Enantioselective determination of R- and S-(alpha-bromoisovaleryl)urea in plasma using high-performance liquid chromatography after solid-phase extraction.

A stereoselective method has been developed for the determination of R- and S-(alpha-bromoisovaleryl)urea in plasma and saliva after oral administration. The chiral separation was carried out on Chiralcel OJ or OD columns with hexane--2-propanol as the mobile phase. The poor detection properties of the analyte required the development of an effective sample pretreatment procedure to enable ultraviolet detection at 210 nm. Solid-phase extraction using hydrophobic Amberlite XAD-2 in combination with washing steps at alkaline and acidic pH completely removed interfering components of the biological matrix and allowed the detection of the optical isomers at concentrations down to 10 ng/ml (0.05 microM). The method was validated by determining the recovery, linearity, accuracy and within-day and between-day repeatability at 50, 200 and 2000 ng/ml. Application to the analysis of plasma and saliva samples is demonstrated.     

Concomitant polymorphs of 1,3‐bis(3‐fluorophenyl)urea

Hydrogen bonding between urea functionalities is a common structural motif employed in crystal‐engineering studies. Crystallization of 1,3‐bis(3‐fluorophenyl)urea, C₁₃H₁₀F₂N₂O, from many solvents yielded concomitant mixtures of at least two polymorphs. In the monoclinic form, one‐dimensional chains of hydrogen‐bonded urea molecules align in an antiparallel orientation, as is typical of many diphenylureas. In the orthorhombic form, one‐dimensional chains of hydrogen‐bonded urea molecules have a parallel orientation rarely observed in symmetrically substituted diphenylureas.     

Development and validation of an intrinsic dissolution method for nimodipine polymorphs

The polymorphs of nimodipine, Modification I (Mod I), the metastable racemate, and Modification II (Mod II), the stable conglomerate, were evaluated by means of the intrinsic dissolution procedure. For this purpose, a hydro alcoholic solution (ethanol:water, 50:50, v/v) was selected as the dissolution medium, maintained at 37±0.5°C. Different rotation speeds were tested (50, 75 and 100 rpm) and the lower one was chosen for the test validation. Although the sample initially characterized as polymorph Mod I presented higher intrinsic dissolution rates in all the conditions tested, no statistical differences were noticed between the two polymorphs. This result can be attributed to the partial solution-mediated phase transformation from Mod I to Mod II, detected through X-ray powder diffraction and differential scanning calorimetry. Also, reliable intrinsic dissolution rate data were acquired for the polymorph Mod II. The dissolution method was validated, being considered stable, specific, linear, sensible, accurate and precise.      

Role of urea in alkaline dissolution of cellulose

To elucidate the role of urea in dissolution of cellulose in aqueous alkali-urea solvent, the dissolution process was monitored by differential scanning calorimetry and X-ray diffractometry. Urea had no direct interaction with cellulose in dissolution process, but promoted the decrease of crystallinity. Moreover, the addition of urea increased the dissolved fraction of cellulose in the solvent by 1.5–2.5 times and improved the thermal stability of the solution. Urea might help alkali hydrate to penetrate into crystalline region of cellulose by stabilizing the alkali-swollen cellulose molecules, leading to an increase in dissolved fraction of cellulose. This stabilization may be due to the local accumulation of urea on the hydrophobic surface, preventing the hydrophobic association of dissolved cellulose molecules.     

Rapid dissolution of cellulose in LiOH/urea and NaOH/urea aqueous solutions

Rapid dissolution of cellulose in LiOH/urea and NaOH/urea aqueous solutions was studied systematically. The dissolution behavior and solubility of cellulose were evaluated by using (13)C NMR, optical microscopy, wide-angle X-ray diffraction (WAXD), FT-IR spectroscopy, DSC, and viscometry. The experiment results revealed that cellulose having viscosity-average molecular weight ((overline) M eta) of 11.4 x 104 and 37.2 x 104 could be dissolved, respectively, in 7% NaOH/12% urea and 4.2% LiOH/12% urea aqueous solutions pre-cooled to -10 degrees C within 2 min, whereas all of them could not be dissolved in KOH/urea aqueous solution. The dissolution power of the solvent systems was in the order of LiOH/urea > NaOH/urea > KOH/urea aqueous solution. The results from DSC and (13)C NMR indicated that LiOH/urea and NaOH/urea aqueous solutions as non-derivatizing solvents broke the intra- and inter-molecular hydrogen bonding of cellulose and prevented the approach toward each other of the cellulose molecules, leading to the good dispersion of cellulose to form an actual solution.     

Kinetics of cross-nucleation between polymorphs

We report the first kinetic measurement of cross-nucleation between polymorphs, a newly discovered phenomenon important to the theory and control of crystallization. d-Mannitol crystallized from its melt first as the least stable delta polymorph and then as the second least stable alpha polymorph, with alpha nucleating on delta. The kinetics of cross-nucleation was determined from the frequencies of alpha nuclei appearing on delta spherulites, the distances between alpha and delta nuclei, and the growth rate of the delta spherulite. The presence of poly(vinylpyrrolidone), a noncrystallizing, melt-miscible additive, increased the rate of cross-nucleation.     

Two polymorphs of chlorido(cyclohexyldiphenylphosphine)gold(I)

The title compound, [AuCl(C₁₈H₂₁P)], a monomeric two‐coordinate gold(I) complex, has been characterized at 100 K as two distinct monoclinic polymorphs, one from a single crystal, (Is), and one from a pseudo‐merohedrally twinned crystal, (It). The molecular structures in the two monoclinic [P2₁/n for (Is) and P2₁/c for (It)] polymorphs are similar; however, the packing arrangements in the two lattices differ considerably. The structure of (It) is pseudo‐merohedrally twinned by a twofold rotation about the a* axis.     

Sulfated poly-amido-saccharides (sulPASs) are anticoagulants in vitro and in vivo

Anticoagulant therapeutics are a mainstay of modern surgery and of clotting disorder management such as venous thrombosis, yet performance and supply limitations exist for the most widely used agent – heparin. Herein we report the first synthesis, characterization, and performance of sulfated poly-amido-saccharides (sulPASs) as heparin mimetics. sulPASs inhibit the intrinsic pathway of coagulation, specifically FXa and FXIa, as revealed by ex vivo human plasma clotting assays and serine protease inhibition assays. sulPASs activity positively correlates with molecular weight and degree of sulfation. Importantly, sulPASs are not degraded by heparanases and are non-hemolytic. In addition, their activity is reversed by protamine sulfate, unlike small molecule anticoagulants. In an in vivo murine model, sulPASs extend clotting time in a dose dependent manner with bleeding risk comparable to heparin. These findings support continued development of synthetic anticoagulants to address the clinical risks and shortages associated with heparin.

Heparin mimicking sulfated poly-amido-saccharides (sulPASs) are anticoagulants resistant to heparanases and reversed by protamine sulfate. In an in vivo murine model, sulPASs extend clotting time without the increased risk of bleeding.     

Linear free energy relationships between dissolution rates and molecular modeling energies of rhombohedral carbonates

Bulk and surface energies are calculated for endmembers of the isostructural rhombohedral carbonate mineral family, including Ca, Cd, Co, Fe, Mg, Mn, Ni, and Zn compositions. The calculations for the bulk agree with the densities, bond distances, bond angles, and lattice enthalpies reported in the literature. The calculated energies also correlate with measured dissolution rates: the lattice energies show a log-linear relationship to the macroscopic dissolution rates at circumneutral pH. Moreover, the energies of ion pairs translated along surface steps are calculated and found to predict experimentally observed microscopic step retreat velocities. Finally, pit formation excess energies decrease with increasing pit size, which is consistent with the nonlinear dissolution kinetics hypothesized for the initial stages of pit formation.     

Two polymorphs of tris(ethylenediamine)cobalt(III) tetrathioantimonate(V)

Details of the structures of two polymorphs of tris(ethylenediamine)cobalt(III) tetrathioantimonate(V), [Co(C₂H₈N₂)₃][SbS₄], are reported. The first polymorph crystallizes in the orthorhombic space group Pna2₁, whereas the second polymorph belongs to the tetragonal space group P4₂bc. Both structures contain octahedral [Co(en)₃]³⁺ cations (en is ethylenediamine) and tetrahedral [SbS₄]³⁻ anions, which are interconnected via various N—H...S hydrogen bonds to form two different types of three‐dimensional network.     

Quantification of pharmaceutical polymorphs and prediction of dissolution rate using theophylline tablet by terahertz spectroscopy

Theophylline has an anhydrous form and a monohydrated form, and the dissolution rate of the anhydrous form is higher than that of the monohydrated form. Terahertz (THz) spectra of theophylline tablet containing the theophylline anhydrous form, monohydrated form, microcrystalline cellulose and magnesium stearate exhibited a specific absorption peak at 0.96 THz, where the theophylline anhydrous form demonstrated an absorption peak. Additionally, the intensity of the peak at 0.96 THz gradually decreased as the proportion of the anhydrous form decreased. The multivariate data analysis was performed to correlate the THz spectra of theophylline tablets with the ratio of the theophylline anhydrous form. The calibration model used to predict the mixing ratio of the theophylline anhydrous form from the THz spectra achieved root-mean-squared errors of cross-validation (RMSECV) of 2.89%, a slope of 0.9934 and an R(2) of 0.9927. In addition, there were intentions to develop a prediction model for the dissolution rate of theophylline from the drug product. The dissolution rate of theophylline tablet was gradually delayed as the proportion of the anhydrous form was decreased. The multivariate data analysis was performed to correlate the THz spectra of theophylline tablets with the dissolution rate. The calibration model used to predict the percentage of theophylline dissolved in 45 min from the THz spectra achieved an RMSECV of 3.29%, a slope of 0.9260 and an R(2) of 0.9423. Furthermore, there were no significant differences between the predicted and measured percentages of theophylline dissolved in 45 min in the theophylline tablets that were stored at 84% relative humidity (RH) and 25 °C for 12 h or 3 d.     

Redox-driven sulfate ion transfer between two tripodal tris(urea) receptors

Two anion receptors with the same tripodal scaffold but different signaling groups are employed to control intermolecular anion transfer via an electrochemical stimulus, which is detected by the change of the fluorescence intensity before and after electrochemical oxidation of the ferrocenyl units.     

Thermally activated transformations in stable and metastable copper(II) pyrovanadate polymorphs

The structural transformations of α- and β′-Cu₂V₂O₇ phases over the entire temperature range of their existence and α → β′-Cu₂V₂O₇ and β′ → β-Cu₂V₂O₇ polymorphic transitions in α-Cu₂V₂O₇ are described from the crystal-chemical standpoint. Variations in the parameters of the polyhedral blocks of the α-Cu₂V₂O₇ structure implies that the greatest deformations occur with a negative and near-zero bulk thermal expansion in the range from room temperature to 400°C. The compression and rotation of vanadium-oxygen diortho groups is accompanied by unbending of zigzag copper-oxygen chains, with the distances between them unchanged, which is the reason for the anomalous volume expansion of the structure. Thermal distortion of β′-Cu₂V₂O₇ is insignificant. The thermal expansion coefficients (TECs) of unit cell parameters are as follows: α _a = ?1.36 × 10^?5 1/K, α _b = 1.95 × 10^?5 1/K, α _c = 1.37 × 10^?5 1/K, α_β = ?0.18 × 10^?5 1/K, and α _V = 1.93 × 10^?5 1/K. We demonstrate that the low-temperature Cu₂V₂O₇ phase can be formed without admixtures of metastable β-Cu₂V₂O₇ upon slow cooling (at about 1 K/min) of the high-temperature phase.     

Two new polymorphs of trans‐bis(hinokitiolato)copper(II)

The title complex [systematic name: trans‐bis(3‐iso­propyl‐7‐oxo­cyclo­hepta‐1,3,5‐trienolato)copper(II)], [Cu(C₁₀H₁₁O₂)₂],is a substance possessing antimicrobial activity. The compound crystallizes in a number of polymorphic forms, the structures for two of which are reported here. Stacks of square‐planar mol­ecules exhibiting weak intermolecular copper–olefin π interactions (not observed in earlier reports on this substance) are described. The mol­ecules have crystallographically imposed inversion symmetry, with stacking and copper–olefin π distances ranging from 3.226 (2) to 3.336 (1) Å.     

Morphology and Crystalline Structure of Inclusion Compounds Formed between Poly（ethylene glycol） and Urea

The poly（ethylene glycol） （PEG, with Mw 2000）-urea inclusion compound （IC） crystallized at high temperature region showed two typical orientations, flat-on and edge-on crystals. 2D-XRD and polarized FTIR spectroscopy revealed that the PEG chains within urea channels were perpendicular to the substrate in fiat-on oriented crystals, while PEG chain axes were parallel to the substrate and lay along the growth direction in the edge-on crystals. FT1R absorption bands of PEG in the ICs are sensitive to orientation of the crystals. A scheme of PEG chain packing in the urea IC channel was proposed, which could explain the orientation of the crystal nucleus causing the two types of morphologies. Furthermore, functioning of PEG2000 chain end with analine had significantly influence on the morphology and orientation of the inclusion compound crystals, due to the defects caused by large terminal groups included in the urea channel.