Effect of sulfobutyl ether-ß-cyclodextrin and propylene glycol alginate on the solubility of clozapine.

Clozapine (CLZ) is an atypical antipsychotic medication used in the treatment of schizophrenia and is poorly soluble in water (0.05 mM). In this study, we have investigated the effect of ß-cyclodextrin (CD) and its derivatives on the solubility of CLZ. The solubility of the CLZ was measured to generate a phase solubility diagram, and the interaction between CLZ and sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) in aqueous solution was observed by 1H- and 2D rotating-frame Overhauser enhancement spectroscopy (ROESY)-NMR methods. Moreover, the synergistic effect of SBE-ß-CD and water-soluble polymers, including polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium salt, polyvinyl alcohol, sodium alginate, and propylene glycol alginate (PGA), on the solubility of CLZ was investigated. The results show that the solubility of CLZ with 1 w/v% PGA was 7.6 mM, which was almost four times greater than that of CLZ without PGA in a 15 mM SBE-ß-CD solution. In contrast, the solubility of CLZ with 1 w/v % PGA in an aqueous solution decreased by one-third relative to that of CLZ in a 15 mM SBE-ß-CD solution. 2D ROESY-NMR indicated that a CLZ/SBE-ß-CD/PGA ternary complex formed. It was found that the combination of PGA and SBE-ß-CD enhanced the solubility of CLZ.

A new solvate of epalerstat, a drug for diabetic neuropathy.

Epalerstat {systematic name: (5Z)-5-[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl-idene]-4-oxo-2-sulfanyl-idene-1,3-thia-zolidine-3-acetic acid} crystallized as an acetone monosolvate, C15H13NO3S2·C3H6O. In the epalerstat mol-ecule, the methyl-propyl-enediene moiety is inclined to the phenyl ring and the five-membered rhodamine ring by 21.4 (4) and 4.7 (4)°, respectively. In addition, the acetic acid moiety is found to be almost normal to the rhodamine ring, making a dihedral angle of 85.1 (2)°. In the crystal, a pair of O-H⋯O hydrogen bonds between the carb-oxy-lic acid groups of epalerstat mol-ecules form inversion dimers with an R22(8) loop. The dimers are linked by pairs of C-H⋯O hydrogen bonds, enclosing R22(20) loops, forming chains propagating along the [101] direction. In addition, the acetone mol-ecules are linked to the chain by a C-H⋯O hydrogen bond. Epalerstat acetone monosolvate was found to be isotypic with epalerstat tertra-hydro-furan solvate [Umeda et al. (2017 ▸). Acta Cryst. E73, 941-944].

Epalrestat tetra-hydro-furan monosolvate: crystal structure and phase transition.

The title compound, epalrestat {systematic name: (5Z)-5-[(2E)-2-methyl-3-phenyl-prop-2-en-1-yl-idene]-4-oxo-2-sulfanyl-idene-1,3-thia-zolidine-3-acetic acid}, crystallized as a tetra-hydro-furan monosolvate, C15H13NO3S2·C4H8O. Epalrestat, an important drug for diabetic neuropathy, has been reported to exist in polymphic, solvated and co-crystal forms. In the mol-ecule reported here, the phenyl ring is inclined to the rhodamine ring by 22.31 (9)°, and the acetic acid group is almost normal to the rhodamine ring, making a dihedral angle of 88.66 (11)°. In the crystal, pairs of O-H⋯O hydrogen bonds are observed between the carb-oxy-lic acid groups of epalerstat mol-ecules, forming inversion dimers with an R22(8) loop. The dimers are linked by pairs of C-H⋯O hydrogen bonds, forming chains along [101]. The solvate mol-ecules are linked to the chain by a C-H⋯O(tetra-hydro-furan) hydrogen bond. A combination of thermal analysis and powder X-ray diffraction revealed that title compound desolvated into epalerstat Form II. One C atom of the tetra-hydro-furan solvate mol-ecule is positionally disordered and has a refined occupancy ratio of 0.527 (18):0.473 (18).

Enhanced dissolution and skin permeation profiles of epalrestat with ß-cyclodextrin derivatives using a cogrinding method.

Epalrestat (EPL) is a water-insoluble drug (14µM) that inhibits aldose reductase. This study investigated the interactions between ß-cyclodextrin (CD) derivatives and EPL to determine the solubilizing effect on EPL from phase solubility diagrams. We improved the solubility of EPL in water by adding ß-CD derivatives. Moreover, the solubility of EPL mixed with ß-CD derivatives by cogrinding in a ball mill method was about 2-3 times higher than those of EPL with the same CD concentration (5mM) calculated from phase solubility diagrams. In addition, we investigated the effect of ß-CD derivatives on in vitro percutaneous absorption of EPL through hairless mouse skin. Among the coground mixtures of EPL and ß-CD derivatives, the mixture containing methyl (ME)-ß-CD showed the strongest enhancement of EPL skin permeation. Furthermore, adding 10wt% urea as a skin permeation enhancer after cogrinding with ME-ß-CD improved the flux of EPL 300 times compared to the flux of EPL alone. This result indicates the ME-ß-CD ground mixture system with urea has potential as a new transdermal drug delivery system of EPL for diabetic neuropathy.

Investigation of Discoloration of Furosemide Tablets in a Light-Shielded Environment.

We observed that uncoated furosemide tablets turned yellow in a light-shielded automatic packaging machine and discoloration of the furosemide tablets was heterogeneity and occurred on the surface of the tablets only. The machine was equipped with an internal blower to maintain a constant temperature. Therefore, we investigated the effect of air flow on the discoloration of the furosemide tablets using a blower in a dark environment. The color difference (ΔE) of the furosemide tablets increased linearly as the blowing time increased. We performed structural analysis of the yellow compound in the furosemide tablets by LC-MS and identified the compound as a hydrolysate of furosemide. This suggested that furosemide hydrolysis was accelerated by the air flow. The furosemide tablets were prepared with the most stable furosemide polymorph, form I. X-Ray powder diffractometry and IR spectroscopy showed that during tablet preparation, no crystal transition occurred to an unstable furosemide polymorph. Furthermore, IR spectroscopy showed that the crystal form of furosemide in the yellow portion of the tablets was form I. To elucidate the factors producing the discoloration, we investigated the effect of humidity and atmosphere (air, oxygen, and nitrogen) on the discoloration of the furosemide tablets. The results suggested that the discoloration of the furosemide tablets was accelerated by oxidation, although humidity did not affect the hydrolysis. Therefore, we concluded that the discoloration of the furosemide tablets in the automatic packing machine was caused by acceleration of oxidative degradation by air flow.

The role of nitric oxide in radiation damage.

This study investigated the role of nitric oxide in radiation-induced damage by examining changes in mouse serum nitrate concentrations after irradiation. In addition, the contribution of S-2-aminoethylisothiourea 2HBr (AET) to the mechanisms of radiation damage protection was also clarified. The serum nitrate concentration increased as soon as 1.5 h after irradiation, and after 2.5 to 3.0 h the concentrations were significantly higher compared with normal levels. Normal levels were re-established after 12 h. Post-irradiation serum nitrate concentrations increased dose-dependently with irradiation dose (19.6-31.5 Gy). AET suppressed increases in the serum nitrate concentration following irradiation while 2-mercaptoethylamine HCl (MEA) did not. AET has an inhibitory effect on inducible nitric oxide synthase (iNOS); therefore, the increase in nitric oxide after irradiation may be produced by iNOS. Combined administration of irradiation and lipopolysaccharide (LPS) induced a significant increase in serum nitrate concentration, and a significant decrease in survival rate, compared with irradiation alone. The administration of AET or aminoguanidine increased survival rate following irradiation. In contrast to findings after LPS administration, IL-1beta and IFN-gamma were not determined in serum following irradiation. Existing iNOS is activated by irradiation, and nitric oxide production appears to increase without iNOS induction. Thus, the irradiation-induced increase in nitric oxide may be related to lethal injury.