Andrew S. Tatton

Probing Hydrogen Bonding in Cocrystals and Amorphous Dispersions Using 14N–1H HMQC Solid-State NMR

Cocrystals and amorphous solid dispersions have generated interest in the pharmaceutical industry as an alternative to more established solid delivery forms. The identification of intermolecular hydrogen bonding interactions in a nicotinamide palmitic acid cocrystal and a 50% w/w acetaminophen-polyvinylpyrrolidone solid dispersion are reported using advanced solid-state magic-angle spinning (MAS) NMR methods. The application of a novel (14)N-(1)H HMQC experiment, where coherence transfer is achieved via through-space couplings, is shown to identify specific hydrogen bonding motifs. Additionally, (1)H isotropic chemical shifts and (14)N electric field gradient (EFG) parameters, both accessible from (14)N-(1)H HMQC experiments, are shown to be sensitive to changes in hydrogen bonding geometry. Numerous indicators of molecular association are accessible from this experiment, including NH cross-peaks occurring from intermolecular hydrogen bonds and changes in proton chemical shifts or electric field gradient parameters. First-principles calculations using the GIPAW approach that yield accurate estimates of isotropic chemical shifts, and EFG parameters were used to assist in assignment. It is envisaged that (14)N-(1)H HMQC solid state NMR experiments could become a valuable screening technique of solid delivery forms in the pharmaceutical industry.

Identifying guanosine self assembly at natural isotopic abundance by high-resolution 1H and 13C solid-state NMR spectroscopy.

By means of the (1)H chemical shifts and the proton-proton proximities as identified in (1)H double-quantum (DQ) combined rotation and multiple-pulse spectroscopy (CRAMPS) solid-state NMR correlation spectra, ribbon-like and quartet-like self-assembly can be identified for guanosine derivatives without isotopic labeling for which it was not possible to obtain single crystals suitable for diffraction. Specifically, characteristic spectral fingerprints are observed for dG(C10)(2) and dG(C3)(2) derivatives, for which quartet-like and ribbon-like self-assembly has been unambiguously identified by (15)N refocused INADEQUATE spectra in a previous study of (15)N-labeled derivatives (Pham, T. N.; et al. J. Am. Chem. Soc.2005, 127, 16018). The NH (1)H chemical shift is observed to be higher (13-15 ppm) for ribbon-like self-assembly as compared to 10-11 ppm for a quartet-like arrangement, corresponding to a change from NH···N to NH···O intermolecular hydrogen bonding. The order of the two NH(2)(1)H chemical shifts is also inverted, with the NH(2) proton closest in space to the NH proton having a higher or lower (1)H chemical shift than that of the other NH(2) proton for ribbon-like as opposed to quartet-like self-assembly. For the dG(C3)(2) derivative for which a single-crystal diffraction structure is available, the distinct resonances and DQ peaks are assigned by means of gauge-including projector-augmented wave (GIPAW) chemical shift calculations. In addition, (14)N-(1)H correlation spectra obtained at 850 MHz under fast (60 kHz) magic-angle spinning (MAS) confirm the assignment of the NH and NH(2) chemical shifts for the dG(C3)(2) derivative and allow longer range through-space N···H proximities to be identified, notably to the N7 nitrogens on the opposite hydrogen-bonding face.

Probing intermolecular interactions and nitrogen protonation in pharmaceuticals by novel 15N-edited and 2D 14N-1H solid-state NMR

We report the applications of two novel magic-angle spinning (MAS) solid-state NMR methods, 1J15N-1H spectral editing and 2D 14N-1H HMQC, to the characterisation of nitrogen functional groups in two pharmaceutical compounds, cimetidine and tenoxicam. The 1J15N-1H spectral editing method can readily differentiate the number of protons directly bonded to a nitrogen site and is not susceptible to motional effects. This enables confirmation of proton transfer, therefore proving or disproving amine salt formation, which is of high significance to the properties of a drug. The recently developed 2D 14N-1H HMQC method can demonstrate the presence of specific hydrogen bonding interactions and thus aid in identifying molecular association. First-principles calculations of NMR chemical shifts and quadrupolar parameters using the GIPAW method were combined with experimental data to assist with spectral assignment and the identification of the hydrogen bonding motifs.

Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions.

The difficulty to find a relevant in vitro dissolution test to evaluate poorly soluble drugs is a well-known issue. One way to enhance their aqueous solubility is to formulate them as amorphous solid dispersions. In this study, three formulations containing itraconazole (ITZ), a model drug, were tested in seven different conditions (different USP apparatuses and different media). Two of the formulations were amorphous solid dispersions namely Sporanox®, the marketed product, and extrudates composed of Soluplus® and ITZ produced by hot melt extrusion; and the last one was pure crystalline ITZ capsules. After each test, a ranking of the formulations was established. Surprisingly, the two amorphous solid dispersions exhibited very different behavior depending primarily on the dissolution media. Indeed, the extrudates showed a better release profile than Sporanox® in non-sink and in biphasic conditions, whilst Sporanox® showed a higher release profile than the extrudates in sink and fasted simulated gastric conditions. The disintegration, dynamic light scattering and nuclear magnetic resonance results highlighted the presence of interaction between the surfactants and Soluplus®, which slowed down the erosion of the polymer matrix. Indeed, the negative charge of sodium dodecyl sulfate (SDS) and bile salts interacted with the surface of the extrudates that formed a barrier through which the water hardly diffused. Moreover, Soluplus® and SDS formed mixed micelles in solution in which ITZ interacts with SDS, but no longer with Soluplus®. Regarding the biphasic dissolution test, the interactions between the octanol dissolved in the aqueous media disrupted the polymer--ITZ system leading to a reduced release of ITZ from Sporanox®, whilst it had no influence on the extrudates. All together these results pointed out the difficulty of finding a suitable in vitro dissolution test due to interactions between the excipients that complicates the prediction of the behavior of these solid dispersions in vivo.

14N–1H heteronuclear multiple-quantum correlation magic-angle spinning NMR spectroscopy of organic solids

Abstract 14N–1H heteronuclear multiple-quantum correlation (HMQC) solid-state magic-angle spinning (MAS) NMR spectra recorded at a 1H Larmor frequency of 850 MHz are presented for the dipeptide β-AspAla. A modified version of the pulse sequence presented by Gan et al. (Chem. Phys. Lett. 435 (2007) 163) that utilises rotary resonance recoupling (R3) at the n = 2 condition (ν1 = 2νR) is employed. Spectra recorded with a short recoupling period (under 200 μs) show two correlation peaks corresponding to the NH and NH3 moieties in the dipeptide. The quadrupolar product, PQ = CQ √ [1 + (ηQ2/3)], is determined experimentally as 3.1 MHz (NH) and 1.0 MHz (NH3) by a comparison of the 14N and 15N isotropic chemical shifts which differ due to the isotropic second-order quadrupolar shift for the spin I = 1 14N nucleus. It is shown that the peak sensitivities increase markedly upon increasing the MAS frequency from 30 to 45 to 60 kHz due to a combination of the reduced residual dipolar broadening of the 1H resonances and a lengthening of the coherence lifetimes under R3 recoupling. Increasing the recoupling period leads to the observation of additional peaks corresponding to longer range intra- and intermolecular NH proximities. Reasonable agreement is evident upon comparing the experimental build-up of correlation peak intensity to that observed for eight-spin density-matrix simulations.

Nanodiamond promotes surfactant-mediated triglyceride removal from a hydrophobic surface at or below room temperature

We demonstrate that ca. 5 nm nanodiamond particles dramatically improve triglyceride lipid removal from a hydrophobic surface at room temperature using either anionic or nonionic surfactants. We prepare nanodiamond-surfactant colloids, measure their stability by dynamic light scattering and use quartz crystal microbalance-dissipation, a technique sensitive to surface mass, in order to compare their ability to remove surface-bound model triglyceride lipid with ionic and nonionic aqueous surfactants at 15-25 °C. Oxidized, reduced, ω-alkylcarboxylic acid, and ω-alkylamidoamine surface-modified adducts are prepared, and then characterized by techniques including (13)C cross-polarization (CP) magic-angle spinning (MAS) NMR. Clear improvement in removal of triglyceride was observed in the presence of nanodiamond, even at 15 °C, both with nanodiamond-surfactant colloids, and by prior nanoparticle deposition on interfacial lipid, showing that nanodiamonds are playing a crucial role in the enhancement of the detergency process, providing unique leads in the development of new approaches to low-temperature cleaning.

Reinforced poly(hydroxyurethane) thermosets as high performance adhesives for aluminum substrates

Poly(hydroxyurethane) (PHU) thermosets reinforced with (functional) nanofillers were developed to design high performance adhesives for bare aluminum. Solvent-free cyclic carbonate/amine/PDMS formulations loaded with native, epoxy- or cyclic carbonate-functionalized ZnO nanofillers were premixed before deposition and thermal curing onto Al. The results highlight that the addition of PDMS prevents PHUs from delamination of the Al surface by increasing the adhesive hydrophobicity and thus limiting the water uptake. The dispersion of functional fillers within PHUs improves their thermal and mechanical properties. Benchmarking of the adhesive performances of the reinforced PHU glues with existing PHU formulations attests the benefits of dispersing functional fillers and PDMS within a resin and evidences a 270% increase of the shear strength of reinforced PHU adhesives compared to formulations reported in the literature.

Unexpected effects of third-order cross-terms in heteronuclear spin systems under simultaneous radio-frequency irradiation and magic-angle spinning NMR

We recently noted [R. K. Harris, P. Hodgkinson, V. Zorin, J.-N. Dumez, B. Elena, L. Emsley, E. Salager, and R. Stein, Magn. Reson. Chem. 48, S103 (2010)] anomalous shifts in apparent (1)H chemical shifts in experiments using (1)H homonuclear decoupling sequences to acquire high-resolution (1)H NMR spectra for organic solids under magic-angle spinning (MAS). Analogous effects were also observed in numerical simulations of model (13)C,(1)H spin systems under homonuclear decoupling and involving large (13)C,(1)H dipolar couplings. While the heteronuclear coupling is generally assumed to be efficiently suppressed by sample spinning at the magic angle, we show that under conditions typically used in solid-state NMR, there is a significant third-order cross-term from this coupling under the conditions of simultaneous MAS and homonuclear decoupling for spins directly bonded to (1)H. This term, which is of the order of 100 Hz under typical conditions, explains the anomalous behaviour observed on both (1)H and (13)C spins, including the fast dephasing observed in (13)C{(1)H} heteronuclear spin-echo experiments under (1)H homonuclear decoupling. Strategies for minimising the impact of this effect are also discussed.