Promazine Research Articles

Energetics of Drug-Additive Systems at the Cloud Point

The energetics of clouding in amphiphilic drugs, promazine hydrochloride and nortriptyline hydrochloride, in the presence of additives, such as alcohols and surfactants, are reported. The additives which assist in micellar growth like long-chain alcohols and cyclohexanol give negative ΔsH0 and TΔsS0 values, whereas cationic and nonionic surfactants increase the randomness in the system and hence TΔsS0 becomes positive. Anionic surfactants at low concentrations retard micellar growth and hence on increasing the concentration TΔsS0 values change from positive to negative.

Phase Separation Study of a Surface-Active Drug, Promazine Hydrochloride, in Presence of Surfactants and Ureas

Abstract As clouding in drugs causes high concentration of drug at a particular site which may prove harmful to the body, the clouding behaviour of a tricyclic phenothiazine drug promazine hydrochloride (PMZ) in aqueous solutions has been studied in the presence of surfactants and ureas. The cloud point (CP) decreases with increase in pH due to deprotonation of the drug molecules. Addition of non-ionic and cationic (conventional as well as Gemini) surfactants increased the CP whereas anionic surfactants showed a peaked profile. The urea family additives influenced the CP in both ways that depended whether they contain >C=O or >C=S moiety: the former interacts with the micelles and lowers the CP while the latter (due to its electropositive character) may not interact and hence CP increases. Dye solubilization results indicate micellar growth with the addition of surfactants in PMZ solutions. The results are interpreted taking cognizance of mixed micelle formation, hydrophobic interactions, and/or change in solvent structure.

Use of TLC with densitometric detection for determination of impurities in chlorpromazine hydrochloride, trifluoperazine dihydrochloride, promazine hydrochloride, and doxepin hydrochloride

A TLC-densitometric method has been established for determination of impurities in chlorpromazine hydrochloride, trifluoperazine dihydrochloride, promazine hydrochloride, and doxepin hydrochloride. Statistical analysis of the data showed the method is precise and highly sensitive. Results from linear regression analysis of the calibration plots were indicative of good linear relationships over wide ranges of concentration. Application of densitometric UV detection at 254 nm and at the wavelengths of maximum absorbance of the substances resulted in increased detectability of zones in the chromatograms compared with visual inspection under a UV lamp. The conditions described enable objective quantitative evaluation of the limiting concentrations of impurities.

Thermodynamic Studies of Drug−α-Cyclodextrin Interactions in Water at 298.15 K: Promazine Hydrochloride/Chlorpromazine Hydrochloride + α-Cyclodextrin + H2O Systems

Data on osmotic coefficients have been obtained for a binary aqueous solution of two drugs, namely, promazine hydrochloride (PZ) and chlorpromazine hydrochloride (CPZ) using a vapor pressure osmometer at 298.15 K. The observed critical micelle concentration (cmc) agrees excellently with the available literature data. The measurements are extended to aqueous ternary solutions containing fixed a concentration of alpha-cyclodextrin (alpha-CD) of 0.1 mol kg(-1) and varied concentrations (approximately 0.005-0.2 mol kg(-1)) of drugs at 298.15 K. It has been found that the cmc values increase by the addition of alpha-CD. The mean molal activity coefficients of the ions and the activity coefficient of alpha-CD in binary as well as ternary solutions were obtained, which have been further used to calculate the excess Gibbs free energies and transfer Gibbs free energies. The lowering of the activity coefficients of ions and of alpha-CD is attributed to the existence of host-guest (inclusion)-type complex equilibria. It is suggested that CPZ forms 2:1 and 1:1 complexed species with alpha-CD, while PZ forms only 1:1 complexed species. The salting constant (ks) values are determined at 298.15 K for promazine-alpha-CD and chlorpromazine-alpha-CD complexes, respectively, by following the method based on the application of the McMillan-Mayer theory of virial coefficients to transfer free energy data. It is noted that the presence of chlorine in the drug molecule imparts better complexing capacity, the effect of which gets attenuated as a result of hydrophobic interaction. The results are discussed from the point of view of associative equilibria before the cmc and complexed equilibria for binary and ternary solutions, respectively.

Spectrophotometric Assay of Metoclopramide Hydrochloride in pharmaceutical preparations via oxidative coupling Reaction with proma zine Hydrochloride and N-Bromosuccinimide

spectrophotometric Assay of Metoclopramide Hydrochloride in pharmaceutical preparations via oxidative coupling Reaction with proma zine Hydrochloride and N-Bromosuccinimide

Trypanosoma cruzi Dihydrolipoamide Dehydrogenase as Target for Phenothiazine Cationic Radicals. Effect of Antioxidants

Myeloperoxidase (MPO), myoglobin (Mb) and horseradish peroxidase (HRP), catalyzed the generation of radical-cations by one-electron oxidation of phenothiazines (PTZ). The transient formation of these radicals (PTZ+.) was confirmed by ESR and optical spectroscopy. These species are reactive towards Trypanosoma cruzi LADH (T. cruzi LADH), T. cruzi trypanothione reductase (T. cruzi TR) and possibly other macromolecule targets. Both T. cruzi enzymes were irreversibly inactivated. T. cruzi LADH inactivation depended on: a) PTZ structure, peroxidase nature and the rate production of PTZ+. radical cations; b) incubation time; c) the presence of an antioxidant that intercepts free radicals. The production of PTZ+. radical cations, which is essential for T. cruzi LADH inactivation, is correlated with the electron donor ability of the substrates, as qualified by the Hammett sigmapara constant for the subtituent in the 2-position of the PTZ. Promazine (PZ), trimeprazine (TMPZ) and thioridazine (TRDZ) were the most effective inactivating agents, whereas trifluophenothiazines with CF3 group at 2-position (Trifluoperazine (TFP), fluphenazine (FFZ) and trifluopromazine (TFPZ)), and propericyazine (PCYZ) with CN group at 2-position, were much less active or inactive, all in close agreement with their higher or lowest electron donor ability, respectively. Comparison of inactivation values for T. cruzi LADH and mammalian heart LADH demonstrated a greater sensitivity of T. cruzi LADH to various PTZ studied. Thiol compounds, tyrosine, dopa, tryptophan, NADH, ascorbate and trolox prevented T. cruzi LADH inactivation by the peroxidase/H2O2 systems in agreement with their ability to suppress PTZ+. radical cations. The role of these radicals as enzyme inhibitors, or as generators of secondary free radicals and metabolite depletors may contribute to explain the trypanocidal effect as well as other chemotherapeutic actions of PTZ.

Determination of phenothiazines in pharmaceutical formulations and human urine using capillary electrophoresis with chemiluminescence detection

A CE instrument coupled with chemiluminescence (CL) detection was designed for the determination of promethazine hydrochloride (PTH) and promazine hydrochloride (PMH) in real samples. An important enhancement of the CL emission of luminol with potassium ferricyanide was observed in the presence of these phenothiazines; so this system was selected for their detection after CE separation. Parameters affecting the electrophoretic separation were optimized in a univariate way, while those affecting CL detection were optimized by means of a multivariate approach based on the use of experimental designs. Chemometrics was also employed for the study of the robustness of the factors influencing the postcolumn CL detection. The method allows the separation of the phenothiazines in less than 4 min, achieving LODs of 80 ng/mL for PMH and 334 ng/mL for PTH, using sample injection by gravity. Electrokinetic injection was used to obtain lower LODs for the determination of the compounds in biological samples. The applicability of the CE-CL method was illustrated in the determination of PTH in pharmaceutical formulations and in the analysis of PMH in human urine, using a previous SPE procedure, achieving an LOD of 1 ng/mL and recoveries higher than 85%.

Amelioration of the ability to decolorize dyes by laccase: relationship between redox mediators and laccase isoenzymes in Trametes versicolor

The effect of redox mediators in the dye decolorization by two laccase isoenzymes from Trametes versicolor cultures supplemented with barley bran has been investigated. All the redox mediators tested, 1-hydroxybenzotriazole (HBT), promazine (PZ), para-hydroxybenzoic acid (pHBA) and 1-nitroso-2-naphthol-3,6-disulfonic acid (NNDS), led to higher dye decolorization than those obtained without mediator addition. Among the different tested mediators, PZ was the most effective one at a low range of concentration (0.5–50 µM) and the natural mediator employed, pHBA did not improve significantly the degree of decolorization, and was slightly inhibitory.

Electrochemical, Chemical and Enzymatic Oxidations of Phenothiazines

AbstractThe oxidation of several phenothiazine drugs (phenothiazine, promethazine hydrochloride, promazine hydrochloride, trimeprazine hydrochloride and ethopropazine hydrochloride) has been carried out in aqueous acidic media by electrochemical, chemical and enzymatic methods. The chemical oxidation was performed in acetic acid with hydrogen peroxide or in formate buffers using persulfate. The enzymatic oxidation was performed in acetate or ammonium formate buffer by the enzyme horseradish peroxidase in the presence of H2O2. Molecules with, in the lateral chain, two carbon atoms (2C) separating the ring nitrogen and the terminal nitrogen, showed two parallel oxidation pathways, that is (i) formation of the corresponding sulfoxide and (ii) cleavage of the lateral chain with liberation of phenothiazine (PHZ) oxidized products (PHZ sulfoxide and PHZ quinone imine). Molecules with three carbon atoms (3C) separating the two nitrogens were oxidized to the corresponding sulfoxide. The chemical oxidation of all the studied molecules by hydrogen peroxide resulted in the corresponding sulfoxide with no break of the lateral chain. Oxidation by persulfate yielded, for the 3C derivatives, only the corresponding sulfoxide, but it produced cleavage of the lateral chain for the 2C derivatives. The origin of the distinct oxidation pattern between 2C and 3C molecules might be related to steric effects due to the lateral chain. The data are of interest in drug metabolism studies, especially for the early search. In the case of 2C phenothiazines, the results predict the possibility of an in vivo cleavage of the lateral chain with liberation of phenothiazine oxidized products which are known to produce several adverse side effects.

Application notes on the use of softer X-rays for anomalous powder diffraction

An in-vacuum diffractometer has been modified to collect powder diffraction data from a sample of promazine hydrochloride. Strong anomalous contrast has been observed at, or close to, the sulphur edge. Based on the data collected, a bespoke diffractometer has been designed that, together with minor changes to the geometry of the experiment, will enable the routine collection of powder data at absorption edges below 5.5 keV.

Development and validation of a capillary electrophoresis method for the determination of phenothiazines in human urine in the low nanogramper milliliter concentration range using field-amplified sample injection

A capillary zone electrophoresis (CZE) method with ultraviolet-visible detection has been established and validated for the determination of five phenothiazines: thiazinamium methylsulfate, promazine hydrochloride, chlorpromazine hydrochloride, thioridazine hydrochloride, and promethazine hydrochloride in human urine. Optimum separation was obtained on a 64.5 cm x 75 microm bubble cell capillary using a buffer containing 150 mM tris(hydroxymethyl)aminomethane and 25% acetonitrile at pH 8.2, with temperature and voltage of 25 degrees C and 20 kV, respectively. Naphazoline hydrochloride was used as an internal standard. Field-amplified sample injection (FASI) has been applied to improve the sensitivity of the detection. Considering the influence of parameters affecting the on-line preconcentration (nature of preinjection plug, sample solvent composition, injection times, and injection voltage) and due to the significant interactions among them, in this paper we propose for the first time the application of a multivariate approach to carry out the study. The optimized conditions were as follows: preinjection plug of water for 7 s at 50 mbar, electrokinetic injection for 40 s at 6.2 kV, and 32 microm of H3PO4 in the sample solvent. Also, a solid-phase extraction (SPE) procedure is developed to obtain low detection limits and an adequate selectivity for urine samples. The combination of SPE and FASI-CZE-UV allows adequate linearities and recoveries, low detection limits (from 2 to 5 ng/mL), and satisfactory precisions (3.0-7.2% for an intermediate RSD %).

Substitution and Solvent Effects on the Photophysical Properties of Several Series of 10-Alkylated Phenothiazine Derivatives

The photophysical properties of several 2-substituted, 10-alkylated phenothiazines were measured in several solvents to investigate the relevance of the molecular structure in their photophysics and consequent photochemistry. Because the interaction modes of each drug and its corresponding species strongly depend on the variety of microenvironments in the cells, the properties of each one of these species must also be determined separately to understand fully the mechanism of action of the drug and the mechanism of its side effects. Information on the chemical interactions of the different species at the cellular level can be inferred from the corresponding electronic properties. In this work, we present absorption, steady-state, and time-resolved emission, laser flash photolysis, and quantum theoretical results for the ground state, the first excited singlet and triplet states, and the cation radical of promazine hydrochloride (PZ), 2-chlorpromazine hydrochloride (CPZ), 2-trifluoromethylpromazine hydrochloride (TFMPZ), 2-trifluoromethylperazine dihydrochloride (TFMP), 2-thiomethylpromazine (TMPZ), and thioridazine hydrochloride (TR). The corresponding nonalkylated phenothiazines are included as references. The photophysical properties of this drug family depend more on the solvent and the 2-substituents than on the dialkylaminopropyl chain. The largest effect was found for the triplet state of the 2-halogenated derivatives in phosphate buffer (PBS). Both the quantum yield and the lifetime of this intermediate drop to less than 5% of the corresponding value in organic solvents. The triplet state of halogenated promazines is efficiently quenched by a proton-transfer mechanism, and the rate of this quenching correlates very well with the phototoxicity of the promazine drugs. Therefore, we postulate that this species is directly related to the phototoxic side effect of neuroleptic drugs.

Determination of thiazinamium, promazine and promethazine in pharmaceutical formulations using a CZE method

We present the validation of a developed method using capillary zone electrophoresis (CZE) for quantitative analysis of three phenothiazines: thiazinamium methylsulphate (TMS), promazine hydrochloride (PMH) and promethazine hydrochloride (PTH) in pharmaceutical formulations. The influence of various parameters affecting the CZE separation (buffer pH and concentration, acetonitrile percentage, capillary temperature and applied voltage) was investigated by means of multivariate optimization using experimental designs so as to obtain the highest efficiency. The method allows the separation of the phenothiazines in 5.0 min at optimized conditions: 100 mM tris(hydroxymethyl)-aminomethane (Tris) buffer at a pH 8.0, 15% acetonitrile, capillary with 58.5 cm in length at 25 °C and a voltage of 30 kV. Detection occurred at 254 nm. Acceptable precision (relative standard deviation (R.S.D.) 5.3%) and linearity were achieved using the internal standard (IS) method. The limits of detection (LODs) were 2.8 μg ml −1 for TMS and 3.3 μg ml −1 for PMH and PTH. The method has been successfully applied in the analysis of pharmaceutical formulations.

Phenothiazine Drugs as Redox Mediators in Horseradish Peroxidase Bioelectrocatalysis

The homogeneous bioelectrocatalytic response between the enzyme Horseradish Peroxidase (HRP) and two structurally related phenothiazine drugs, promazine (PMZ), and promethazine (PMTZ), has been studied in acetate buffer pH 4.5, in the presence of hydrogen peroxide. Experiments were realized by cyclic voltammetry (CV) and chronoamperometry (CA) at a solid paraffin based carbon paste electrode. Distinct CV and CA patterns were observed for those structurally related isomers. The molecule PMZ behaved classically, as most phenothiazine drugs, with formation of the corresponding sulfoxide via an intermediate, relatively stable and electrochemically reversible, PMZ cation radical. Catalytic currents were obtained during the electroreduction of the latter due to the presence of the HRP/H2O2 system in solution which regenerated the cation radical. PMTZ electro- and enzymatic oxidation gave no corresponding stable cation radical but the molecule suffered a lateral chain breakdown with liberation of the phenothiazine nucleus (PHZ). The latter behaved reversibly at the electrode and catalytic currents were observed during the phenothiazine cation radical electroreduction. The overall rate constant between the phenothiazine drugs and HRP/H2O2 was determined by CA giving 3.8 × 105 and 2.9 × 105 M−1s−1 for PMZ and PMTZ(PHZ), respectively.

APPLICATION OF THE REACTION OF PROMAZINE HYDROCHLORIDE WITH CHROMIUM(VI) IN VOLUMETRIC AND SPECTROPHOTOMETRIC ANALYSIS

ABSTRACT Promazine hydrochloride (PMH) reacts in acidic medium with K2Cr2O7 forming coloured oxidation product. This property is exploited for using PMH as redox indicator in chromatometry. The spectra of oxidation products of PMH in UV and IR regions were recorded. The optimal conditions for the formation of these products and their electrochemical behaviour are described. K2Cr2O7 precipitates PMH from aqueous solutions as ion-association compound. The compound is sparingly soluble in water but can be quantitatively extracted into ethyl acetate. The extraction constant of this compound is determined and the extractive spectrophotometric method for the determination of PMH in pharmaceuticals is elaborated.

Construction and Evaluation of a Promazinium Cation-Selective Electrode

The construction of a plasticised PVC matrix-type promazinium cation-selective membrane electrode and its use in the potentiometric determination of promazine hydrochloride in pharmaceutical preparations are described. It is based on the use of the ion-associate species, formed by promazinium cation and tetraphenylborate (TPB) counter ion. The basic electrode performance characteristics are evaluated according to IUPAC recommendations. It exhibited a linear response for 1 × 10−2−1 × 10−5 M of promazine hydrochloride solutions with a cationic Nernstian slope over the pH range 2–6. Common organic and inorganic cations showed negligible interference. Direct potentiometric determination of 1 × 10−2−1 × 10−5 M aqueous promazine hydrochloride using this membrane electrode system showed an average recovery of 99.5% with a mean standard deviation of 1.5%. This electrode was successfully used for monitoring the titration of promazine hydrochloride with sodium tetraphenyl borate and for determining promazine hydrochloride in ampoules.

Simultaneous quantification of promazine hydrochloride and its sulfoxide in pharmaceutical preparations.

The use of derivative UV-spectrophotometry is proposed for the simultaneous quantification of promazine hydrochloride in the presence of sulfoxide, and vice versa. For this purpose, mathematical parameters were established for generating derivative spectra of analytes. The determination of promazine was made using the first-order derivative (deltalambda = 10 nm, second polynomial degree) at 268 nm. The quantification of sulfoxide was achieved by applying third-derivative spectra (deltalambda = 14 nm, sixth polynomial degree) based on measurements of the amplitude at 342 - 344 nm. An elaborated method was successfully used to determine analytes in commercial promazine pharmaceuticals. The obtained results agreed well with those obtained by the HPLC method.

Differential-Pulse Polarographic Determination of Some N-Substituted Phenothiazine Derivatives in Dosage Forms and Urine Through Treatment with Nitrous Acid

A highly sensitive differential-pulse (DPP) polarographic method is described for the determination of three N-substituted phenothiazine derivatives, chlorpromazine (CZ), promazine (PZ) and promethazine (PMZ). The method involves the use of nitrous acid as an oxidant. Polarographically-active sulphoxides with diffusion-current constants (Id) of 2.53, 3.05 and 3.37 were obtained for CZ, PZ and PMZ, respectively. The polarographic waves were characterized as being diffusion-controlled, irreversible and partly affected by adsorption phenomena. All parameters affecting the oxidation process and polarographic behaviour were optimized and incorporated into the procedure. The limiting current-concentration plots in the DPP mode were rectilinear over the range: 0.006–0.1 mM, 0.005–0.08 mM and 0.008–0.1 mM for CZ, PZ and PMZ, respectively, with minimum detectability (S/N=3) of 3 × 10−7 M for CZ and PZ, and 4 × 10−7 M for PMZ, respectively. The kinetic parameters of the electrode reaction, including rate constant, free energy of activation ΔG and effect of temperature on both parameters were studied. The proposed method was successfully applied to the determination of phenothiazines in dosage forms; the results obtained were in agreement with those given with the official methods. The method was further applied to the determination of promazine in spiked human urine. The percentage recovery was 96.86 ± 0.30. The advantages of the proposed method over other reported methods were discussed. A proposal of the electrode reaction was made.

Effects of caffeine and promazine hydrochloride on plasma catecholamines in thoroughbreds at rest and during treadmill exercise.

Our aim was to investigate plasma catecholamine responses to so-called 'doping' drugs and exercise in Thoroughbreds. Plasma adrenaline (Ad) and noradrenaline (NA) were determined after the administration of caffeine and promazine hydrochloride (PRZ) using a high performance liquid chromatographic method. Caffeine or PRZ was administered i.m. to Thoroughbreds and its effects on plasma catecholamines at rest and during exercise were compared with the saline control. The treadmill exercise was performed 1 h after administration. A dose of 5.0 mg/kg bwt caffeine was found to significantly increase both plasma Ad and NA levels but this was not the case for the 2.5 mg/kg bwt dose and their peak levels at 1.5 h were about 3 and 2.5 times as compared with the control values at 1.5 h (Ad: mean +/- s.e. 21.2 +/- 2.8 pg/ml, NA: 55.5 +/- 4.1 pg/ml), respectively. Both 1.0 and 1.5 mg/kg bwt PRZ doses reduced the plasma Ad to below the detection limit (10 pg/ml) and significantly reduced the plasma NA. The 2.5 mg/kg bwt caffeine dose significantly increased plasma Ad and NA during exercise and approximately doubled their maximal values as compared with the saline control (Ad: mean +/- s.e. 12.328 +/- 4.733 ng/ml, NA: 9.997 +/- 4.146 ng/ml). The 1.5 mg/kg bwt PRZ dose decreased the plasma Ad during exercise but the effect was not significant. On the other hand, PRZ significantly increased the plasma NA as compared with the saline control. In conclusion, the present study demonstrates that the plasma catecholamine responses to caffeine and PRZ were modified by exercise. It is probable that the modification may be related to exercise-induced activation of the sympathetico-adrenal axis.

Routine determination of molecular crystal structures from powder diffraction data

The state of the art in determining molecular crystal structures from powder diffraction data using a global optimisation method is illustrated with a fast, automated simulated annealing approach to solving the previously unknown crystal structures of capsaicin, thiothixene and promazine hydrochloride.