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We attempted to improve the solubility of poorly water-soluble drugs by preparing drug-loaded polyvinyl alcohol (PVA) nanofibers as a solid dispersion system via emulsion electrospinning. Probucol (PBC), a poorly water-soluble drug, was used as a model drug. Nanofibers were electrospun using an oil/water (o/w) emulsion consisting of PBC dissolved in an immiscible solvent, such as ethyl acetate, and an aqueous PVA phase. PBC-containing PVA nanofibers with diameters ranging from 300 to 600 nm were obtained by electrospinning from o/w emulsions. The physical properties of the nanofibers were affected by the degrees of polymerization and hydrolysis of the PVA grades. In PVA nanofibers prepared without a surfactant, PBC existed in an amorphous state, and the dissolution of PBC was greatly improved. PBC dissolution was lower in PVA nanofibers with 30% PBC content compared to those with 11% or 20% PBC. In PVA nanofibers prepared using the surfactant P80 as an emulsifier, PBC was partially crystallized; however, the PBC was homogenously dispersed, and dissolution was improved, even in PVA nanofibers containing 30% PBC. PVA nanofibers produced by o/w emulsion electrospinning were demonstrated to be suitable solid dispersion systems enabling robust controlled release of poorly water-soluble drugs.

In order to relieve pain due to oral mucositis, we attempted to develop mucoadhesive microparticles containing indomethacin (IM) and gel preparations with IM microparticles that can be applied to the oral cavity. The mucoadhesive microparticles were prepared with a simple composition consisting of IM and polyvinyl alcohol (PVA). Two kinds of PVA with different block properties were used, and microparticles were prepared by heating-filtration and mixing-drying. From the X-ray powder diffraction patterns, differential scanning calorimetry thermograms, and morphological features of the IM microparticles, IM should exist as polymorphic forms in the microparticles. Rapid drug release properties were observed in the IM microparticles. Increased drug retention was observed in IM microparticles containing PVA, and the IM-NK(50) gel, using a common block character PVA and heating-filtration, showed good long-term drug retention properties. In vivo experiments showing significantly higher drug concentrations in the oral mucosa were observed with IM microparticles prepared by heating-filtration, and the IM-NK(50) gel maintained significantly higher drug concentrations in the oral mucosa. From these results, the IM-NK(50) gel may be useful as a preparation for relieving oral mucositis pain.

Proton-transfer reactions of two systems, ionization of a series of small carbon acids in water (the Pearson system) and reactions of substituted phenylnitromethanes, were examined in detail computationally. Comparison of experimental reactivity and pK(a) with calculated relative activation barrier and reaction energy for the Pearson system suggested that the origin of the well-know nitroalkane anomaly does not reside in the reactivity but in the equilibrium. For the reactions of substituted phenylnitromethanes, proton transfers among three species, PhCH(2)NO(2), PhCHNO(2)(-), and PhCH=NO(2)H, were examined, and the role of the aci-nitro species (PhCH=NO(2)H) was evaluated on the basis of its stability and reactivity. Protonation of PhCHNO(2)(-) by H(2)O was suggested to occur kinetically on the oxygen site, but due to its instability PhCH=NO(2)H does not contribute to the overall reaction energetics. The protonation of PhCHNO(2)(-) under acidic conditions occurs on the oxygen site to give PhCH=NO(2)H both kinetically and thermodynamically. The aci-nitro species thus formed appears to give PhCH(2)NO(2) via intramolecular H(2)O-mediated proton transfer, but a possibility of the route through PhCHNO(2)(-)-C-protonation would not be fully eliminated.

The reaction of an α-haloketone with a nucleophile has three reaction channels: carbonyl addition, direct substitution, and proton abstraction. DFT calculations for the reaction of PhCOCH(2)Br with OH(-) showed that there exists an addition/substitution TS on the potential energy surface, in which OH(-) interacts with both the α- and carbonyl carbons. The intrinsic reaction coordinate calculations revealed that the TS serves as the TS for direct substitution for XC(6)H(4)COCH(2)Br with an electron-donating X or a X less electron-withdrawing than m-Cl, whereas the TS serves as the TS for carbonyl addition for derivatives with a X more electron-withdrawing than m-CF(3). Trajectory calculations starting at respective TS indicated that the single TS can serve for the two mechanisms, substitution and addition, through path bifurcation after the TS for borderline substrates. The reaction is the first example of dynamic path bifurcation for fundamental reaction types of carbonyl addition and substitution.

The reversible deprotonation of 3(2H)-furanone (3H-O) and 3(2H)-thiophenone (3H-S) by a series of delocalized carbanions and by CN(-), and the identity proton transfer of 3H-O to its conjugate base (3(-)-O) and of 3H-S to 3(-)-S have been studied at the MP2//6-31+G** level. The main objective has been to examine to what extent the aromaticity of 3(-)-O and 3(-)-S is expressed at the transition state of these reactions and how the intrinsic barriers are affected by the transition state aromaticity. Aromaticity parameters such as NICS values, HOMA and Bird Indices indicate a disproportionately high degree of aromatic stabilization of the transition state. This stabilization results in a reduction of the intrinsic barriers which is most clearly manifested in the identity reactions. However, these reductions are relatively modest compared to those reported previously for the identity proton transfers from the benzenium ion to benzene and of cyclopentadiene to its conjugate base, reflecting the smaller aromatic stabilization of 3(-)-O and 3(-)-S compared to those of benzene and cyclopentadienyl anion.

The phase diagrams, i.e., the pressure—temperature—composition diagrams of each system tetra-, penta-, and hexaoxyethylene dodecyl ether (C 12 E 4 , C 12 E 5 , and C 12 E 6 ,respectively) vs water, have been determined by the use of the observation that the transmittance of the solution changes sharply with the change of the dissolved state of the solute. The temperature—pressure phase diagrams involve the regions of the micellar solution, the liquid surfactant phase + water phase, the hydrated solid + water phase, and the liquid crystal + water phase. The cloud temperature increased and its increasing rate became smaller with increasing pressure. By considering that the cloud temperature—composition curve is a liquid—liquid mutual solubility curve and the idea of “associated solution” of Prigogine and Defay, we derived the thermodynamic quantities (enthalpy, entropy, and volume) accompanied by the separation of the liquid surfactant phase from the water phase above the cloud temperature for the C 12 E 5 —water system. The enthalpy and entropy changes were positive and depended little on pressure, while the volume change was positive and decreased, tending to zero, with the pressure up to 300 MPa. This suggests that hydrophobic bonding as well as the partial dehydration of oxyethylene groups of surfactant contribute to the separation of the liquid surfactant phase from the water phase. In the composition—pressure diagram close to the regions of the micellar solution and the hydrated solid + water phase for the C 12 E 5 —water system, a sudden increase in the solubility of surfactant at a certain pressure was found with decreasing pressure and at constant temperature, which corresponds to the Krafft phenomenon and can be attributed to the effective dissolution of surfactant as a micellar form in water.

In order to determine the pressure dependence of the maximum additive concentration (MAC) of octane or decane in the aqueous solution of octaoxyethylene dodecyl ether (C12E8, 1% w/w), the pressure dependence of the cloud points and that of the temperatures of the solubilization limit for the solutions containing various concentrations of the alkane were determined by the change in transmittance of the solution. The MAC monotonously decreased with increasing pressure up to 300 MPa at a constant temperature below the cloud point. This relation is different from that obtained for the solubilized systems in which β-phenylethyl alcohols are solubilized in aqueous solutions of cetyltrimethylammonium bromide: the MAC versus pressure relation with a maximum near 100 MPa [Part I, J. Colloid Interface Sci.94, 348 (1983)]. The difference may be associated with the differences of the incorporation sites of solubilizates in micelles and of their solubility in the bulk (water); i.e., alkanes are incorporated into the micelle core and dissolve very little in water, while β-phenylethyl alcohols penetrate into the palisade layer close to the micelle surface and dissolve slightly in water. The pressure dependence of the MAC was analyzed by means of the pseudophase model for micelles. The conventional pseudophase model in which the Laplace pressure inside a micelle is not allowed failed to explain the MAC-pressure relation; however, the corpuscular pseudophase model, taking into account the Laplace pressure, could quantitatively explain the relation well. It can therefore be concluded that the Laplace pressure obviously contributes to the micellar solubilization of the alkanes.