A method for the prediction of shelf life of pharmaceutical preparations under nonisothermal shelf condition has been developed using an analog computer. When the temperature fuction is 1/T=f(t), dk/dt=-E/R×kf' (t) is derived, and the drug remaining undecomposed is calculated using this equation and the reaction rate equation. Shelf life of the preparations can be predicted when the reciprocal of shelf temperature approximates to the sine curve or Fourier series. The calculated results were in good agreement with the experimental values when four pharmaceutical preparations were stored in three different places for 1 year and the reciprocals of this temperature change were expressed as Fourier series.

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1. Cystine solution colors brown on addition of nickel ion and sodium dithionite. This coloration reaction occurs in the vicinity of pH7 and the degree of coloration increases according to the concentration of nickel ion, sodium dithionite, and cystine. For the mechanism of this reaction, it was assumed that cystine is reduced to cysteine by sodium dithionite and cysteine forms a complex with nickel ion. Then the complex produces a sulfide on reaction with sodium dithionite, the sulfide binds to the complex, and the resulting complex is brown. 2. Cystine solution also colors brown on addition of potassium borohydride in place of sodium dithionite as a reducting reagent. As alanine and cysteine are detected together in the solution, it may be that a part of cysteine, reductive product of cystine, is transformed to sulfide and alanine by reductive desulfurization in the presence of a nickel ion. The sulfide forms the same brown complex with cysteine and nickel ion as that described above.

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An antihypertensive agent, 2-(2, 6-dichlorobenzylidenehydrazino)-1, 4, 5, 6-tetrahydropyrimidine hydrochloride (OT-24), was obtained by the nuclear reduction of 2-(2, 6-dichlorobenzylidenehydrazino)pyrimidine using palladium-carbon catalyst in acid solution. A number of new tetrahydropyrimidines containing benzylidenehydrazino and benzylhydrazino substituents were synthesized together with several related compounds.

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A new isoflavone glycoside, kakkalide, was isolated from the methanol extract of fresh flower of Pueraria thunbergiana BENTH., and its chemical structure was determined as irisolidone-7-β-D-xylopyranosyl-6-O-β-D-glucopyranoside

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Critical micelle concentrations of bis(2-ethylhexyl) sodium 2-sulfonatosuccinate (Aerosol OT ; abbr. AOT-Na) and its lithium or potassium substituted salt (abbr. AOT-Li or AOT-K) in water were determined by surface-tension measurement at 25-45°. The heat of micelle formation was obtained from heat-of-dilution measurement using a twintype microcalorimeter at 25-45°. Critical micelle concentrations of AOT-Li, AOT-Na, and AOT-K were 3.0, 2.5, and 2.3×10^-3M at 25°, respectively, and vary slightly with the increase of temperature, showing minimum near 30° for or all salts, which was ascertained from the fact that the enthalpy of micelle formation for these salts changes coincidentally from endothermic(e.g., 0.5 kcal/mole at 25°) to exothermic (e.g., 1.6 kcal/mole at 45°) taking null value at 30°. From these data, the partial molar Gibbs free energy, enthalpy, and entropy of micelle formation were calculated, indicating the significant difference of values according to the kind of counter-ion. The analysis of heat capacitiy, i.e., temperature coefficient of enthalpy, of micelle formation suggests the agglomeration of two hydrophbic chains of these salts, even in monomeric dispersion, in water.

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Consecutive determination of vitamin K's by their reaction with some thiol compounds has been examined by polarography in 80% ethanol containing acetate buffer and sodium perchlorate. Vitamin K₁ (Ib), K₂ (Ic), and K₃ (Ia) exhibited well-defined polarographic reduction waves in this medium, but their half-wave potentials were so close together that these vitamins cannot be determined simultaneously by a conventional polarography. In the absence of oxygen in solution, Ia reacts with thiol compounds to form naphthohydroquinones having a thioether linkage, while, Ib and Ic do not react with thiol compounds as a result of an interference of the alkyl substituents at both 2- and 3- positions in these vitamins. These facts can be applied to the consecutive determination of Ia and Ib (or Ic). The total concentration of Ia and Ib (or Ic) in solution is easily obtained by the measurement of the height of the reduction wave. The addition of thiol compounds to the solution gives no effect on the diffusion current of Ib (and also of Ic) but causes a significant decrease in that of Ia. Then the addition of an excess amount of thiol compounds results in the complete disappearancd of the diffusion current of Ia, and consequently the concentrations of Ia and Ib (or Ic) are determined. Among the thiol compounds used in this experiment, the use of thioglycolic acid in the solution of pH at around 6.2 was found to be the most suitable for the present purpose. This method was applied to the mixed solutions of Ia-Ib and Ia-Ic with satisfactory results.

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4-Ethoxycarbonyl-1, 2, 3, 4-tetrahydroisoquinoline derivatives (III) were synthesized by the reaction of 2-ethoxycarbonyl-2-(3-hydroxyphenyl) ethylamine (II) with several carbonyl compounds, and hydrolyzed to give 4-carboxy-1, 2, 3, 4-tetrahydroisoquinoline derivatives (I) which were expected to show anti-inflammatory action. This cyclization reaction proceeded by the use of the free base (II) or its hydrochloride. This forms a novel type of phenolip cyclization.

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As a part of studies on the participation of intestinal flora in the metabolism of food additives, some properties of azo- and nitro-reductase systems of intestinal bacteria and liver microsomes were compared. The bacterial reductase was prepared from the lyophilized cells of E. coli by ultrasonic disruption. Most of azo- and nitro-reductase activity which required flavin mononucleotide and nicotinamide adenine dinucleotide phosphate was found in the 105000×g supernatant. The bacterial reductase was much more effective than liver microsomes in the reduction of water-soluble sulfonated azo dyes and p-nitrobenzoic acid. However, fat-soluble azo dyes, such as Oil Yellow AB and OB, were not reduced by either of the enzyme systems. Some difference in the substrate specificity for azo dyes, was observed between the two enzyme systems and there was a remarkable difference in the inhibitory effect by CO, KCN, O₂, and chelating agents.

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The healing process of local lesions after the intramuscular injection of acetic acid into the muscularis vastus lateralis in rabbits was examined in order to establish a new method for determining local irritation due to intramuscular injection of drugs. It was assumed that the healing period of a lesion depends on its volume and found that the volume is closely correlated with the volume index (V.I.), i.e., the product of the major and minor axes of the largest cross section and the length of the lesion. Equations establishing the relationship between the V.I. and healing period of injection-produced lesions were worked out, on the basis of which it was possible to calculate the theoretical healing period of lesions with considerable accuracy by using the V.I. values two and or seven days after the injection. There was a marked loss of muscle weight 15 days or more after the injection of a highly concentrated solution, whereas the atrophy-time curves flattened with the healing of lesions. Histopathologically, marked fibrosis and fatty infiltrations were observed within and in the surrounding lesions in markedly atrophied muscles.

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A peak analysis method resolving overlapping bands in ultraviolet absorption spectra of organic compounds was presented. The method was based on the assumption that every component band can be expressed by the Gaussian function. Three parameters (E_0j, ν_0j, δ_j) were considered to be obtainable for each case by the method of least squares so as to resolve the observed spectrum as satisfactorily as possible. Application of the method to the spectra of salicylaldehyde azine, p-hydroxybenzaldehyde azine, and benzaldehyde azine showed that the method is useful. Theoretical transition energies and oscillator strengths of salicylaldehyde azine calculated by the semiempirical SCF-MO method of Pariser-Parr-Pople type were compared with the results of peak analysis.

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Four new sesquiterpenoids, furanocaulesone-A (I), (+)-aoifuranone (II), furanocaulesone-B (III), and furanocaulesone-C (IV), were isolated from the essential oil of the subterranean part of A sarum caulescens (Aristolochiaceae). Structures of these substances were determined from chemical and spectroscopic evidences.

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3, 6-Dimethylpyridazine 1, 2-dioxide (I) was reacted with phosphoryl chloride, followed with sodium methoxide, to give 4-chloro-5-methoxy-3, 6-dimethylpyridazine (Va), 4, 5-dimethoxy-3, 6-dimethylpyridazine (VI), 3-methoxymethyl-4-methoxy-6-methylpyridazine (VII), and 3, 6-bis(methoxymethyl)pyridazine (VIII). It was presumed that 4, 5-dichloro-3, 6-dimethylpyridazine (II), 3-chloromethyl-4-chloro-6-methylpyridazine (III), and 3, 6-bis(chloromethyl)pyridazine (IV) were produced in the reaction. When the reaction of I carried out with phosphoryl bromide at room temperature, deoxygenation occurred and 3, 6-dimethylpyridazine 1-oxide (XII) was obtained preferentially. Treatment of I with acetyl anhydride at 138° for 3 hr gave 3-acetoxymethyl-6-methylpyridazine 1-oxide (XVII) and 3, 6-bis(acetoxymethyl)pyridazine (XVIII) in 4% and 2% yields, respectively.

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Relationship between porosity and compressive stress by tapping was investigated. The magnitude of tapping impacts was observed with vibration pickup and oscilloscope as the acceleration. The samples were packed loosely into a graduated cylinder and tapped with constant tapping height (△h) repeatedly until there was no decrease in apparent volume (Va) of the sample. The porosity obtained in this way was termed porosity of level-off state (ε_e). When no more change it Va was observed, the acceleration of samples becames identical to the acceleration of the tapping table. Consequently, compressive stress f and pressure p are given as, f=Ma and p=f/A, where α and M are the acceleration and mass of the samples, respectively, and A is the cross sectional area of a graduated cylinder. Measurement of εe under various acceleration conditions gave the relationship between f and ε_e. Applicability of the usual compression equations to tapping compaction was examined but no equation was applicable to tapping. The new relationship between α and ε_e was obtained as ε_e=k₁(1/a)+k₂, where k₁ and k₂ are constants k₂ is obtained by extrapolation of ε_e to α→∞ graphically, and signifies the closest packed porosity of the random packed powder bed. ε_e obtained by extrapolation of ε_e to α=1 is considered to mean the loosest packed porosity of the powder bed at the gravitational field. Both the closest and loosest porosity have not been obtained precise1y thus far.

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Reaction of 5-nitro-2-furoyl isothiocyanate (1) and 5-nitro-2-thiofuroyl isocyanate (2), having a strong electron-withdrawing group, with β-aminocrotonates (3a-d) was examined. The products from the reaction of 1 with 3a-d were proved to be isothiazoles (5a-d) from chemica1 and spectral evidences. And of the expected compounds such as 1, 2- and 1, 4-adducts (4 and 6) and pyrimidines (7) were not obtained by these reactions. The isothiazoles were probably formed from 1, 2-addition of 3 to 1 giving 1 : 1 adducts (4), followed by cyclization with loss of hydrogen. In order to examine the role of the nitro group in this reaction, p-nitrobenzoyl and 2-furoyl isothiocyanate (10a and 10b) were treated with 3b under the same conditions, resulting in the formation of pyrimidines (11a and 11b) ; the corresponding isothiazoles (12a and 12b) were obtained in the presence of bromine as an oxidizing agent. Formation of isothiazoles (5a-d) from 1, without oxidizing agents appeared to be specific for nitrofuran derivatives. On the other hand, the products from the reaction of 2 with 3a-c were found to be linear 1;2-adducts (14a-c) from spectral evidinces.

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Cimigenol xyloside (I) (0.16mmol) was hydrolyzed at pH 6.2-6.6 for 4 days in about 50% aqueous methanol (390ml) with sodium meta-periodate (4.0mmol), cyclohexlamine (39mmol), and acetic acid (36mmol). Cimigenol-3-formate (V) and the genuine aglycone, cimigenol (II), were obtained as the genin part in respective yields of 51% and 32%. This hydrolytic procedure was applied to the hydrolyses of 25-O-acetyl-cimigenol xyloside (VII) and bacoside-A₁(X) and -A₂(XI), giving results analogous to that of I. It was concluded that the formyl carbon of the formates (V and IX) obtained by this hydrolysis originated from C-1 atom of the sugar miety, xylose, of glycosides I and VII, indicating the site of the glycosidic linkages in these glycosides.

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From the underground parts of Cimicifuga japonica were isolated cimigenol xyloside (II), 25-O-acetylcimigenol xyloside (VI), and two new triterpene glycosides, VII named 25-anhydrocimigenol arabinoside, mp 272-274°, [α]_D +29.7° and VIII, mp 280-281°, [α]_D-23.7°. On acid hydrolysis, VII afforded a ketone (XI), C₃₀H₄₆O₄·CH₃OH, mp 182-184° (from MeOH), [α]_D+35.4°, as the major product of the aglycone part, and arabinose as the sugar part. From chemical properties of XI and comparison of its spectral data with those of dahurinol (III), 16, 23-epoxy-cycloart-25-ene-3β, 24-diol-15-one was proposed as the structure of XI. Degradative hydrolysis of VII with NaIO₄-cyclohexylamine gave two products, the genuine aglycone 25-anhydrocimigenol (XIV), C₃₀H₄₆O₄, mp 194-195°, [α]_D+61.3°, and its 3-formate (XIII), mp 181-183°. On the basis of chemical and spectral evidences, XIV was presumed to be 25-anhydrocimigenol, which was confirmed by chemical derivation of cimigenol (I) to XIV. The formyloxy group of XIII was found to be located in C-3 position from comparison of its NMR spectrum with that of 25-anhydrocimigenol-3-acetate (XVI), indicating the site of the glycosidic linkage of VII. These results showed that VII is 25-anhydrocimigenol arabinoside (formula VII). The ketone (XI) is one of the artificia1 products formed from 25-anhydrocimigenol (XIV) on acid hydrolysis of VII, and a possible reaction mechanism for conversion of XIV into XI was suggested.

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The carbohydrate and amino acid composition of non-dialyzable β-glucuronidase isolated from guinea pig urine was determined. The carbohydrate composition was hexose 9.5%, methylpentose 3.6%, hexosamine 14.2%, uronic acid 7.1%, and sialic acid 2.3%. The mo1ar ratio of mannose to galactose was 1 : 1 and the hexosamine consisted of both glucosamine and galactosamine in a ratio of 5 : 1. The polypeptide portion of the inhibitor consisted of 70 amino acid residues according to the amino acid analysis. No aromatic or S-containing amino acids were present in the inhibitor, and a small amount of sulfate group was detected in it. On the basis of these results, it was concluded that the non-dialyzable β-glucuronidase inhibitor was a glycopeptide composed of a carbohydrate, amino acids, and a sulfate. Molecular weight of about 10000 was estimated for this inhibitor from the amino acid analysis and gel filtration.

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A method for the prediction of shelf life of pharmaceutica1 preparations under noniso thermal shelf condition has been developed using a digital computer. When the temperature function is T=f(t), k=k₀exp E/R×[1/f(0)-1/f(t)] is derived, and by substitution of this equation into the reaction rate equation, the drug remaining undecomposed is calculated by numerical integration. The calculated results were in good agreement with the experimental values when four pharmaceutical preparations were stored in three different places for 1 year and the temperature changes were expressed as Fourier series.

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The content of free amino acids in six genera, eleven species, of Polyporaceae family was found to be not characteristic for the species. Variation in amino acids according to their habitat was not observed.

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Chloroform extracts of callus cultures of Lithospermum erythrorhizon were tested for antimicrobial activity against three gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Sarcina lutea). The extract of callus tissues (Strain M-231a) containing shikonin derivatives in a large quantity showed high antibacterial action similar to the extract of intact roots. On the other hand, callus cultures (Strains M-18 and M-386) containing a small quantity of shikonin derivatives showed low antimicrobial activities. Furthermore, no significant activity against any bacteria was observed in callus tissues of M-231a or M-18 when shikonin biosynthesis during culture period had been inhibited by 2, 4-dichlorophenoxyacetic acid or light.

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From the volatile oil of the fruits of Paederia chinensis, dimethyl disulfide, cis-3-hexen-1-ol, benzyl alcohol, phenethyl alcohol, methyl salicylate, and five kinds of fatty acid were isolated and identified. Kaempferol, quercetin, and caffeic acid were also isolated from the residue of steam distillation. By the methylation of crude substance and following alumina chromatography, ursonic acid was identified as its methyl ester.

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The acid dissociation equilibria in aqueous solutions of serotonin (5-HT) and 5-hydroxytryptophan (5-HTP) were studied by potentiometry at 25°and μ=0.1(NaClO₄). Microscopic equilibrium constants shown in chart 1 were calculated by three different methods. Methods A and B are based on the assumption that k_n is the same as the dissociation constants of tryptamine·HCl and 5-methoxytryptamine·HCl, respectively. In method C, the absorbance at 322 nm is taken as a measure of the concentration of the dissociated phenol. Results are listed in Tables I and II. 5-HT was found to be present completely in cationic form at the physiological pH of 7.4, and about 30% each as neutral and zwitterionic form at pH 10.5, whereas about 60% of 5-HTP was found to be present in the form corresponding to neutral form of 5-HT at pH 10.4.

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α-Amyrin, betulin, betulinic acid and wistin were isolated from the bark of Wisteria floribunda DC., and afromosin, ursolic acid, formononetin β-sitosterol-3-O-β-D-glucoside, wistin, and ononin from its wood.

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Cyclic carboxylic anhydrides were reduced to the corresponding lactones with NaBH₄. In the case of maleic anhydride (I) and 1, 8-naphthalenedicarboxylic anhydride (XIX), the reduction proceeded further and, both 2-buten-4-olide (II) and γ-butyrolactone (III) were obtained as the product. Reduction of XIX gave the lactone (XX), hemiacetal (XXI), ether (XXII), and dialcohol (XXIII). XXII was presumably derived from XXI by subsequent dehydration reaction.

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2-Phenyl-7-methoxy-4H-1, 3-benzothiazine (IV), a rearrangement-cyclization product, was obtained by the Bischler-Napieralski reaction of N-(3-methoxyphenylthiomethyl)-benzamide (I). The structure of IV was elucidated by desulfurization. In addition, some analogous cyclization reactions were carried out.

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Methylation of dihydroprotoberberine-type enamines, dihydropalmatine (Ia) and dihydroberberine (Ib), with formaldehyde gave 13-methylprotoberberines, dehydrocorydaline (IIa) and 13-methylberberine (IIb) and dimeric protoberberines, 13, 13'-ethylenebis(palmatine) (IVa) and 13, 13'-ethylene-bis(berberine) (IVb), respectively. The structure of these dimeric products was deduced from chemical and spectral data, and established by an alternative synthesis.

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