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The complexes of polyethylene oxide (PEO) with guanidine hydrochloride and with phenobarbital were subjected to differential scanning calorimetry (DSC), polarized infrared (IR) spectroscopy and X-ray fiber photography, confirming the formations of the complexes and discussing the structures of PEO molecules in the complexes in comparison with PEO-urea complex or original samples of PEO. The formations of the complexes of PEO with urea, with guanidine hydrochloride and with phenobarbital were confirmed by DSC curves of physical mixtures of the respective original components. It may be concluded on the basis of the results by X-ray fiber photography that the three dimentional structure regarding the fiber identity period are different among ordinary PEO, PEO-guanidine hydrochloride complex and PEO-phenobarbital complex. The polarized IR spectroscopy informed that PEO molecule in PEO-guanidine hydrochloride complex may have a structure not so different from the 72 helix in the ordinary PEO. It was assumed that PEO molecule in PEO-phenobarbital complex is more distorted than that in PEO-guanidine hydrochloride complex in comparison with intact one, as the fiber identity period was considered to consist of one chemical unit.

The Kinetics between thiamine propyl disulfide or its homologes and L-cysteine were studied under the experimental conditions determined in the preceding paper. The effects of alkyl substitution of TPD on kinetic parameter were also studied, using thiamine benzyl disulfide, thiamine allyl disulfide, and thiamine hydroxyethyl disulfide. The following conclusions were drawn from the results presented. 1) From an analysis of the pH-rate profile of the reaction which followed a second order kinetics throughout the pH range of 3.5 to 13.2, the reaction was revealed as the combination of the following elementary reactions. [numerical formula] where HG1-SS-Pr is the protonated form of TPD, NH3+-Cy-S- is protonated cysteine anion, and k1, k2 and k3 are specific rate constants of individual elementary reactions. The values determined were 1.82, 0.261 and 1.10 in 104L. mole-1 min. -1for k1, k2 and k3, respectively. 2) No detectable effect of ionic strength and buffer concentration on the rate constant was observed at pH 4.0 on Reaction (I). 3) The activation energy obtained from an Arrhenius type plot was 12.3 and 10.9 kcal./mole for Reaction (I) and (II) after correction for ionic dissociation of thiol and amino groups in cysteine. 4) From the kinetic data tabulated on TPD derivatives, the order of the reactivity was TBD>TAD-TOED>TPD. The activation energies of Reaction (I) were about 10 to 12 kcal./mole.

1) The intestinal absorption of aminopyrine as a representative of the basic drugs was investigated to prove the validity of equation (1) described previously. 2) From the three evidences, that is, a good fit of the data at pH 7.01 to equation (3), the statistical treatment of all the data, and the experiment at equilibrium state, it is concluded that aminopyrine penetrates the intestinal barrier with each specific coefficient, Pu and Pi, according to equation (1). 3) Respective values of the coefficients were statistically determined and the estimated value of Pu was 0.00266 (cc./cm./min.) and that of Pi 0.000242 (cc./cm./min.). From the ratio of Pu/Pi, it may be expected that aminopyrine is absorbed in its undissociated form according to Overton's hypothesis. 4) A fact that aminopyrine slowly penetrates the intestine is consistent with the result reported by Hogben, et al.

As an approach to an understanding of the membrane action of phenothiazines, the adsorption from solution was investigated using such adsorbents as carbon black (CB), graphite (GP), silica gel (SG) and polyethylene (PE), and relating the results with other physico-chemical and biological activities of the drugs. The adsorption isotherms by CB and GP were in accordance with Langmuir equation. In the case of SG, the phenomenon looked like a multilayer adsorption. Phenothiazines were considered to be classified into three groups according to the adsorbability by PE. The adsorbed amount was influenced by the molecular volume of R10'N at 9-position, sulfoxide group at 5-position, and the bulkiness of substituent at 2-position. The adsorbed amount increased with pH of buffer solution between 5 and 8, and it was considered that pH had influence on the hydrophobic and hydrophilic balance of the molecule. The decrease in adsorption with addition of urea demonstrated that the adsorption of phenothiazines proceeded on the hydrophobic interaction. The adsorbability of phenothiazines by CB increased with the surface tension lowering of solution and also with the partition coefficient in CHCl3-0.2N HCl. It was shown that the adsorbability have relation to the neuroleptic and the haemolytic activities.

In order to discuss the entropy increase on the adsorption process of tryptophan by carbon black from aqueous solution, the water-tryptphan interaction was investigated on the basis of solubility properties of tryptophan in water and in aqueous urea solution. Calculating the thermodynamic functions of the dissolution of tryptophan in water, the entropy change was negative, meaning that the water structure changed to more ordered one by dissolving tryptophan in water, that is, an iceberg might be formed in the neighborhood of hydrophobic moiety of tryptophan, i. e., indole group. Calculating the thermodynamic functions of the transfer of tryptophan from aqueous solution to aqueous urea solution, the entropy change increased with the concentration of urea and the enthalpy change was negligible, as were contrary to those of a general complex formation. It was reasonable that the solubility of tryptophan increased with the entropy increase through the break-down of iceberg with the addition of urea in aqueous solution of tryptophan, i. e., through the decrease of hydrophobic bonding. Finally it was concluded that the entropy increase overcame the enthalpy increase in the adsorption of tryptophan by carbon black from aqueous solution. In other words, the adsorption was forced with the entropy increase caused by the change of water structure.

Solubility properties of L-tryptophan in aqueous solution was discussed on the basis of the effects of 3rd component on the optical rotatory dispersion (ORD) and on the adsorption by carbon black. ORD data showed the optical rotation of L-tryptophan around 450 mμ was suitable in analyzing the effect of 3rd component on it. Adsorption data indicated the respective hydrophobicities of the present 3rd components. Alcohols and glycols were classified into three types according to the similarities in hydrophobicity and in structure. Except for urea, formamide and dimethylsulfoxide, there was found a correlation between the ORD and the adsorption data. Alcohols were considered to give effect selectively on the indole group of L-tryptophan, while glycols to give effect also on the moiety other than the indole group. Urea and formamide might give effect on the hydrophilic moiety of L-tryptophan to result in the decrease in optical rotation, but this effect was considered to have no relation to the increase in solubility. Analyzing the relationship between the ORD and the adsorption data, the present 3rd components were classified into three types, corresponding to the previous classification according to solubility studies. Finally, the results verified the concept regarding the contact of 3rd component with L-tryptophan to result in the increase in solubility in aqueous solution.

1. While the isotonic phosphate buffer (pH 6.0∼6.4) was recirculatingly perfused through the rat small intestine for 3 hours, volume of the solution was constant. 2. When the isotonic phosphate buffered solution (pH 6.0∼6.4) containing sulfonamide was recirculatingly perfused through the rat small intestine in vivo, the logarithm of residual ratio of the drug vs. time curve was a straight line. 3. From the slope of the straight line, apparent permeability coefficient, pa, was obtained. The constants were : Sulfaguanidine (0.0×10-3 cm./min.) ; Sulfathiazole (0.9×10-3) ; Sulfanilamide (1.0×10-3) ; Sulfamethoxypyridazine (1.7×10-3) ; Sulfisomezole 3.2×10-3). 4. It may be suggested that the permeability coefficient of sulfisomezole from intestinal lumen (isotonic phosphate buffered solution at pH 6.0∼6.4) into plasma is much larger than that from plasma into intestinal lumen. 5. The Pa-pH diagrams of four sulfonamides were obtained.

Considerations on the colorimetric determination with dye as a weak acid-weak base reaction have been described. Other applications in the pharmaceutical fields are suggested. Several equations were derived on which are based the following five items : 1) Some of organic acids may be determined by colorimetry with a basic dye as well as with organic bases. 2) The dye which combined with sample reaches maximum value at a certain pH value. 3) Dissociation constants of a sample and of a dye should preferably be as large as possible. 4) The calibration curve is linear. 5) In general, the ratio of combination of a sample and a dye is nearly in integral ratio, such as 1 : 1.

The kinetic investigation about the factors affecting the biliary excretion was tried with azo and indigoid dye in rat. Five azo dyes, i.e., Azorubin S, Amaranth, New Coccine, Ponceau R, Ponceau SX, and Indigo Carmine as indigoid dye were used. (1) All dyes except New Coccine used here began to be excreted within 2-5 min and the peak of the excretion rate appeared between 10 and 20 min after administration. But as for New Coccine which had the very low excretion ratio, the delay of the excretion was observed and the peak of the excretion rate was hardly observed. (2) The dose dependency of biliary excretion which had been found in riboflavin was also found in dyes, and accordingly, the dependency was considered not to be specific to a biological substance such as riboflavin. (3) In the excretion rate constant, all dyes which showed high dose type excretion pattern had two rate constants k1 and k2 as shown in riboflavin, and the ratios of them were between 1.4 and 3. (4) It was also found that not only the number of sulfonate groups, but also the position of them had an effect on the biliary excretion ratio. (5) The biliary excretion pattern of Indigo Carmine which is likely to be excreted in urine was not different essentially from those of azo dyes of which the ratio was high.

The adsorbability of 22 ortho-, meta- and para-mono- or-disubstituted benzoic acid derivatives by carbon black from aqueous solution (pH 7.4) was correlated with that on graphite from solution (pH 7.0), but not with pKa, partition coefficient and plain size of molecule. The adsorbability of o-nitro, -methyl, -chloro and -bromobenzoic acids was less than that of the respective metha- and para-substituted compounds. The thermodynamic functions for ortho-substituted benzoic acids also were different from those for meta- and para-substituted ones, except for amino- and hydroxybenzoic acids. Plotting the solubility of caffein in the solutions containing benzoic acid derivatives and the free energy change of complex formation with caffein, respectively, against the adsorbability of the acid derivatives on carbon black, there were found correlations in both cases without excepting for ortho-substituted ones. A linear relationship was observed between the free energy change of binding to serum albumin and the adsorbability on carbon black of benzoic acid derivatives without excepting for ortho-substituted ones. These two results suggested that both the complex formation with caffein and the protein binding of benzoic acid derivatives take place on the basis of the electrostatic and the hydrophobic interactions.

The dissolution rate constants of barbital polymorphs in water were measured by rotating disk method. The phase transition took place by compression during preparing of the disk. Combining the Levich equation and the concept of consecutive process first proposed by Berthoud, the rate constant of interfacial chemical reaction and that of transport process were obtained separately, and the diffusion coefficient also was calculated. These values were reasonable compared with data found in many references, and the theoretical diffusion coefficient calculated according to the Wilke and Othmer equations. The activation energies of transport process and chemical reactionwere obtained from the temperature dependence. Furthermore, the solubility data obtained by the finite differences diagram method affordedthe heat of transition, transition temperature and entropy change between Phase I and Phase III.

The hydrolysis of phthalylsulfathiazole at 60° was studied. The pH-rate profile was similar to that of phthalamic acid in acidic region, and rate constant of intramolecular reaction was 1.12×10-3 sec-1. In strong alkaline region the rate was proportional to hydroxide ion concentration and the rate constant was 3.80×10-6 liter·mole-1 sec-1. Reaction species were discussed in relation to observed rate constants and the rate expression was presented. ΔHn was 18.1 kcal/mole and ΔSn was -17.9 e.u.

The adsorption of trytophan by carbon black from aqueous solution was studied for an approach to an understanding of biopharmaceutical phenomena, comparing with the adsorptions by keratin, silica gel and graphite. The stereoselective adsorption, which took place on keratin, was not observed in the case of carbon black. The interaction of tryptophan with the carbon black surface might be originated by the orientation of hydrophobic moiety on the surface, being free from steric hindrance of the other moiety. While the amount of tryptophan adsorbed on silica gel increased with the acidity, the adsorption by carbon black did not depend distinctively on pH in the region of pH 3 to 9, though some part of the carbon black surface was considered to have a polarity. Tryptophan might be adsorbed preferentially on the nonpolar part of the surface where the indole group adopted the parallel orientation. The adsorption of tryptophan by carbon black increased with temperature. In order to discuss this unusual phenomenon, the thermodynamic functions were calculated, showing the entropy effect was predominant in the course of adsorption. It was suggested that the adsorption in this system might be forced with the entropy increase through the change of water structure caused by break-down of the iceberg enclosing the tryptophan molecule in solution.

The dissolution rates of benzoic acid derivatives in water and in urea solution were measured by rotating disk method. The data of the dissolution in urea solution showed a good agreement qualitatively with the process in which there exist some reaction and the equilibrium is reached rather slowly in the diffusion layer and the solutes are transferred into the bulk solution under non-equilibrium state. That is, the dissolution rate constant, KT, and the saturated concentration, CO, showed the dependence on the lapse of time, and the initial dissolution rate constant, KT(t→o), was almost the same as the value of KT observed on the dissolution in water.

A model was proposed to analyze the dissolution phenomena involving simultaneous phase changes and its experimental demonstration was done with p-hydroxybenzoic acid and phenobarbital which change to the respective hydrates during dissolution. The mathematical expression for the dissolution according to this model was given by equation (3) or (4). Conbining the rotating disk method with the above equations, it was possible to determine the rate constant of crystallization process, kr, and the saturated concentration of anhydrate, CSA, which are hardly obtainable by other usual methods. At the same time, the rate constant of transport process, kt, and the saturated concentration of hydrate, CSH, were obtained. Analyzing the values of kt, kr, CSA, and CSH obtained at various temperatures, the activation energies of transport and crystallization process and the thermodynamic functions of the transition from anhydrate were determined, being reasonable compared with the past data reported on organic medicinals. The transition temperatures obtained from the intersections of the van't Hoff plots regarding anhydrate and hydrate were 84°for p-hydroxybenzoic acid and 37°for phenobarbital. In the case of p-hydroxybenzoic acid, (CSA-CSH) increased with temperature in the experimental temperature region.

1) Attempt was made to suppress the hydrolysis of acetylsalicylic acid with anionic (sodium laurylsulfate), cationic (cetylethyldimethylammonium bromide and benzalkonium chloride), and nonionic (Emulgen 120) surfactants. The hydrolysis of the undissociated form of acetylsalicylic acid is suppressed by the three kinds of surfactants and that of the anionic form is suppressed by cetylethyldimethylammonium bromide and benzalkonium chloride. 2) Through the ultraviolet spectra and the partition coefficient, it was ascertained that the undissociated form of acetylsalicylic acid is solubilized with the above three kinds of surfactants and the anionic form interacts with only a cationic surfactant.

Experimental conditions for the kinetic study of exchange reaction between thiamine propyl disulfide (TPD) and L-cysteine were examined where the possible side reactions shown in Chart 1 proved by thin-layer chromatography could be safely ignored. The following conclusions were drawn from the results obtained. 1) It was proved that the formation of thiamine was the main product and the formation of propylmercaptan was negligible when the reactants were mixed in a molar ratio of 1 : 1 and an initial concentration of 1×10-3∼5×10-5 molar. 2) The exchange reaction followed second order kinetics examined from half-life, the plot of integrated equation, and the result of pseudo first order reaction converted by experimental conditions. The rate constants observed were 1.723 and 444.4 L. mole-1 min. -1at 15°and pH 4.6 and 8.0, respectively. 3) The rate constant of the thiamine formed from TPD and propylmercaptan which was the largest side reaction among the various possibilities, was 0.607 L. mole-1 min. -1 at pH 4.6 and 15°as a second order reaction.

1. Two types of equations expressing the velocity of acid neutralizing reaction of antacids were discussed. One was the calcium carbonate type, for which the initial increase of pH, (dx/dt)t=0, was convenient to compare the velocity of reaction. The other was DAHG type, for which the apparent order of reaction, n, the finished time, t∞, and the pH flexional time, tυ, were convenient to compare the antacid reactivity quantitatively.2. The activation energy of reaction between powdered marble and hydrochloric acid was estimated to be about 6, 400 calories.3. The velocity of reaction between DAHG and acid depended upon the kind of samples or acids used.4. The activation energy of reaction between DAHG and acid was estimated to be about 20, 000 colories.5. The rapid increase of pH at the initial stage of reaction between DAHG and acid was considered to be due primarily to the absorption of acid by the test sample.6. The change of pH at the final stage of reaction between DAHG and acid was considered to be dependent upon the hydrolysis of aluminum ion produced and the adsorption effect of the test sample.

The permeation of phenothiazines through cellulose membrane was investigated as a successive study of the adsorption from aqueous solution reported in a previous paper. The permeability decreased with the increase in molecular weight of phenothiazines. The activation energy of permeation was close to those of diffusion of usual organic medicinals in water. Any remarkable effect of pH on the permeation was not observed in the present conditions. It was demonstrated from these results that the permeation of phenothiazines through cellulose membrane proceeds on the basis of a diffusion through pore. In comparison with the diffusion constant of levomepromazine maleate in aqueous solution evaluated from the dissolution rate by the rotating disk method, the interaction coefficient of the diffusion through cellulose membrane was given as 0.453.

The kinetic studies were conducted on the reaction between propyl propane-thiol-sulfinate (PrSSOPr) or -thiolsulfonate (PrSSO2Pr) and 1-cysteine. The reactions were shown by the following equations. PrSSOPr+CySH→CySSPr+(PrSOH) 2(PrSOH)→PrSSOPr+H2O and PrSSO2Pr+CySH→CySSPr+PrSO2H The studies were carriepd out at an acidic pH because of the very fast rates of these reactions. The reaction species of cysteine was proved to be the protonated S-anion, RN+H3·S-. The values of the enthalpy of activation and the entropy of activation were calculated to be 8.4 kcal/mole, -15.1 e.u. for PrSSOPr and 2.9 kcal/mole, -19.2 e. u. for PrSSO2Pr.

The drug release property from the six commercial sugar coated tablets which contain antipyretic and analgesic igredients were estimated from comparison of the urinary excretions after the oral ingestion of tablets and the dissolved solutions in human. The igredients are sulpyrine, aminopyrine, phenacetin, bucetin, N-acetyl-p-aminophenol, salicylamide and Al-acetylsalicylate. The over-all mean value of the time of fifty per cent drug release in the gut was 1.62 hr. The mean availability was as good as 96.2 per cent. The release rate of Al-acetylsalicylate was slower than the others in statistically significant and also the instances of poor availability of the drug were observed. The merits of the convolution equation method for the estimation of release rate in vivo were demonstrated in the case of the compounded drug.

Kinetic studies were conducted on the reaction between thiamine and propyl propane-thiolsulfinate (PrSSOPr) or -thiolsulfonate (PrSSO2Pr) to give thiamine propyl disulfide (B1SSPr). The folllowing mechanisms were suggested for the reaction with PrSSOPr. [chemical formula] (1) B1SH+PrSSOPr→^^(k5)B1SSPr+(PrSOH) (2) [chemical formula] (3) The reaction with PrSSO2Pr was more complicated, since the hydrolysis of PrSSO2Pr was not neglected, as shown in the following equations. B1SH+PrSSO2Pr→^^(k3)B1SSPr+PrSO2H (4) PrSSO2Pr+H2O→^^(k4)(PrSOH)+PrSO2H (5) The rate of conversion to thiol-type thiamine was found to be the rate limiting step and k1 determined as 1.66×10-4 sec-1 at pH 8 and 37°. The validity of the discussion was supported by the agreement between the experimental data and the simulation curves by analog computation.

The disk of sulfonamide was made by compression of the powder and the dissolution rate was measured by rotating it in water under various conditions. The results obtained are : 1. The concentration-time curve of dissolution was obtained with a good reproducibility and it did not depend on the thickness of disk, the size and shape of the flask which contained the liquid, and the depth of the disk from water level. 2. The dissolution rate constant, KT, did not depend on the surface area of the disk and the volume of the liquid of 50 to 200 ml. During the dissolution experiment, disintegration of disk could not be considered to occur. 3. KT did not depend on the compressional pressure to make disk under 1 to 5 tons/cm2. This showed that the dissolution depended on the apparent geometrical surface area, not on the intrinsic surface area of solid. 4. KT was proportional to the square root of rotating velocity of the disk. 5. The activation energy of dissolution of sulfadiazine was about 3.5 Kcal./mole. 6. The values of KT of five kinds of sulfaonamides were quite coincident with the values calculated according to the Arnold equation. The values of saturated concentration, CO, were coincident with the values of solubility, CS, observed. 7. From the results obtained, it would be possible to give the following conclusions : I) From the measurement of dissolution rate by the rotating disk method, KT and CO can be obtained separately with a high confidence on the value. ii) The dissolution of sulfonamide is in accordance with the Noyes-Nernst equation concerning the transport controlled dissolution. The Levich Equation is also established.

Acylcholinesters (C3 to C12) were synthesized and the stabilization effect by sodium lauryl sulfate (SLS) against hydrolysis were studied at pH 7.7. 1) The apparent distribution of cholinesters between aqueous and micellar phases of SLS solution was measured by condensation method. The correlation between the apparent distribution and the magnitude of stabilization effect was observed. 2) The hydrolytic rate of cholinesters was suppressed from 1/2 to 1/250 by the addition of 0.5% SLS. The longer the acyl chain length of cholinesters, resulted the greater the stabilization effects of SLS. There was no apparent relation between chain length and rate constant without SLS. 3) When cholinesters were mixed with SLS in aqueous solution, transient turbidity formation was observed, which was considered to be due to the metathesis. A complete dissociation of three salts concerning to the metathesis was proved by the determination of conductivity. 4) The solubility of acylcholine iodides in water was high and that of in organic solvents was limited by the polarity of the cholinesters regardless of their acylchain length. Therefore, the mechanism of stabilization from hydrolysis was considered via the solubilization of acylcholine-lauryl sulfate ion pair into micellar phase. 5) From the correlation mentioned above, it was presumed that the site of solubilization and/or the dimentional change of micelle might affect the stabilization from hydrolysis.

Reaction between DAHG and organic acid, i.e., salicylic acid, trichloroacetic acid, monochloroacetic acid, or formic acid, was examined and the following results were obtained. 1. Three stages of the reaction, i.e., the initial, the main, and the final stages, were observed with the progress of dissolution of DAHG in acid. 2. The initial stage is concerned with the rapid increase of pH, which was considered to be due primarily to the adsorption of acid by DAHG and also to the dissolution of aluminum ion on the surface of DAHG. 3. The rate of dissolution of DAHG at the main stage was in accordance with equation (2). 4. The order of the reaction with respect to the hydrogen ion was influenced by the dissociation constant. 5. The effect of anion on the apparent rate constant, K2, was condiered to be a specific property of that anion and not applicalbe to any generalization. 6. The estimated activation energy was 23, 000∼25, 000 calories, indicating that the reaction between DAHG and organic acid might be chemically controlled. 7. At the final stage, corresponding to the reaction in the higher pH region than about 4, the increase of aluminum ion was ceased apparently.

The adsorption of phenols by carbon black from aqueous solution was investigated. to discuss the mechanism of interaction on the adsorbent surface, referring to the partition coefficient in n-octanol/water system, Px.The shape of adsorption isotherm was discussed with respect to the position of substituents and also the degree of dissociation.There was found a linear relationship between Langmuir constant a and log Px. This result was explained thermodynamically on the assumption of a surface layer on the carbon black, concluding that the surface layer is considered to play the similar role to n-octanol layer in the partition experiment.Free energy of adsorption calculated from Langmuir constant b seemed to be an apparent one and to be influenced predominantly by the free energy of binding.Regarding the relationship between the adsorbed amount at an identical equilibrium concentration, Mc, and the equilibrium concentration at an identical adsorbed amount, Cm, the following equation was derived:log Mc=(1/λ)log (1/Cm)+κwhere λ and κ are constant.Plotting log Mc against log Px the derivatives were classified into groups I and II, suggesting the increase in adsorption of group I may be predominantly due to the tendency of the hydrophobic bonding, while that of group II may be influenced by the free energy of binding in addition to the tendency of the hydrophobic bonding.

The results obtained as follows were satisfactory enough to demonstrate the hydrophobic bonding mechanism of the adsorption of tryptophan by carbon black from aqueous solution and also the causative role of the hydrophobic moiety of molecule. Calculating the thermodynamic functions of the adsorption by carbon black from aqueous urea solution, the absoulte values of both free energy change and entropy change decreased, as was considered to be originated from the change of property of tryptophan in solution with the addition of urea. That is, the iceberg enclosing the tryptophan molecule in solution was broken down with the addition of urea. Glycine and leucine were negligibly little adsorbed by carbon black from aqueous solution. Phenylalanine was less adsorbed than tryptophan. These results followed the order of hydrophobicity of molecule. The temperature dependence of the adsorption of phenylalanine was usual one, that is, an energy-predominant adsorption took place contrary to the case of tryptophan, while leucylglycylphenylalanine gave the same type of temperature dependence as tryptophan. This means the entropy change of adsorption of phenylalanine was too small to overcome the enthalpy effect.

The disappearance of ethoxybenzamide from a rabbit plasma after an intravenous injection was studied. 1. The distribute phase after the injection could not be neglected, and the two compartmental model was applied to analize the time course of plasma concentration. 2. The iterative least square method with a digital computer was proposed to obtain pharmacokinetic constants and their statistical values. 3. The present method gave the unique parameters independent of personal error for drawing straight lines in the semilogarithmic plots of plasma concentration vs. time, and it could test the adoptability of data for the model.

The reaction between dried aluminum hydroxide gel (DAHG) and acid was represented by_??_where n is nearly zero is both cases of hydrochloric acid and nitric acid, and 0

1) Sodium lauryl sulfate (SLS) was hydrolysed in acidic solution at a high temperature, and the rate of hydrolysis was dependent on not only H+ concentration but also SLS. concentration. It was recognized that the rate of reaction was increased strikingly in the region of a certain concentration of SLS. 2) When the Critical micelle concentration (CMC) of SLS was determined by solubilization method with dye (Sudan III), it was approximately coincident with region of a certain concentration where the rate of reaction increased strikingly. 3) On the contrary to acidic solution, in alkaline solution, SLS above the CMC was a little more stable than that of below.

The aqueous solutions of 24 benzoyl derivatives were perfused through the samll intestine of anesthetized rats. The absorption rate coefficient calculated from the slope of the straight line which was obtained from the logarithmic plots of the residual ratio vs. time was used for comparison of the intestinal absorption rates of these foreign organic compounds. In each series (benzoic acid-, benzaldehyde-, methyl benzoate-series), the absorption rate decreased as the number of hydroxyl groups increased. When comparing the monohydroxyl derivatives in each series, the o-isomer was absorbed faster than m- and p-isomers, but this was not true of methoxyl derivatives. From these facts, it is suggested that Danielli's model may be applied to the intestinal absorption of foreign organic compounds.

In the previous papers, the authors reported the kinetic studies on the factors affecting the biliary excretion using Azo, Indigoid and Triphenylmethane dyes. The further study was tried using Xanthene dyes, Fluorescein and Bromsulphthalein, and the effect of halogenation was discussed. Four Xanthene dyes, i.e. Eosine Y, Phloxine B, Erythrosine B, Rose Bengal, and Fluorescein and Bromsulphthalein were used. (1) The excretion behaviors were similar to those of Azo and Triphenylmethane dyes which had the dose dependency, but the excretion ratios showed common larger values than 75% except Fluorescein which had no halogen group. (2) It was found that the halogen group had great influence on the biliary excretion as well as the sulfonate group. And it was also suggested that the effect of halogen group depended on the total electro negativity of substituents. And furthermore it was found that the increasing in molecular weight had not so much effect than the increasing of polarity. (3) It was also suggested that the -I gave the delay of excretion in the early period and this was probably due to the larger uptake into liver cells. (4) BSP showed markedly concentrical excretion pattern and large excretion ratio in a short period and it was found that these characteristic behavior was mainly ascribed to both halogen groups and sulfonate groups.

Alkaline degradation of propyl propanethiolsulfonate (PrSSO2Pr) was investigated to study the reaction mechanism for the synthesis of thiamine derivatives of disulfide type. It was postulated that PrSSO2Pr degrades to thiolsulfinate (PrSSOPr) and sulfinic acid (PrSO2H) eventually as shown in the following equations. PrSSO2Pr+OH-→PrSO2-+(PrSOH) 2(PrSOH)→^^(fast)PrSSOPr+H2O The values of the enthalpy of activation and the entropy of activation were calculated to be 8.2 kcal/mole and -21.7 e. u. PrSSOPr underwent alkaline degradation as PrSSO2Pr did, but the rate was rather smaller than that of PrSSO2Pr.