NMR crystallographic techniques are used to validate a structure of -piroxicam determined from powder X-ray diffraction (PXRD) with a relatively poor R-factor. Geometry optimisation of PXRD-and singlecrystal XRD-derived structures results in convergence to the same energy of the structures, with minimal atomic displacements, and good agreement of gauge-included projector augmented wave (GIPAW) calculated and experimentally determined NMR 1 H, 13 C and 15 N chemical shifts and 14 N quadrupolar parameters. Calculations on isolated molecules combined with 2D magic-angle spinning (MAS) 1 H doublequantum (DQ) and 14 N-1 H NMR experiments confirm the 3D packing arrangement of -piroxicam. NMR crystallography is shown to be an effective means of validating crystal structures that might otherwise be considered sceptically on the basis of diffraction data alone.

We have employed for the first time Raman spectroscopic imaging along with multi-variate curve resolution (MCR) analysis to investigate in real time and in-situ the dissolution mechanisms that underpin amorphous solid dispersions, with data being collected directly from the dosage form itself. We have also employed a novel rotating disk dissolution rate (RDDR) methodology to track, through the use of high-performance liquid chromatography (HPLC), the dissolution trends of both drug and polymer simultaneously in multi-component systems. Two formulations of poorly water-soluble felodipine in a polymeric matrix of copovidone VA64 which have different drug loadings of 5% and 50% w/w were used as models with the aim of studying the effects of increasing the amount of active ingredient on the dissolution performance. It was found that felodipine and copovidone in the 5% dispersion dissolve with the same dissolution rate and that no Raman spectral changes accompanied the dissolution, indicating that the two components dissolve as single entity, whose behaviour is dominated by water-soluble copovidone. For the 50% drug-loaded dispersion, partial RDDR values of both felodipine and copovidone were found to be extremely low. MCR Raman maps along with classical Raman/X-ray powder diffraction (XRPD) characterisation revealed that after an initial loss of copovidone from the extrudate the drug re-crystallises, pointing to a release dynamics dependent on the low water solubility and high hydrophobicity of felodipine. Raman imaging revealed different rates of transition from amorphous to crystalline felodipine at different locations within the dosage form.

A versatile in situ multi-microscopy approach to study the dissolution kinetics of single crystals is described, using the loop diuretic drug furosemide as a testbed to demonstrate the utility of the approach. Using optical microscopy and scanning ion-conductance microscopy (SICM) in combination, the dissolution rate of individual crystallographically independent crystal faces can be measured quantitatively while providing a direct visualization of the evolution of crystal morphology in real time in three dimensions. Finite element method (FEM) models using experimental data enables quantitative analysis of dissolution fluxes for individual faces and determination of the limiting process -mass transport or interfacial kinetics -that regulates dissolution. A key feature of the approach is that isolated crystals (typically < 60 µm largest characteristic dimension) in solution during dissolution experience high and well defined diffusion rates. The ability to obtain this quantitative information for individual crystal faces suggests a pathway to understanding crystal dissolution at the molecular level and regulating bioavailability, for example, through manipulation of crystal morphology. AbstractA versatile in situ multi-microscopy approach to study the dissolution kinetics of single crystals is described, using the loop diuretic drug furosemide as a testbed to demonstrate the utility of the approach. Using optical microscopy and scanning ion-conductance microscopy (SICM) in combination, the dissolution rate of individual crystallographically independent crystal faces can be measured quantitatively while providing a direct visualization of the evolution of crystal morphology in real time in three dimensions. Finite element method (FEM) models using experimental data enable quantitative analysis of dissolution fluxes for individual faces and determination of the limiting process -mass transport or interfacial kinetics -that regulates dissolution. A key feature of the approach is that isolated crystals (typically < 60 µm largest characteristic dimension) in solution during dissolution experience high and well defined diffusion rates. The ability to obtain this quantitative information for individual crystal faces suggests a pathway to understanding crystal dissolution at the molecular level and regulating bioavailability, for example, through manipulation of crystal morphology.

No abstract

The search for nitric oxide cheletropic traps (NOCTs) of the 7,7,8,8-tetraalkyl-o-quinodimethane type which would have properties appropriate for monitoring the formation of nitric oride in cell cultures and in vivo by magnetic resonance techniques is described. In addition to the necessary condition that a NOCT reacts rapidly with NO to yield a persistent nitroxide radical, two additional properties were sought: (i) thermal stability at the temperature of interest (37 "C) and (ii) water solubility. To these ends, a number of 1 ,1,3,3-tetraailcyIyl-2-indanones (and a related naphthalene derivative) were synthesized and subjected to UV photolysis in solution, a procedure which generally (though not in all cases) caused the elimination of carbon monoxide and formation of the corresponding o-quinodimethane. The thermal instability of many of these compounds is due to a 1,S-sigmatropic hydrogen atom transfer which, for example, converts 7,7,8,8-tetramethyl-o-quinodimethane (1) to o-isopropyl-a-methylstyrene ( 1 4 with a half-life of only ca. 140 s at 37 "C. Several o-quinodimethanes were discovered which were, for all practical purposes, completely stable at 37 OC. The most suitable lipid-soluble NOCT discovered was 7-(2-indenyl)-7,8,8-trimethyl-o-quinodimethane (5),which is stable and reacts very rapidly with NO to form a persistent nitroxide. Various derivatives of 5 were also examined and found to be equally, or almost equally, effective NOCTs. Water solubility was explored by addition of water-solubilizing groups to the ring of 1. The carboxylic acid group, 13, was found to be particularly suitable, since the carboxylate anion 14 conferred excellent water solubility without interfering with either the nitric oxide trapping reaction or the necessary photoelimination of carbon monoxide frpjn the starting indanone. Of even greater importance, the carboxylate group had no apparent effect on the rate of the thermal 1,s-sigmatropic rearrangement; Le., the rates of decay of 14 and 1 were equal within experimental error. It is concluded that NOCTs of the o-quinodimethane class having long lifetimes and a high reactivity toward NO can now be prepared with appropriate lipophilic, hydrophilic, or amphiphilic properties. These NOCTs should prove suitable for exploratory use in biological systems.