Design of resonance Rayleigh scattering and spectrofluorimetric methods for the determination of the antihistaminic drug, hydroxyzine, based on its interaction with 2,4,5,7-tetraiodofluorescein: Evaluation of analytical eco-scale and greenness/whiteness algorithms.

In this work, two validated approaches were used for estimating hydroxyzine HCl for the first time using resonance Rayleigh scattering (RRS) and spectrofluorimetric techniques. The suggested approaches relied on forming an association complex between hydroxyzine HCl and 2,4,5,7-tetraiodofluorescein (erythrosin B) reagent in an acidic media. The quenching in the fluorescence intensity of 2,4,5,7-tetraiodofluorescein by hydroxyzine at 551.5 nm (excitation = 527.5 nm) was used for determining the studied drug by the spectrofluorimetric technique. The RRS approach is based on amplifying the RRS spectrum at 348 nm upon the interaction of hydroxyzine HCl with 2,4,5,7-tetraiodofluorescein. The spectrofluorimetric methodology and the RRS methodology produced linear results within ranges of 0.15-1.5 µg ml-1 and 0.1-1.2 µg ml-1, respectively. LOD values for these methods were determined to be 0.047 µg ml-1 and 0.033 µg ml-1, respectively. The content of hydroxyzine HCl in its pharmaceutical tablet was estimated using the developed procedures with acceptable recoveries. Additionally, the application of four greenness and whiteness algorithms shows that they are superior to the previously reported method in terms of sustainability, economics, analytical performance, and practicality.

Efficient synthesis of deuterium labeled hydroxyzine and aripiprazole.

Hydroxyzine and aripiprazole are active pharmaceutical ingredients that have been largely acknowledged for their antipsychotic properties. Deuterium labeled isotopes of hydroxyzine and aripiprazole are internal standards that can aid in the further research of non-isotopic forms via quantification analysis using HPLC-MS/MS. The synthesis of hydroxyzine-d8 was accomplished by coupling piperazine-d8 with 4-chlorobenzhydryl chloride followed by the reaction of the first intermediate with 2-(2-chloroethoxy) ethanol to afford 11.7% of hydroxyzine-d8 with 99.5% purity. The synthesis of aripiprazole-d8 was also achieved in two steps. 1,4-Dibromobutane-d8 reacted with 7-hydroxy-3,4-dihydro-2(1H)-quinolinone. The first intermediate was then coupled with 1-(2, 3-dichlorophenyl)piperazine hydrochloride to produce 33.4% of aripiprazole-d8 with 99.93% purity.

Harnessing spectrophotometry resolution power for determining ternary mixture for respiratory disorders treatment in their pharmaceutical formulation.

A ternary mixture incorporating Hydroxyzine hydrochloride (HYX), Ephedrine hydrochloride (EPH) and Theophylline (THP) frequently prescribed for the treatment of respiratory diseases. Herein, two spectrophotometric methods are designated and applied to resolve these three components in their mixture. Method A is ratio-subtraction combined with derivative spectrophotometry, where THP can be determined directly at its λmax 271 nm (neither HYX or EPH interfere), then for determination of HYX and EPH, the ternary mixture was divided by 22 µg/mL of THP and after subtraction of the plateau region, HYX can be determined directly at its λmax 234.2 nm (absence of EPH intervention). Finally, the third derivative (3D) spectrophotometric approach was utilized to estimate EPH by detecting the peak amplitude at 222 nm with Δλ = 4 and a scaling factor 100. Principal Component Regression (PCR) and Partial Least Squares (PLS), two multivariate calibration approaches, were applied effectively in Method B. This method effectively quantified the mixture under investigation by using the absorption spectra obtained from suitable solutions of the three components in the 210-230 nm region. The calibration models were evaluated using cross-validation with PCR and PLS, producing statistical characteristics that demonstrate the effectiveness of the calibration models. Synthetic and pharmaceutical preparations were also used to conduct external validation. In pharmaceutical formulation, these methods were successfully applied to analyze HYX, EPH, and THP without overlap from formulation's excipients. Moreover, the study's findings were statistically contrasted with those of earlier reported HPLC method. Appraisal approaches were used to determine whether the new spectrophotometric methods had an adverse environmental impact involving the Green Analytical Procedure Index (GAPI) and the AGREE (Analytical Greenness). These evaluations delivered information about the methods' eco-friendliness and sustainability, proving that they are in line with ecologically attributed practices. Furthermore, the Blue Applicability Grade Index (BAGI) was utilized to identify and verify the feasibility and practicality of the suggested approaches.

Dextrin-assisted gel electromembrane extraction of chiral drugs: Improving the extraction efficiency and investigation of enantioselectivity of extraction.

The present study investigates the use of dextrins (maltodextrin, ß-cyclodextrin, and hydroxypropyl-ß-cyclodextrin) to improve the efficiency of the agarose-based gel electromembrane extraction technique for extracting chiral basic drugs (citalopram, hydroxyzine, and cetirizine). Additionally, it examines the enantioselectivity of the extraction process for these drugs. To achieve these, dextrins were incorporated into either the sample solution, the membrane, or the acceptor solution, and then the extraction procedure was performed. Enantiomers were separated and analyzed using a capillary electrophoresis device equipped with a UV detector. The results obtained under the optimal extraction conditions (sample solution pH: 4.0, acceptor solution pH: 2.0, gel membrane pH: 3.0, agarose concentration: 3 % w/v, stirring rate: 1000 rpm, gel thickness: 4.4 mm, extraction voltage: 62.3 V, and extraction time: 32.1 min) indicated that incorporating dextrins into either the sample solution, membrane or the acceptor solution enhances extraction efficiency by 17.3-23.1 %. The most significant increase was observed when hydroxypropyl-ß-cyclodextrin was added to the acceptor solution. The findings indicated that the inclusion of hydroxypropyl-ß-cyclodextrin in the sample solution resulted in an enantioselective extraction, yielding an enantiomeric excess of 6.42-7.14 %. The proposed method showed a linear range of 5.0-2000 ng/mL for enantiomers of model drugs. The limit of detection and limit of quantification for all enantiomers were found to be < 4.5 ng/mL and <15.0 ng/mL, respectively. Intra- and inter-day RSDs (n = 4) were less than 10.8 %, and the relative errors were less than 3.2 % for all the enantiomers. Finally, the developed method was successfully applied to determine concentrations of enantiomers in a urine sample with relative recoveries of 96.8-99.2 %, indicating good reliability of the developed method.

Two-step liquid phase microextraction combined with capillary electrophoresis: a new approach to simultaneous determination of basic and zwitterionic compounds.

In this work, two-step hollow fiber-based liquid-phase microextraction procedure was evaluated for extraction of the zwitterionic cetirizine (CTZ) and basic hydroxyzine (HZ) in human plasma. In the first step of extraction, the pH of sample was adjusted at 5.0 in order to promote liquid-phase microextraction of the zwitterionic CTZ. In the second step, the pH of sample was increased up to 11.0 for extraction of basic HZ. In this procedure, the extraction times for the first and the second steps were 30 and 20 min, respectively. Owing to the high ratio between the volumes of donor phase and acceptor phase, CTZ and HZ were enriched by factors of 280 and 355, respectively. The linearity of the analytical method was investigated for both compounds in the range of 10-500 ng mL(-1) (R(2) > 0.999). Limit of quantification (S/N = 10) for CTZ and HZ was 10 ng mL(-1) , while the limit of detection was 3 ng mL(-1) for both compounds at a signal to noise ratio of 3:1. Intraday and interday relative standard deviations (RSDs, n = 6) were in the range of 6.5-16.2%. This procedure enabled CTZ and HZ to be analyzed simultaneously by capillary electrophoresis.

Chiral separation and quantitation of cetirizine and hydroxyzine by maltodextrin-mediated CE in human plasma: effect of zwitterionic property of cetirizine on enantioseparation.

In the present study, a very simple CE method for chiral separation and quantitation of zwitterionic cetirizine (CTZ), as the main metabolite of hydroxyzine (HZ), and HZ has been developed. In addition, the effect of zwitterionic property of CTZ on enantioseparation was investigated. Maltodextrin, a linear polysaccharide, as a chiral selector was used and several parameters affecting the separation such as pH of BGE, concentration of chiral selector and applied voltage were studied. The best BGE conditions for CTZ and HZ enantiomers were optimized as 75 mM sodium phosphate solution at pH of 2.0, containing 5% w/v maltodextrin. Results showed that, compared to HZ, pH of BGE was an effective parameter in enantioseparation of CTZ due to the zwitterionic property of CTZ. The linear range of the method was over 30-1200 ng/mL for all enantiomers of CTZ and HZ. The quantification and detection limits (S/N=3) of all enantiomers were 30 and 10 ng/mL, respectively. The method was used to quantitative enantioseparation of CTZ and HZ in spiked human plasma.

In vitro and in vivo evaluation of hydroxyzine hydrochloride microsponges for topical delivery.

Hydroxyzine HCl is used in oral formulations for the treatment of urticaria and atopic dermatitis. Dizziness, blurred vision, and anticholinergic responses, represent the most common side effects. It has been shown that controlled release of the drug from a delivery system to the skin could reduce the side effects while reducing percutaneous absorption. Therefore, the aim of the present study was to produce an effective drug-loaded dosage form that is able to control the release of hydroxyzine hydrochloride into the skin. The Microsponge Delivery System is a unique technology for the controlled release of topical agents, and it consists of porous polymeric microspheres, typically 10-50 µm in diameter, loaded with active agents. Eudragit RS-100 microsponges of the drug were prepared by the oil in an oil emulsion solvent diffusion method using acetone as dispersing solvent and liquid paraffin as the continuous medium. Magnesium stearate was added to the dispersed phase to prevent flocculation of Eudragit RS-100 microsponges. Pore inducers such as sucrose and pregelatinized starch were used to enhance the rate of drug release. Microsponges of nearly 98% encapsulation efficiency and 60-70% porosity were produced. The pharmacodynamic effect of the chosen preparation was tested on the shaved back of histamine-sensitized rabbits. Histopathological studies were driven for the detection of the healing of inflamed tissues.

Formulation and assessment of hydroxyzine HCL solid lipid nanoparticles by dual emulsification technique for transdermal delivery.

Hydroxyzine HCL (HHCL) is an antihistamine, used for the treatment of allergic skin conditions. The purpose of this study was to achieve a dual phase drug delivery rate across the intact skin, to enhance HHCL permeation through the stratum corneum, to assess the peripheral H1-antihistaminic activity and the extent to which HHCL was systemically absorbed from transdermal gel loaded with solid lipid nanoparticles (SLNs), as well as to avoid its extreme bitterness. According to 23 factorial design, eight formulations of HHCL-SLNs were prepared by the double emulsification method. Lipid type (XA), surfactant concentration (XB) and co-surfactant concentration (XC) were the independent variables. All formulations were characterized for their surface morphology, particle size, entrapment efficiency and in-vitro drug release study. The optimized formula that provides greater desirability was then incorporated into the transdermal gel. In addition, the efficacy of the developed gel was tested in-vivo using 2,4-Dinitrochlorobenzene induced atopic dermatitis as lesion model in mice. F4 showed an average diameter 111 nm ± 0.03, zeta potential - 30 MV ± 2.4 and EE 75.2% ± 4.4. TEM images showed spherical, smooth morphology with uniform particles distribution. In-vivo study demonstrated potent antipruritic efficacy of transdermal gel in atopic dermatitis such as induced lesions compared to HHCL gel. Hence, HHCL solid lipid nanoparticles transdermal gel may be considered as potential for delivery of HHCL and alternatively to traditional oral use.

The Role of Alcohol Dehydrogenase in Drug Metabolism: Beyond Ethanol Oxidation.

Alcohol dehydrogenases (ADHs) are most known for their roles in oxidation and elimination of ethanol. Although less known, ADHs also play a critical role in the metabolism of a number of drugs and metabolites that contain alcohol functional groups, such as abacavir (HIV/AIDS), hydroxyzine (antihistamine), and ethambutol (antituberculosis). ADHs consist of 7 gene family numbers and several genetic polymorphic forms. ADHs are cytosolic enzymes that are most abundantly found in the liver, although also present in other tissues including gastrointestinal tract and adipose. Marked species differences exist for ADHs including genes, proteins, enzymatic activity, and tissue distribution. The active site of ADHs is relatively small and cylindrical in shape. This results in somewhat narrow substrate specificity. Secondary alcohols are generally poor substrates for ADHs. In vitro-in vivo correlations for ADHs have not been established, partly due to insufficient clinical data. Fomepizole (4-methylpyrazole) is a nonspecific ADH inhibitor currently being used as an antidote for the treatment of methanol and ethylene glycol poisoning. Fomepizole also has the potential to treat intoxication of other substances of abuse by inhibiting ADHs to prevent formation of toxic metabolites. ADHs are inducible through farnesoid X receptor (FXR) and other transcription factors. Drug-drug interactions have been observed in the clinic for ADHs between ethanol and therapeutic drugs, and between fomepizole and ADH substrates. Future research in this area will provide additional insights about this class of complex, yet fascinating enzymes.

Analytical performance evaluation of ADVIA Chemistry Carbamazepine_2 assay: minimal cross-reactivity with carbamazepine 10, 11-epoxide and none with hydroxyzine or cetirizine.

Carbamazepine is an anticonvulsant requiring routine therapeutic drug monitoring. Recently, Siemens Healthcare Diagnostic Division released a new carbamazepine assay: ADVIA Chemistry Carbamazepine_2 (Carbamazepine_2) for application on ADVIA analyzers. We evaluated the analytical performance of this assay as well as its potential cross-reactivities with carbamazepine 10, 11-epoxide, hydroxyzine, and cetirizine. The within-run and between-run precisions of the Carbamzepine-2 assay were <6% and limit of detection was 0.5 microg/ml using ADVIA 1800 analyzer. The assay was linear up to a carbamazepine concentration of 20.0 microg/ml. The new method compared well with a widely used carbamazepine EMIT 2000 assay on the Hitachi 917 analyzer. Using 75 patients' specimens (where carbamazepine concentrations varied from 0.5 to 21.7 microg/ml) and carbamazepine EMIT 2000 as the reference method (x-axis), we observed the following regression equation: y=1.04 x+0.32 (r=0.99). The new carbazepine_2 method was not affected by a hemoglobin concentration of 1,000 mg/dl, conjugated or unconjugated bilirubin concentration of 60 mg/dl, and triglyceride concentration of 1,000 mg/dl. In addition, this assay showed no cross-reactivity with hydroxyzine or cetirizine and demonstrated minimal cross-reactivity with carbamazepine 10, 11-epoxide. We conclude that the ADVIA Chemistry carbamazepine_2 assay has adequate precision and accuracy for routine therapeutic drug monitoring of carbamazepine in clinical laboratories.

Physicochemical, pharmacological and pharmacokinetic properties of the zwitterionic antihistamines cetirizine and levocetirizine.

Cetirizine, marketed as a racemic mixture containing both levocetirizine and dextrocetirizine, is a member of the second generation H(1) antihistamines clinically used for the treatment of symptoms associated with seasonal allergic rhinitis. Recently, its single R-enantiomer levocetirizine has been approved by the FDA as the newest antihistamine. Cetirizine is a piperazine derivative related to the first generation H(1) antagonist hydroxyzine, and is the major metabolite in the blood circulation after hydroxyzine administration in humans. The acid functionality of cetirizine in combination with one of the basic nitrogens of piperazine ring makes this compound a very unique zwitterion. The molecular structure of cetirizine allows its carboxylic group to interact with the basic nitrogen via folded conformers, therefore, it possesses relatively high lipophilicity at physiological pH (LogD=1.5). While both cetirizine and hydroxyzine possess high affinity at the H(1) receptor, the R-configured levocetirizine has much slower dissociation rate from the H(1) receptor than R-hydroxyzine, making it an insurmountable antagonist. In addition, the pharmacokinetics of cetirizine significantly differs from those of the basic and lipophilic hydroxyzine. For example, cetirizine has much lower CNS penetration than hydroxyzine, which may be explained by the zwitterionic structure of cetirizine and its P-glycoprotein activity. Cetirizine exhibits high intestinal absorption in humans and its oral bioavailability is estimated to be greater than 70%. Very importantly, cetirizine, especially levocetirizine, has a negligible interaction with the liver enzymes, and is mainly excreted in the urine as the parent despite its high plasma protein binding (88 approximately 96%). The recommended dose of levocetirizine is 5 mg once daily, while its pharmacokinetic half-life is about 7 h in humans. This review will focus on the physicochemical, pharmacological and pharmacokinetic properties of cetirizine and levocetirizine in comparison with those of hydroxyzine. The zwitterionic cetirizine displays distinct advantages over the basic hydroxyzine in several categories such as slow receptor dissociation rate, high selectivity, negligible liver enzyme interaction and low CNS penetration. Therefore, cetirizine, or its single isomer levocetirizine, might serve a good example for medicinal chemists to design zwitterionic drugs from a basic, acidic or neutral lead molecule for peripheral biological targets.

Identification of compounds that suppress Toxoplasma gondii tachyzoites and bradyzoites.

Drug treatment for toxoplasmosis is problematic, because current drugs cannot eradicate latent infection with Toxoplasma gondii and can cause bone marrow toxicity. Because latent infection remains after treatment, relapse of infection is a problem in both infections in immunocompromised patients and in congenitally infected patients. To identify lead compounds for novel drugs against Toxoplasma gondii, we screened a chemical compound library for anti-Toxoplasma activity, host cell cytotoxicity, and effect on bradyzoites. Of 878 compounds screened, 83 demonstrated >90% parasite growth inhibition. After excluding compounds that affected host cell viability, we further characterized two compounds, tanshinone IIA and hydroxyzine, which had IC50 values for parasite growth of 2.5 µM and 1.0 µM, respectively, and had no effect on host cell viability at 25 µM. Both tanshinone IIA and hydroxyzine inhibited parasite replication after invasion and both reduced the number of in vitro-induced bradyzoites, whereas, pyrimethamine, the current therapy, had no effect on bradyzoites. Both tanshinone IIA and hydroxyzine are potent lead compounds for further medicinal chemistry. The method presented for evaluating compounds for bradyzoite efficacy represents a new approach to the development of anti-Toxoplasma drugs to eliminate latency and treat acute infection.

Hydroxyzine, promethazine and thioridazine interaction with phospholipid monomolecular layers at the air-water interface.

In this work the interaction of Hydroxyzine, Promethazine and Thioridazine with Langmuir films of dipalmitoylphosphatidylcholine (dpPC) and dipalmitoylphosphatidic acid (dpPA), is studied. Temporal variations in lateral surface pressure (pi) were measured at different initial pi (pi(i)), subphase pH and drug-concentration. Drugs with the smallest (PRO) and largest (HYD) molecular size exhibited the lowest adsorption (k(a)) and the highest desorption (k(d)) rate constant values, respectively. The affinity binding constants (K(b)) obtained in monolayers followed the same profile (K(b,PRO) < K(b,HYD) < K(b,THI)) of the egg-PC/water partition coefficients (P) determined in bilayers. The drug concentration required to reach the half-maximal Deltapi at pi(i) = 14 mN/m (K(0.5)), was very sensitive to pH. The maximal increment in pi upon drug incorporation into the monolayer (deltapi(max)) will depend on the phospholipid collapse pressure (pi(c)), the monolayers's compressibility and drug's size, shape and charge. The higher pi(c) of dpPC lead to higher pi(cut-off) values (maximal pi allowing drug penetration), if compared with dpPA. In dpPC and dpPA pi(cut-off) decreased as a function of the molecular size of the uncharged drugs. In dpPA, protonated drugs became electrostatically trapped at the monolayer surface hence drug penetration, monolayer deformation and pi increase were impaired and the correlation between pi(cut-off) and drug molecular size was lost.

Enantioselective UFLC Determination of Hydroxyzine Enantiomers and Application to a Pharmacokinetic Study in Rabbits.

Hydroxyzine is the first generation H1 receptor antagonist drug that is now marketed as a racemic mixture. The paper describes a validated enantioselective liquid chromatography method for the resolution of hydroxyzine enantiomers and cyclizine (internal standard) from 200 µL of rabbit plasma by liquid-liquid extraction technique using n-hexane and isopropanol. Hydroxyzine enantiomers were resolved at 10.2 and 11.1 min with good baseline resolution (Rs = 1.9) on a Lux amylose-2 chiral column (250 mm × 4.0 mm, 5 microns) at ambient room temperature. The mobile phase consisted of n-hexane-ethanol-diethylamine (90:10:0.1 v/v/v) pumped at 0.9 mL/min. The eluted enantiomers were detected at 254 nm. The linear calibration curve was constructed in the range 20-1000 ng/mL for both the (S)- and (R)-enantiomers. The intra- and inter-day precision were 0.16-2.6% and 0.2-1.92% for (S)-hydroxyzine and (R)-hydroxyzine, respectively. The method was successfully applied to determine the kinetic parameters of (S)- and (R)-hydroxyzine enantiomers in rabbits. The results illustrate that the disposition of hydroxyzine enantiomers is not stereoselective in rabbits.

Transport of hydroxyzine and triprolidine across bovine olfactory mucosa: role of passive diffusion in the direct nose-to-brain uptake of small molecules.

Hydroxyzine and triprolidine have both been reported to reach the CNS following nasal administration. The objective of this study was to investigate their in vitro permeation across bovine olfactory mucosa in order to further characterize the biological and physicochemical parameters that influence direct nose-to-brain transport. In vitro experiments were conducted using Sweetana-Grass (Navicyte) vertical diffusion cells to evaluate the effect of directionality, donor concentration and pH on the permeation of hydroxyzine and triprolidine across excised bovine olfactory mucosa. These studies demonstrated that the Jm-s (mucosal-submucosal flux) and Js-m (submucosal-mucosal flux) of hydroxyzine and triprolidine across the olfactory mucosa were linearly dependent upon the donor concentration without any evidence of saturable transport. Hydroxyzine inhibited the efflux of P-gp substrates like etoposide and chlorpheniramine across the olfactory mucosa. Both hydroxyzine and triprolidine reduced the net flux (Js-m-Jm-s) of etoposide with IC50 values of 39.2 and 130.6 microM, respectively. The lipophilicty of these compounds, coupled with their ability to inhibit P-gp, enable them to freely permeate across the olfactory mucosa. Despite the presence of a number of protective barriers such as efflux transporters and metabolizing enzymes in the olfactory system, lipophilic compounds such as hydroxyzine and triprolidine can access the CNS primarily by passive diffusion when administered via the nasal cavity.

Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic H1-receptor antagonist.

The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = log PZ = 1.5), whereas its H-bonding capacity is relatively large (delta log PZ > or = 3.1). Conformational, electronic, and lipophilicity potential calculations revealed that zwitterionic cetirizine experiences partial intramolecular charge neutralization in folded conformers of lower polarity. Pharmacokinetic investigations have shown the drug to be highly bound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine does not differ from "second-generation" antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg-1, smaller than that of exchangeable water) implies a low affinity for lean tissues such as the myocardium and is compatible with the absence of cardiotoxicity of the drug. The zwitterionic nature and modest lipophilicity of cetirizine may account for this pharmacokinetic behavior. The suggestion is offered that cetirizine and analogous zwitterions, whose physicochemical, pharmacokinetic, and pharmacodynamic properties differ from those of "first-" and "second-generation" drugs in this class, could be considered as "third-generation" antihistamines.

Interaction of substituted phenoxazine chemosensitizers with bovine serum albumin.

The binding of 10-[3'-[N-bis(hydroxyethyl)amino]propyl]phenoxazine [BPP], 10-[3'-[N-bis(hydroxyethyl)amino]propyl]-2-chlorophenoxazine [BPCP], 10-[3'-[N-bis-(hydroxyethyl)amino]propyl]-2-trifluoromethylphenoxazin e [BPFP], 10-(3'-N-pyrrolidino propyl)-2-chlorophenoxazine [PPCP] or 10-(3'-N-pyrrolidinopropyl)-2-trifluoromethylphenoxazine [PPFP] to bovine serum albumin (BSA) has been measured by gel filtration and equilibrium dialysis methods. The binding of these modulators to bovine serum albumin based on dialysis experiments has been characterized by the following parameters: percentage (beta) of bound drug, the association constant 'K1', the apparent binding constant 'k' and the free energy deltaFdegrees. The binding of phenoxazine derivatives to bovine serum albumin is correlated with their octanol-water partition coefficient, log10P. In addition, the displacing activity of hydroxyzine and acetylsalicylic acid on the binding of phenoxazines to albumin has been studied. The results of the displacing experiments showed that the phenoxazine benzene rings and the tertiary amines attached to the side chain of the phenoxazine moiety are bound to a hydrophobic area on the albumin molecule.

Computational prediction and experimental selectivity coefficients for hydroxyzine and cetirizine molecularly imprinted polymer based potentiometric sensors.

In spite of the increasing usages number of molecularly imprinted polymers (MIPs) in many scientific applications, the theoretical aspects of participating intra molecular forces are not fully understood. This work investigates effects of the electrostatic force, the Mulliken charge and the role of cavity's backbone atoms on the selectivity of MIPs. Moreover, charge distribution, which is a computational parameter, was proposed for the prediction of the selectivity coefficients of MIP-based sensors. In the computational approaches and experimental study, methacrylic acid (MAA) was chosen as the functional monomer and ethylene glycol dimethacrylate (EGDMA) as the cross linker for hydroxyzine and cetirizine imprinted polymers. Ab initio, DFT B3LYP method was carried out on molecular optimization. With regard to results obtained from molecules optimization and hydrogen bonding properties, possible configurations of 1:n (n≤5) template/monomer complexes were designed and optimized. The binding energy for each complex in gas phase was calculated. Depending on the most stable configuration, hydroxyzine and cetirizine imprinted polymer models were designed. The calculations including the porogen were also investigated. The theoretical charge distributions for the template and some potential interfering molecules were calculated. The results showed a correlation between the selectivity coefficients and the theoretical charge distributions. The results surprisingly show that charge distribution based model was able to predict the selectivity coefficients of MIP based potentiometric sensors.

Evaluation of dispersive liquid-liquid microextraction in the stereoselective determination of cetirizine following the fungal biotransformation of hydroxyzine and analysis by capillary electrophoresis.

We developed a capillary electrophoresis (CE) and dispersive liquid-liquid microextraction (DLLME) method to stereoselectively analyze hydroxyzine (HZ) and cetirizine (CTZ) in liquid culture media. The CE analyses were performed on an uncoated fused-silica capillary; 50mmolL(-1) sodium borate buffer (pH 9.0) containing 0.8% (w/v) S-ß-CD was used as the background electrolyte. The applied voltage and temperature were +6 kV and 15 °C, respectively, and the UV detector was set to 214 nm. Chloroform (300 µL) and ethanol (400 µL) were used as the extraction and disperser solvents, respectively, for the DLLME. Following the formation of a cloudy solution, the samples were subjected to vortex agitation at 2000 rpm for 30s and to centrifugation at 3000 rpm for 5 min. The recoveries ranged from 87.4 to 91.7%. The method was linear over a concentration range of 250-12,500 ng mL(-1) for each HZ enantiomer (r>0.998) and 125-6250 ng mL(-1) for each CTZ enantiomer (r>0.998). The limits of quantification were 125 and 250 ng mL(-1) for CTZ and HZ, respectively. Among the six fungi studied, three species were able to convert HZ to CTZ enantioselectively, particularly the fungus Cunninghamella elegans ATCC 10028B, which converted 19% of (S)-HZ to (S)-CTZ with 65% enantiomeric excess.