lake City, UT 84112–0850, USA, Fax: (+1) 801-581-8433Search for more papers by this author First published: 07 August 2006 https://doi.org/10.1002/anie.200601070Citations: 29 † We thank Jack Simons and Henry S. White for helpful discussions and the continued partial support by the Department of Energy Division of Materials Science (Grant Nos. DE-FG03-93ER45504, and DE-FG03-94ER14452). Computer resources were provided by the Center for High Performance Computing at the University of Utah. naverage≈2/3−, TCNB=Tetracyanobenzene Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract On a reduced charge: The reduction of 1,2,4,5-tetracyanobenzene (TCNB) with tetrakis(dimethylamino)ethylene (TDAE) forms [TDAE][TCNB]3⋅MeCN. Characterization reveals that the [TDAE]2+ ion is present, and that TCNB is reduced forming diamagnetic [TCNB]32−. The reduced TCNB units (see picture) are best described as [TCNB]≈0.5−[TCNB]≈1−[TCNB]≈0.5− containing fractionally charged organic species. Citing Literature Supporting Information Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2006/z601070_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume45, Issue32August 11, 2006Pages 5322-5326 RelatedInformation

The principal (13)C chemical-shift values for the pi-[TCNE](2)(2-) dimer anion within an array of counterions have been measured to understand better the electronic structure of these atypical chemical species in several related TCNE-based structures. The structure of pi-[TCNE](2)(2-) is unusual as it contains two very long C-C bond lengths (ca. 2.9 Angstroms) between the two monomeric units and has been found to exist as a singlet state, suggestive of a (1)A(1g) (b(2u)(2)b(1g)(0)) electronic configuration. A systematic study of several oxidation states of [TCNE](n) (n = 0, 1-, 2-) was conducted to determine how the NMR chemical-shift tensor values change as a function of electronic structure and to understand the interactions that lead to spin-pairing of the monomer units. The density functional theory (DFT) calculated nuclear shielding tensors are correlated with the experimentally determined principal chemical-shift values. Such theoretical methods provide information on the tensor magnitudes and orientations of their principal tensor components with respect to the molecular frame. Both theoretical and experimental ethylenic chemical-shielding tensors reveal high sensitivity in the component, delta(perpendicular), lying in the monomer molecular plane and perpendicular to the pi-electron plane. This largest shift dependence on charge density is observed to be about -111 ppm/e(-) for delta(perpendicular). The component in the molecular plane but parallel to the central C=C bond, delta(parallel), exhibits a sensitivity of approximately -43 ppm/e(-). However, the out-of-plane component delta'(perpendicular) shows a minimal dependence of -2.6 ppm/e(-) on the oxidation state (n) of [TCNE](n). These relative values support the claim that it is changes within the ethylenic pi-electrons and not the sigma-electrons that best account for the dramatic variations in bonding and shift tensors in this series of compounds. Concerning the intraion bonding, relatively weak Wiberg bond orders between the two monomeric components of the dimer correlate with the long bonds linking the two [TCNE(*)](-) monomers. The chemical-shift tensors for the cyano group, compared to the ethylene shifts, exhibit a reduced sensitivity on the TCNE oxidation state. The experimental principal chemical-shift components agree (within typical errors) with the calculated quantum mechanical shieldings used to correlate the bonding. The embedded ion model (EIM) was used to investigate the typically large electrostatic lattice potential in these ionic materials. Chemical-shielding principal values calculated with the EIM model differ from experiment by +/-3.82 ppm on average, whereas in the absence of an electrostatic field model, the experimental and theoretical results agree by +/-4.42 ppm, which is only a modest increase in error considering the overall ionic magnitudes associated with the tensor variations. Apparently, the effects of the sizable long-range electrostatic fields cancel when the shifts are computed because of lattice symmetry.