Dissolution test on 5 kinds of commercial tablets A-E of water-insoluble vitamin, phytonadion, was performed by USPX VIII method with and without a non-ionic surfactant, polysorbate 80. In addition, a study was made on the pharmaceutical properties of tablets as follows : weight variation, hardness, abrasion, content and disintegration time. Our findings suggested that the effect of the surfactant on the dissolution of phytonadion was achieved by the enhancement of solubilization and wetting of the surface of insoluble granular particles. In the presence of polysorbate 80 at higher levels than the critical micelle concentration (cmc), the influence of the surfactant on phytonadion dissolution varied from brand to brand, and the dissolution ratios increased with increment of the concentration of polysorbate 80 except for one case, which showed a specifically increasing tendency at the region of cmc. However, the maximal dissolution ratio never exceeded 65.0±2.9% (brand C) when the basket was rotated at 50 rpm, and 68.5±10.8% (brand A) at 100 rpm after 90 min. Minimal dissolution ratios at 50 rpm and 100 rpm were 5.8±2.9 and 12.6±3.2% (brand D), respectively.
Alkali fusion of melanin, extracted from Cochliobolus miyabeanus, human hair, and sunflower seeds, was carried out, its decomposition product was extracted with a solvent, and the product was identified by gas chromatography-mass spectrometry. Melanin produced by C. miyabeanus was very similar to that from sunflower seeds, and there was no essential difference between the melanin from human hair and that from sunflower seeds. (the indole type and the catechol type melanin according to the classification by R.A. Nicolaus) Since the carboxylic acid derivative of pyrrole, thought to originate from the indole ring, was detected in the decomposition product of melanin from sunflower seeds, it was concluded that melanin is a heterogeneous polymer and cannot be divided clearly into the indole type or the catechol type, as proposed by Nicolaus and others, and that if a larger amount of indole compounds took part as a monomer at the time of polymerization in vivo, melanin with higher nitrogen content will be formed and, if a larger proportion of phenol compounds not containing nitrogen took part in this polymerization, melanin with lower nitrogen content would be formed.
Penetration of trifluoperazine (TFPeZ), a phenothiazine tranquilizer, into mixed monolayers of dipalmitoyl lecithin (DPL) and cholesterol (CH) was studied by measurement of surface pressure (F)-mean molecular area (A^^-34) curves. The amount of penetration (or adsorption) by TFPeZ was calculated by the modified Gibbs adsorption equation. Adsorption isotherms at a constant A^^-34 showed a type of Langmuir adsorption. Saturated amount of adsorption (Γ∞2) and Langmuir constant (k) were obtained by Langmuir plots. Correlation between those parameters and A^^-34 at various mixing ratios of DPL and CH were discussed. With decreasing A^^-34, Γ∞2 decreased in any DPL-CH mixed monolayer. The relation between Γ∞2 and composition of the monolayer at a constant A^^-34 corresponded well with the state of mixed monolayer, i.e. Γ∞2 is small in expanded monolayer rich in DPL (XDPL>XCH), and increases with decreasing XDPL down to XDPL=0.5. This increase corresponds to changes of the mixed monolayer state, from liquid expanded to solid condensed state. Below XDPL=0.5, in which the mixed monolayer is fully solid, Γ∞2 level is independent of the monolayer composition. Miscibility of penetrated TFPeZ with insoluble components, DPL and CH, was also discussed.
The Reissert reaction of 1, 6-naphthyridine (I) was carried out by the use of triethylbenzylammonium chloride as the phase transfer catalyst. When aliphatic chloride (RCOCl : R=CH3, C2H5, C3H7) was used, the products were the Reissert compounds (IV, V, VI) and 2-(2-acylaminovinyl)-α-acyl-3-pyridineacetonitriles (VII, VIII, IX), while the use of benzoyl chloride gave only the Reissert compound X. Alkaline hydrolysis of VII, VIII, and IX gave I. As a proof of the formation mechanism of I from VII, VIII, and IX, VII was reduced with sodium borohydride to 2-(2-acetamidovinyl)-3-pyridinemethanol (XII) and its acetylation gave 2-(2-acetamidovinyl)-3-pyridinemethyl acetate (XIII). Alkaline hydrolysis of the pseudo-base III gave I. As a proof of the formation mechanism of VII, VIII, and IX, III was submitted to the Reissert reaction over a long period and 2-(2-benzoylaminovinyl)-α-benzoyl-3-pyridineacetonitrile (XIV) was obtained. The Reissert reaction of 4, 7-phenanthroline (XVII) gave the Reissert compound XVIII.
3-methylthioisothiazolo [3, 4-d] pyrimidine-4, 6-(5H, 7H)-diones (IIa, b) were synthesized by treatment with methyl 6-aminouracil-5-carbodithioates prepared by the reaction of 6-aminouracil with carbon disulfide and dimethylsulfate in the presence of alkali, with iodine in dimethyl sulfoxide in a good yield. The reaction of IIa, b with amines, amides, and active methylene compounds gave the corresponding substituted products of methylthio group in II in a good yield.
11-Dimethylaminomethyl-3, 4-dihydro-6-oxo-2H, 6H-1, 3-thiazino [3, 2-b] isoquinoline (IVa) and 11-formyl-3, 4-dihydro-6-oxo-2H, 6H-1, 3-thiazino [3, 2-b] isoquinoline (VI) were synthesized by Mannich reaction and Vilsmeier reaction of 3, 4-dihydro-6-oxo-2H, 6H-1, 3-thiazino [3, 2-b] isoquinolone (I), respectively. 6-Oxo-4H, 6H-1, 3-thiazino [3, 2-b] isoquinoline (XIb) was synthesized from 2-acetoxy-3, 4-dihydro-6-oxo-2H, 6H-1, 3-thiazino [3, 2-b] isoquinoline (IXb) upon treatment with p-tolenesulfonic acid, which was prepared by the Pummerer reaction of I. Reaction of 3, 4-dihydro-6-oxo-2H, 6H-1, 3-thazino [3, 2-b] isoquinoline-1, 1-dioxide (III) with alkyl halides gave monoalkylated (XIII) and dialkylated derivatives (XIV). The anti-inflammatory activity of these compounds was tested by the rat carrageenin paw edema method. IXa, b and VI showed stronger activity than phenylbutazone.
Bovine serum albumin (BSA) is adsorbed slowly to air-water interface from inside the aqueous solution at relatively low concentration. Small amount of adsorbed BSA scarcely increased surface pressure enough to make measurement possible. Lipids were spread after some time for BSA to be adsorbed at the water surface. New method to estimate the adsorbed amount of BSA was devised, and it is concluded that below 1 mg·m-2 the diffusion process is important in adsorption, that unfolding of BSA occurs rapidly and that above 1 mg·m-2, the protein molecules adsorbed are mostly native.
A high performance liquid chromatographic method was developed for the simultaneous determination of vitamin K and vitamin K oxide in biological materials. The method involves n-hexane extraction of plasma or liver homogenate and reversed phase separation on Nucleosil[○!R] C18 with a mobile phase of methanol-ethanol (7 : 3, v/v) followed by fluorometric detection of the reaction products with NaHSO3-HCl and NaBH3CN. Minimum detectable quantity was 2 ng for phylloquinone and menaquinone-4, and 3 ng for phylloquinone oxide and menaquinone-4 oxide, respectively. This method is simpler and more specific than the conventional methods for the determination of vitamin K oxide.
The effects of clofluperol (CLO) and haloperidol (HAL) on the adrenal and hepatic drug-metabolizing enzyme system were studied after oral administration to rats for 1 and 2 weeks. Ten mg/kg of both drugs inhibited animal growth, decreased liver weights and elevated plasma corticosterone levels. CLO, but not HAL, caused pronounced enlargement of the adrenals, the size of which increased with increasing the adrenal CLO contents. Treatment with both drugs led to a decrease in the activities of aminopyrine (AM) N-demethylase and aniline (AN) hydroxylase in liver 9000×g supernatant fraction, decreased liver microsomal cytochrome P-450 levels and reduced the spectral changes of cytochrome P-450 induced by AM or AN. The duration of sleep induced by hexobarbital was prolonged by treatment with both drugs. When CLO (10 mg/kg) was dosed for 2 weeks, the sleep times were extremely protracted.
A convenient synthesis of 3-substituted quinolizidines was developed. Cyclization of 3-[2-(2-chloroethyl) piperidin-1-yl] propionitrile (10) with a base afforded 3-cyanoquinolizidines (13a and 13b) in good yield, which have been transformed to 5-alkyl-3-diarylmethylenequinolizidinium bromides (5), novel antispasmodics. 3-Cyanoquinolizidines (13a and 13b) were converted to 3-ethoxycarbonyl-(14a and 14b), 3-benzoyl-(17a and 17b) and 3-(2-thenoyl)-quinolizidines (18a and 18b), respectively. 3-Ethoxycarbonyl-(14a and 14b) and 3-benzoyl-quinolizidines (17a and 17b) were also obtained by cyclization of the chloroester (11) and the chlorobenzoyl (12), respectively. The stereochemistry of the 3-substituted quinolizidines synthesized here was determined.
Cochliobolus miyabeanus, the pathogenic mold for the leaf spot disease of rice plants, was shake-cultured in a potato medium at 27° for 10 days. A dark brown pigment was extracted from the cultured cells, physical and chemical properties of the pigment were examined, and these properties were compared with those of indole-melanin, extracted from human hair, and of catechol-melanin, extracted from sunflower seeds. It was thereby found that the pigment produced by C. miyabeanus was a melanin, close to the catechol type rather than the indole type from its nitrogen content. However, distribution of molecular weight, solubility, and absorption spectra in the visible and infrared region of this melanin were different from those of other melanins, and it could not be determined definitely as the catechol type.
Substitution reaction of 7-chloro-3-methyl-3H-1, 2, 3-triazolo [4, 5-d] pyrimidine (I) and nucleophiles was carried out and the formation of the corresponding 7-substituted 3-methyl-3H-1, 2, 3-triazolo [4, 5-d] pyrimidine (II) as expected was confirmed. I reacted with various amines to form the corresponding 7-amino derivatives (II-1 to II-8), and also reacted with alkoxide ions to form the corrrsponding 7-alkoxy compounds (II-9 to II-14). The reaction of I with CN ion in dimethylformamide, with ketone in the presence of sodium hydride, and with active methylene compounds resulted in the introduction of the corresponding carbon function into its 7-position. Tautomerism of 7-substituted 3-methyl-3H-1, 2, 3-triazolo [4, 5-d] pyrimidines (II-16 to II-24), formed by the reaction of I with ketones and active methylene compounds, was examined.
A method for simultaneous analysis of α-tocopherol and α-tocopheryl acetate in plasma was investigated using massfragmentography for the purpose of biopharmaceutical studies of α-tocopheryl acetate administered parenterally to animals. α-Tocopherol and α-tocopheryl acetate in plasma were extracted with n-hexane, derivatized by silylation, and determined simultaneously by monitoring at m/e 502 for silylated α-tocopherol and at m/e 430 for α-tocopheryl acetate. This method was rapid and specific, and was satisfactorily employed in the biopharmaceutical studies of α-tocopheryl acetate.
A method for the rapid estimation of gentiopicroside in crude drugs, Gentianae scabrae radix and Gentianae radix, was established by the use of high-speed liquid chromatography. Gentiopicroside is separated on the 25 cm column of Zorbax ODS, using a liquid chromatograph (Shimadzu-Du Pont Model LC-3A) with 5% tetrahydrofuran as the desorption solution, and the separation is completed within 8 min. Gentiopicroside in the crude drugs is extracted with water and the aqueous extract is injected into the column. The content of gentiopicroside was calculated from calibration curves previously prepared using the standard. Precision of the determination is about ±1% and detection limit is 2 ng (S/N ratio, 3). This method is considered to be useful for the evaluation of these crude drugs.
Reaction of isoquinolinium bis (ethoxycarbonyl) methylide (1) with 2-butanone, cyclopentanone, and cyclohexanone gave ethyl 1, 2-dimethylpyrrolo [2, 1-a] isoquinoline-3-carboxylate (9), ethyl 10, 11-dihydro-9H-cyclopenta [3, 4] pyrrolo [2, 1-a] isoquinoline-8-carboxylate (10), and ethyl 9, 10, 11, 12-tetrahydroisoindolo [1, 2-a] isoquinoline-8-carboxylate (11), respectively. Similar reaction of isoquinolinium cyano (ethoxycarbonyl) methylide (12) with cyclopentanone and cyclohexanone gave 10, 11-dihydro-9H-cyclopenta [3, 4] pyrrolo [2, 1-a] isoquinoline-8-carbonitrile (13) and 9, 10, 11, 12-tetrahydroisoindolo [1, 2-a] isoquinoline-8-carbonitrile (14), respectively. Methylide (1) reacted with acetylacetone to give ethyl 2-methylpyrrolo [2, 1-a] isoquinoline-3-carboxylate (3) and ethyl 1-acetyl-2-methylpyrrolo [2, 1-a] isoquinoline-3-carboxylate (15). Similarly, compound 3 and ethyl 3-ethoxycarbonylpyrrolo [2, 1-a] isoquinoline-2-acetate (5) were obtained by the reaction of the methylide (1) with diethyl acetonedicarboxylate.
An antioxidative component in the commercial preparations of sodium copper chlorophyllin was isolated as its methyl ester. The methyl ester was identified as copper chlorin-e6 trimethyl ester by comparison with the authentic sample.