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Studies of speed, resolution, and sensitivity indicate packed column supercritical fluid chromatography is a viable technique for the analysis of antipsychotic drugs. Fourteen such drugs (mostly phenothiazines) were studied from a cyanopropyl liquid chromatography packed column with a tertiary mobile phase of carbon dioxide, methanol, and isopropylamine. An arbitrary mix of 10 components was baseline resolved in approximately 11 min. Detection limits were as low as 125 ppb, with a feasible 10-fold decrease. Without the isopropylamine in the mobile phase, none of the solutes eluted. With the additive, all produced symmetrical peaks and high efficiency (i.e.,80% of theoretical). Changing modifier concentration was the most effective physical parameter for changing retention but had little effect on selectivity. Temperature changes had a modest effect on retention but provided surprisingly large changes in selectivity, with numerous peak reversals occurring over only a 30 degrees C temperature range. In addition, temperature programming was the most effective means to optimize resolution of the 10-component mix. No noticeable loss in efficiency accompanied the temperature programs.

Chlorpromazine N-oxide, fluphenazine N 4 ’-oxide, prochlor-perazine N 4 ’-oxide, sulforidazine N -oxide, and trifluoperazine N 4 ’-oxide were synthesized by oxidation of the designated nitrogen atom in the N- 10 side chain of the respective parent drug with 3-chloroperoxybenzoic acid. In the case of trifluoperazine, a stepwise increase in the amount of oxidant yielded the N 1 ,N 4 -dioxide and N 1 ’, N 4 ’,S-trioxide. The N’,S- dioxides of chlorpromazine and sulforidazine were obtained by hydrogen peroxide oxidation of the appropriate parent drug.

The degradation kinetics of moricizine hydrochloride (1) were examined over a pH range of 0.6 to 6.0 at an ionic strength of 0.3 and 60 degrees C. The disappearance of intact 1 was followed by a stability-indicating HPLC assay. The degradation products, which had approximate solubilities of less than 100 micrograms/mL, precipitated in aqueous solution. The precipitate was collected for HPLC analysis and identification of degradation products. Degradation of 1 was catalyzed by acetate and phosphate buffers and was pH dependent, with the pH of the minimum rate constant located between 2.8 and 3.2. At pH 0.6-2.0, 1 degraded via amide hydrolysis to yield first ethyl (10H-phenothiazin-2-yl) carbamate (2), an amide hydrolysis product, which further oxidized in parallel to give ethyl (3-oxo-3H-phenothiazin-2-yl) carbamate (3), ethyl (10H-phenothiazin-2-yl) carbamate S-oxide (4), and diethyl (3,10'-bi-10H-phenothiazine-2,2'-diyl)bis(carbamate) (5), the dimer of the amide hydrolysis product. At pH 2.2-6.0, 1 degraded via a reverse Mannich reaction, to form the reverse Mannich product ethyl [10-(1-oxo-2-propenyl)-10H-phenothiazin-2-yl] carbamate (6), and by parallel reaction via the described amide hydrolysis pathway. The dimer of the amide hydrolysis product was not detectable at pH greater than 2.8. At pH greater than 4.0, the reverse Mannich product was the predominant degradation product. Degradation of 1 was subject to positive and negative kinetic salt effects at pH 1.0 and 4.0, respectively. Arrhenius plots determined at pH 1.0 and 6.0 were linear between 37 and 70 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

The partition coefficients (Kps) of three N-monodemethylated metabolites of phenothiazines (chlorpromazine (CPZ), triflupromazine, and promazine) between phosphatidylcholine (PC) vesicles (SUV) and water were determined to evaluate their affinity to biomembranes by second-derivative spectrophotometry without any separation procedures. The second derivative spectra showed distinct derivative isosbestic points confirming the entire elimination of the residual background signal effects of the SUV, which were observed in the absorption spectra. From the relationship between PC SUV concentration and the derivative intensity change (DeltaD) of each metabolite induced by its interaction with the PC bilayer, the Kp values were calculated and could be obtained with the R.S.D. of below 10% (n = 5) proving an accuracy of the derivative method. The obtained Kp values were similar to those of the parent drugs (the relative differences were within 15%), although the partition coefficient of N-monodemethylated CPZ measured in an octanol/buffer system was reported to be about 1/18 of CPZ. The results obtained from the PC liposome/buffer system do not contradict with psychoactivity and brain accumulation of N-monodemethylated metabolites of phenothiazines, in contrast to the results of the octanol/buffer system.

Fenoverine is a novel, potent, musculotropic, spasmolytic agent that affects primarily the gastrointestinal tract, bile duct, and female genital organs. A simple, specific, and accurate HPLC method was developed for the determination of fenoverine in capsules and plasma. This method has been successfully applied to stability studies of fenoverine capsules and to a pilot study in a normal, healthy volunteer following oral administration of fenoverine. For the determination of fenoverine in capsules, a Nucleosil 5-micron CN column, with acetonitrile:0.1 M ammonium acetate (60:40) as mobile phase and detection at 254 nm, was employed. The mean correlation coefficient of the calibration curve (n = 6) for the assay was 0.9999 over a concentration range of 24.6 to 147.6 micrograms/mL of fenoverine standard solutions. Fenoverine did not decompose significantly at 4, 45, 55, and 65 degrees C for 3 months. The mean correlation coefficients of within-day and between-day calibration curves were 0.9995 and 0.9999, respectively, over a range of 10 to 1000 ng/mL of fenoverine in plasma. The limit of detection was 10 ng in plasma.

The pH-metric technique was used to determine the ionization constants and distribution coefficients of 10 phenothiazines and five ionizable calcium channel antagonists. Because the studied compounds were poorly water soluble and quite lipophilic with partition coefficients in the range of 3.5 to 5.5, organic cosolvents had to be added for the determination of the ionization constants to avoid precipitation of the free bases. The effect of the cosolvents dioxane and methanol on the extrapolation to pure water was compared. For both cosolvents a very good agreement with accessible published ionization constants was obtained, however the slope of the regression line was much smaller for dioxane, yielding more reliable estimates according to the standard deviation of the extrapolated values. Thus, dioxane might be preferable to methanol as a cosolvent for the determination of ionization constants of sparingly water soluble bases. Also the n-octanol/water partition coefficients were determined and compared with published data and values calculated with the ClogP, ACD, and HINT programs. Although the obtained values were approximate in conformity with the published data, the calculated partition coefficients differed from the experimental ones considerably for the majority of the investigated compounds. Furthermore, the ion pair partitioning and the distribution coefficients at physiological pH 7.4 were determined. The pH-dependent distribution profiles showed the strong influence of the ionization constants and of the distribution of the ion pairs on the overall distribution. This result strongly suggests that greater use should be made of measured distribution coefficients in quantitative structure-activity relationship studies. The potentiometric method is a convenient way to determine the distribution properties of drug molecules at pH values relevant for the biological system under investigation.

A GLC method for the specific identification and quantitation of phenothiazine drugs excreted in urine at the microgram level is described. The phenothiazine drugs and less polar metabolites are isolated by two-phase extraction with ether as an organic extractant. Quantitative determination at the microgram level is done on an acetylated fraction of the alcoholic extract by GLC using a suitable internal standard. The compounds are also identified by examining an aliquot of the final alcoholic extract by TLC for supporting evidence of the GLC method's specificity.

The solution properties of a series of phenothiazine hydrochlorides were studied using light-scattering, viscosity, conductivity, dialysis, and NMR techniques. The aggregates formed are considered to be true micelles, which in water are probably composed of about 10 monomers vertically stacked, with the alkyl side chain and nitrogen group alternating to form an approximately spherical unit in solution. In the presence of sodium chloride the micelles grow and it is thought that the conformation of the aggregate also changes. Calculations of the monomer concentration as a function of total drug concentration above the cmC's give good agreement with data obtained previously from NMR shift data. The free energy of inserting a monomer into a micelle was calculated, and the values obtained are discussed in the light of free energies of solution of the hydrophobic bases. The significance of aggregation, mixed micelle formation, and complexation in biological and pharmaceutical systems containing phenothiazines is discussed.

The rate of phenothiazine degradation in an acidic oxygen-saturated medium was studied. 3H-Phenothiazine-3-one and phenothiazine 5-oxide are produced by parallel reactions, and 7-(10'-phenothiazinyl)-3H-phenothiazine-3-one is produced in a more complex manner. The overall phenothiazine degradation rate appears to be pH independent up to pH 7.0. The degradation kinetics of 10-methylphenothiazine were studied after isolation and identification of its degradation products, 10-methylphenothiazine 5-oxide and 3H-phenothiazine-3-one. The main degradation product is 10-methylphenothiazine 5-oxide; but at low pH values and high temperatures, more 3H-phenothiazine-3-one is formed. The degradation rate of 10-methylphenothiazine is pH independent up to pH 7.

Several Several 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines and their corresponding cyclized 10-(2-arylimino-3-acetylamino-4-thiazolidonyl)phenothiazines were synthetized and characterized by their sharp melting points and elemental analyses. All compounds inhibited nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate and alpha-ketoglutarate selectively, whereas NAD-independent oxidation of succinate remained unaltered. All phenothiazine derivatives exhibited anticonvulsant activity, which was reflected by the 20-60% protection observed against pentylenetetrazol-induced convulsions in mice. The ability of substituted thiosemicarbazidophenothiazines to inhibit cellular respiratory activity was reduced considerably by cyclization to the corresponding substituted thiazolidinophenothiazines. On the other hand, cyclization generally resulted in increased anticonvulsant activity. Thus, the anticonvulsant activity possessed by these substituted phenothiazines bore no relationship with their ability to inhibit selectively the NAD-dependent oxidations. Selective inhibition of NAD-dependent oxidation of pyruvate and alpha-ketoglutarate in isolated rat brain mitochondria by some 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines was concentration dependent and competitive in nature.

A computerized sorting program was used to sort out 120 drugs that have been reported to cause skin sensitization from a data bank of 540 clinically useful drugs. Based on an analysis of functional groups, a number of unique common denominators were found for skin sensitization due to covalent bond formation with body proteins. These include potential epoxide-forming groups such as an electron-deficient benzene ring, a vinyl group, hydroxylamine and N-oxide precursors, drugs capable of forming a benzylic radical, β-lactam derivatives, and α,β-unsaturated ketones. By using multiple-regression analysis, the quantitative structure–activity relationship for skin-sensitizing properties of 3-alkyl catechols and 2,4-dinitrobenzene derivatives are also reported.

The effects of adenosine diphosphate and triphosphate on the periodic acid oxidation of the phenothiazine tranquilizing drugs were studied. The principal effect was a marked reduction in the rate of formation and decay of the drug free radical. The oxidation rates of the nucleotide free drugs seemed to be most strongly influenced by the inductive effects of substituents at the 2-position of the phenothiazine nucleus. However, the oxidation rates of the drugs in the presence of nucleotide were most strongly influenced by the substituents at the 10-position. Variations of the structure of substituents at the 10-position have only a modest effect on the electronic state of the phenothiazine nucleus. Therefore, the marked effect of structural variation in the 10-substituents in the presence of nucleotide on the periodate oxidation rate most likely is an expression of steric effects related to an interaction between drug and nucleotide.

Dose proportionality in some pharmacokinetic parameters for thioridazine and its two active metabolites (mesoridazine and sulforidazine) was investigated in 11 healthy human subjects following oral administration of three single doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by an interval of two weeks. Also, after a further two weeks, another 100-mg dose of thioridazine (divided as 5 mg every 0.5 h) was administered to all the volunteers to investigate the effect of a slow rate of dosage input on the pharmacokinetic parameters of this drug. An HPLC method was used to measure concentrations of thioridazine, mesoridazine, and sulforidazine in plasma samples collected up to 72 h following each dose. Dose proportionality for the three single doses of thioridazine was observed for all three analytes in the area under the plasma concentration versus time curves (AUC infinity 0 or AUCt0) and the maximum plasma concentration (Cmax) in that the relationships between the dose and these parameters were each describable by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose. This suggests nonlinear trends in the elimination kinetics at high doses of thioridazine. When a 100-mg divided oral dose of thioridazine was administered, no statistically significant differences between single and divided doses were observed in the mean AUC infinity 0 or AUCt0 for thioridazine or sulforidazine. A significant decrease in the mean AUC infinity 0 or AUCt0 was observed for mesoridazine after the administration of the divided dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Twenty-nine derivatives of phenothiazine formed relatively stable ions by proton capture under conditions of chemical ionization, using methane or isobutane as reagent gas. Fragments of generally low abundance formed by simple bond cleavage in the trimethylene portion of the side chain and by loss of water or hydrogen halide. Mass spectra obtained from pyrolyzates of amine salts and from the corresponding free bases were essentially identical.

Antihemolytic and antiproteolytic properties of several 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines and their corresponding cyclized 10-(2-arylimino-3-acetylamino-4-thiazolidonyl) phenothiazines were investigated. In vitro protection of hypoosmotic hemolysis of human red blood cells by substituted thiosemicarbazidophenothiazines and substituted thiazolidonyl-phenothiazines was concentration dependent; the degree of protection ranged from 19 to 32 and 26 to 42%, respectively, at a final concentration of 0.1 mM. All phenothiazines exhibited antiproteolytic activity. The in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin by these phenothiazines was concentration dependent and competitive in nature; the degree of inhibition ranged from 30 to 50 and 32 to 79% for substituted thiosemicarbazidophenothiazines and substituted thiazolidonlyphenothiazines, respectively, at a concentration of 1mM. Cyclization of substituted thiosemicarbazidophenothiazines into the corresponding cyclized substitited thiazolidonlyphenothiazines increased the antihemolytic and antiproteolytic effectiveness of these phenothiazines.

A reversed-phase high-performance liquid chromatographic assay using electrochemical detection in the reductive mode has been developed for the analysis of 4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one (1) in plasma to determine drug absorption. Free drug in plasma in concentrations as little as 0.25 ng/mL can be estimated with a mean coefficient of variation (CV) of 6.3 +/- 2.6%. Metabolites which can be converted to the parent drug by acid hydrolysis can be quantified in concentrations of 10 ng/mL or more, with a mean CV of 4.3 +/- 1.9%. To test the procedure, plasma was obtained from dogs receiving 14C-labeled 1. After acid hydrolysis of plasma, the electrochemical assay for parent drug showed good agreement with the radioactive equivalents in plasma, suggesting that parent drug and metabolites can be satisfactorily analyzed by this procedure.

The nature of multiple, sequential, self-association equilibria and the significance of the average degrees of association are discussed. Characteristic patterns of association are examined on the basis of available experimental evidence and suitable theoretical models of self-association and their relationship to molecular structure is indicated. The meaning and significance of the simple two-phase approximation of the micellar hypothesis to the cmC are examined and its application is discussed.

The ability of some substituted phenothiazines to reduce the surface tension of aqueous solutions has been studied in order to evaluate their hydrophobic behavior. Particular emphasis was placed on utilizing conditions that would allow specific structural effects to be isolated quantitatively and to point out situations where this may be difficult to do. Substitution on the phenothiazine ring enhances surface activity in the order CF3 ≫ Cl > H. Changing the position of the chloro group on the ring significantly influences surface activity, the order being 3Cl > 2Cl > 1Cl. The effect on surface activity due to changes in the number of alkyl groups, the degree of branching, and the number of dissociable groups on the alkylamino portion of the molecule also has been evaluated.

Brominations of both 1,2-dihydro-3-keto-3 H -pyrido[3,2,1- kl ]phenothiazine (I) and its sulfoxide (VII) gave 3-hydroxypyrido[3,2,1- kl ]phenothiazinium bromide (VI). Treatment of 3-keto-3 H -pyrido[3,2,1- kl ]phenothiazine (II) with bromine gave 2-bromo-3-hydroxypyrido[3,2,1- kl ]phenothiazinium bromide (XII). Structural assignments of VI and XII have been made on the basis of their spectral properties, correcting those previously reported.

Ultraviolet absorption and attenuated total reflectance infrared spectra of chlorpromazine and 14 possible metabolites have been recorded and analyzed. Structural correlations of the absorption bands are presented and discussed. This collection provides a positive means of identifying chlorpromazine metabolites extracted from body fluids and tissues and separated by chromatographic techniques. Spectral identification can be made on microgram samples.

Three separation techniques for various phenothiazine tranquilizers are reported in this paper. Electrophoresis with suitable buffer systems and proper voltage permitted fast and distinctive migration of these phenothiazine bases, but tailing interfered with the usefulness of this technique. Paper chromatography with salt solutions as solvents proved to be a valuable and easy procedure for the separation of this group of drugs. Thin-layer chromatography with silica gel showed the most accurate separation of phenothiazine compounds. Combination of chromatography with color reaction or fluorescence permitted good differentiation of the various phenothiazine tranquilizers.

A procedure is presented for the quantitative determination of combinations of aspirin, phenacetin, caffeine, and itobarbital with salts of phenothiazine derivatives. The powdered mixture is dissolved and passed through a series of partition chromatography columns. The ingredients are separated by specific trap segments, eluted by selective solvents, and assayed by any suitable procedure. The assay technique offers a rapid and accurate determination of the five ingredients.

In simple aqueous media, the extent of adsorption of various phenothiazine derivatives by kaolin, talc, and activated charcoal is significant. Adsorption by talc and kaolin is dependent upon pH of the medium, while adsorption by activated charcoal is less affected by pH. Adsorption of promazine hydrochloride by all three adsorbents is sensitive to the electrolyte concentration of the medium. A variety of evidence suggests that adsorption of the phenothiazine derivatives by activated charcoal is a result of physical forces related to the tendency of the solute to accumulate at the air-water interface. Adsorption of these compounds by talc and kaolin occurs through more complex mechanisms which cannot be completely elucidated from knowledge obtained in this experiment. The effects of pH and electrolyte concentration may be important to the previously observed action of adsorbents in modifying absorption of promazine from the gastrointestinal tract.

Rates of decay of semiquinones of certain derivatives of phenothiazine were measured in aqueous acetic acid solution using electron spin resonance spectroscopy and visible absorption spectrophotometry. Like that of phenothiazine itself, the semiquinones of the derivatives decayed by a second-order process with a rate constant inversely proportional to acid concentration. The rate results were consistent with a mechanism for the decay process as follows. Semiquinone undergoes rapid one-electron disproportionation by oxidation and reduction. The product of the oxidation (analog of phenazothionium ion) is unstable and is involved in two competing reactions. One is hydrolysis to sulfoxide, which is completely reversible to addition of acid. The other is a two-electron disproportionation producing the corresponding 3-hydroxyphenothiazine. In derivatives substituted on the nitrogen, the 3-hydroxy substitution is highly inhibited. The decay rates of the 3-substituted derivatives obey a Hammett relationship using para -substituent constants, while the 2,10-substituted derivatives obey a Hammett relationship using meta -substituent constants. An interesting relationship involving midpoint electrode potentials upon oxidation of certain 3-substituted phenothiazine derivatives is demonstrated.

A series of 2-( N,N -dialkylaminomethyl)-7-phenylthioindoles was prepared. The Japp-Klingemann reaction followed by Fisher cyclization with polyphosphoric acid gave 7-phenylthioindole-2-carboxylic acid. The lithium aluminum hydride reduction of amides derived from this acid provided the corresponding aminomethyl indoles. Infrared and NMR data are reported.

Methods are described for the identification and differentiation of the 13 pheno-thiazine-type tranquilizers listed in Schedule F of the Canadian Food and Drugs Act. These tranquilizers may be identified by observing the colors formed with certain reagents and by determining the melting points and infrared spectral characteristics of either the picrate or reineckate derivatives.

A method was developed in which phenothiazine derivatives were titrated visually to a colorless end‐point with ceric sulfate. Quantitative recoveries were obtained only for chlorpromazine, acetylpromazine, trifluoperazine, and triflupromazine. The method was also applied to pharmaceutical dosage forms of these drugs. UV photometric detection of the end‐point was found to be applicable only to thiethylperazine and thioridazine. Attempts to develop a quantitative procedure for phenothiazines by photometric titration with cupric perchlorate in acetonitrile were unsuccessful.

A procedure is described for TLC detection and differentiation of the butyrophenone-diphenylbutylpiperidine group and phenothiazine derivatives at the microgram level. A two-dimensional TLC method to separate butyrophenone and diphenylbutylpiperidine compounds is reported. A variety of possible detection reagents were examined. The solvent systems and spray reagents described should be useful for the identification of these drugs in various dosage forms.

A rapid, precise, and accurate high-performance liquid chromatographic procedure is presented for the simultaneous determination of perphenazine and amitriptyline hydrochloride in two-component tablet formulations. An aliquot of a methanolic extract of the tablet, containing trifluoperazine hydrochloride as an internal standard, is chromatographed on a nitrile bonded phase microparticulate column using a 0.005 M ammonium acetate-methanol (20:80) mobile phase. Quantitation is by peak area. The relative standard deviations for the procedure are 0.34 and 0.54% for the simultaneous determination of perphenazine and amitriptyline, respectively. Eight commercial tablet formulations were analyzed and found to contain 96.5-101.5 and 96.5-103.3% of the labeled amounts of perphenazine and amitriptyline hydrochloride, respectively.

UV irradiation (365 nm) of air-saturated methanol solutions of 20 drugs absorbing in the 300--400 nm region gave rise to oxygen uptake, as determined with a polarographic oxygen electrode. The drugs were tested for photosensitizing capability by either a Type I (free radical) or a Type II (single molecular oxygen) mechanism. This testing was done by the inclusion of either acrylamide or 2,5-dimethylfuran in the irradiated drug solution, with observation of the subsequent polymerization or oxidation, respectively. Phenothiazine and thiazide derivatives appear capable of photosensitization by both mechanisms; promethazine, trifluoperazine, and furosemide show relatively high reactivity. Diazepam (weak), hexachlorophene, aminacrine, pyrilamine, tetracycline, demeclocycline, quinine, and anthracene (strong) react only by a Type II mechanism, with a photosensitizing efficiency increasing in the order given. A correlation appears to exist with reports of in vivo photosensitivity.

Hydrazoic acid in the presence of concentrated sulfuric acid and phosphorus pent-oxide has improved the yield of the lactam in the Schmidt reaction of norcamphor. Reduction of the lactam with lithium aluminum hydride gives 3-azabicyclo[3.2.1]-octane in good yields. The synthesis of two new phenothiazine derivatives of this complex amine is reported.

The synthesis and anticholinergic activity of a new series of quaternary oximes of some 10-N-substituted phenothiazines are reported.

The present studies indicate that in the dog chlorpromazine, prochlorperazine, and trifluoperazine are rapidly absorbed from the intestine and that there is a rapid hepatic clearance of the phenothiazines. The biliary and urinary excretions of these compounds are greatly affected by the side chain of the phenothiazine nucleus. The “methylpiperazinylpropyl” side chain (prochlorperazine and trifluoperazine) markedly increases the rate of biliary excretion and reduces the urinary excretion of the parent compounds and/or their metabolites compared with the excretion of chlorpromazine and/or its metabolites (dimethylaminopropyl side chain). Moreover, chlorpromazine and/or its metabolites excreted in bile are reabsorbed from the intestine, resulting in an entero-hepatic recirculation.

A photometric titration procedure is described for the determination of a number of phenothiazine derivatives and their dosage forms. An acidic solution of the drug or dosage form is titrated with standard ceric sulfate solution. The end point is determined photometrically at 420 mG. Quantitative recoveries are reported for 14 phenothiazine derivatives and three dosage forms.

Members of a select group of chlorinated, fluorinated, and unhalogenated phenothiazines of known (i.e., reported) antiemetic potency in dogs were evaluated as pecking syndrome antagonists in pigeons. Assigning to chlorpromazine an arbitrary potency value of 1.0, it was calculated that promazine = 0.1, prochlorperazine = 2.3, triflupromazine = 4.4, trifluoperazine = 7.2, and perphenazine = 10.2. The relationship of these data to the reported antiemetic activity of the compounds is discussed.

The kinetics of dopamine oxidation by dialkylaminoalkylphenothiazine cation radicals (with two- or three-carbon side chains) were investigated. The two-carbon side-chain derivatives have reaction rates higher than the three-carbon ones. For chlorpromazine and promazine, extrapolation of pH 1–6 data shows that reaction rates become very fast at physiological pH.

2-(4'-Hydroxybenzeneazo)benzoic acid is a spectrophotometric probe which shows absorption spectrum changes upon binding to protein. Difference absorption spectra of this probe were used as an indirect measurement of the binding of selected sulfonylurea and phenothiazine drugs to bovine serum albumin. The results obtained using the spectrophotometric probe were similar to data obtained from other methods, especially fluorescent methods. Of the four sulfonylureas studied, tolbutamide showed the highest binding affinity, followed by glyburide, glipizide, and acetohexamide, in that order. The data collected for phenothiazine drugs indicated that chlorpromazine has the highest affinity, followed in order by trifluoperazine, perphenazine, fluphenazine, and promazine. Correlation of these results with chemical composition indicated that the interaction of phenothiazine drugs with bovine serum albumin was of a hydrophobic nature.

A Simple method is reported for the preparation of gram quantities of phenothiazine sulfoxides by aqueous nitrous acid oxidation of phenothiazines at room temperature. The chiral levomepromazine gave rise to diastereoisomeric products analogous to those reported for thioridazine sulfoxidation.

The chemistry of the red color formed during perchloric acid titration of chlorpromazine hydrochloride in acetic acid in the presence of mercuric acetate is discussed. Addition of ascorbic acid prevents the color formation and allows titration using a crystal violet end-point. Ascorbic acid addition also sharpens the potentiometric end-point. Ascrobic acid and its oxidation product, dehydroascorbic acid, being neutral to perchloric acid, do not interfere with the titration.

The effects of chlorpromazine, prochlorperazine, and trifluoperazine on the pressor actions of serotonin, angiotensin, and bradykinin in the perfused vessels of full‐term human placentas were investigated. A significant inhibition of the effect of serotonin was observed with trifluoperazine and chlorpromazine but not with prochlorperazine. This inhibition is attributed to the ability of phenothiazines to cause adrenergic blockade. Because both bradykinin and angiotensin could not be consistently antagonized, it is concluded that they must act primarily via musculotropic mechanisms and only secondarily by stimulation of adrenergic receptors.

Trifluoperazine and pericyazine were formulated using both the hydrochloride and embonate salts, and some comparisons were made with the activity of fluphenazine salt and ester formulations. Simple solutions in polyethylene glycol, gelled aqueous solutions, nonaqueous suspensions, multiple emulsions, and microencapsulated preparations were formulated, and their duration of activity was tested in dogs. While the multiple emulsion system showed some promise, a nylon microcapsule system produced significant prolonged activity of the drug after deep intramuscular injection.

The UV and visible spectra of radical cations of several phenothiazine derivatives were studied using different solvents. The establishment of a relationship between these bands and the R2 and R10 substituents was attempted. The influence of the disolvents on the bands also was studied. The characteristic charge transfer band was observed in the solid state using diffuse reflectance spectroscopy. The R2 substituent did not appear to influence the band, while the R10 substituent influenced the band considerably, probably due to steric effects.

Evaluation of the antibacterial effect of phenothiazine antihistaminics (trimeprazine, promethazine, and fonazine) and phenothiazine tranquilizers (promazine, chlorpromazine, triflupromazine, and propiomazine) on Staphylococcus aureus showed that tranquilizers were more active [minimum inhibitory concentration (MIC) 0.5-1.6 micrograms/mL] than antihistaminics (MIC greater than 1.6 micrograms/mL). The antibacterial activity was found to correlate with both the rate of adsorption of these drugs on the bacterial cells and the surface tension of their solutions. Phenothiazine tranquilizers caused rapid and extensive leakage of potassium ions from bacterial cells, while phenothiazine antihistaminics produced relatively slower leakage of these ions. A study of the effect of the phenothiazines on the antibacterial activity of some antibiotics showed that all phenothiazines produced a synergistic effect with erythromycin and an antagonistic effect with tobramycin. Variable effects were observed with chloramphenicol, and no effect was observed with penicillin. Results were explained on the basis of structural characteristics of the phenothiazines.

The tricyclic amines promazine, promethazine, chlorpromazine, triflupromazine, and trifluperazine form solid ion pairs with ATP in a 1:2 molar ratio. There is a good correlation between the measured Ksp and the apparent diffusion constants of the ion pairs with the critical micelle concentration (CMC) of the corresponding phenothiazines. Solid ion pairs are solubilized by phenothiazine micelles; the binding constants of ATP to drug micelles are calculated from solubility data at 25 degrees C and can be related to the CMC of the phenothiazines.

A sensitive, specific high-performance liquid chromatographic procedure was developed for the determination of plasma ethmozin levels. Basic plasma samples were partitioned with methylene chloride. The organic extract was washed with water and then evaporated to dryness under reduced pressure. The residue was redissolved in 0.2 ml of the mobile phase, consisting of hexane-tetrahydrofuran-methanol-water (66:27:6,30:0.7 v/v), and then chromatographed on a microporous silica column. With a variable-wavelength UV detector set at 268 nm, 10 ng of ethmozin/ml of plasma was measured. The utility of the method for human pharmacokinetic studies was demonstrated.

Four phenothiazine derivatives containing the bis(beta-chloroethyl)aminopropyl side chain were prepared and evaluated in the murine L-1210, P-388, and B-16 melanoma intraperitoneal tumor systems. Moderate P-388 activity was observed. An aminoethyl phenothiazine mustard was compared with the aminopropyl analogs and was superior in all test systems. None of the compounds tested against the murine ependymoblastoma brain tumor system was active.

Contrary to earlier literature reports, the impurities in toluidine blue O were shown by column chromatography, TLC, and mass spectrometry to be N-methyl homologs of 2-methylthionine rather than N-methyl homologs of thionine. Small amounts of 2-methyl-3-amino-7-methylaminophenothiazine and 2-methyl-3,7-diaminophenothiazine were identified in commercial samples of toluidine blue O. However, sample handling and a warm alkaline environment can cause rapid demethylation of the dye.

The distribution of radioactivity at 5‐, 10‐, and 15‐min intervals following the intravenous administration of N ‐ 14 C‐azure C was determined. The concentrations of radioactivity observed indicated that radioactive derivatives of azure C would not be useful pancreas or parathyroid scanning agents.