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.

Microliquid/Liquid Interfacial Sensors: Biomimetic Investigation of Transmembrane Mechanisms and Real-Time Determinations of Clemastine, Cyproheptadine, Epinastine, Cetirizine, and Desloratadine.

Antihistamines relieve allergic symptoms by inhibiting the action of histamine. Further understanding of antihistamine transmembrane mechanisms and optimizing the selectivity and real-time monitoring capabilities of drug sensors is necessary. In this study, a micrometer liquid/liquid (L/L) interfacial sensor has served as a biomimetic membrane to investigate the mechanism of interfacial transfer of five antihistamines, i.e., clemastine (CLE), cyproheptadine (CYP), epinastine (EPI), desloratadine (DSL), and cetirizine (CET), and realize the real-time determinations. Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques have been used to uncover the electrochemical transfer behavior of the five antihistamines at the L/L interface. Additionally, finite element simulations (FEMs) have been employed to reveal the thermodynamics and kinetics of the process. Visualization of antihistamine partitioning in two phases at different pH values can be realized by ion partition diagrams (IPDs). The IPDs also reveal the transfer mechanism at the L/L interface and provide effective lipophilicity at different pH values. Real-time determinations of these antihistamines have been achieved through potentiostatic chronoamperometry (I-t), exhibiting good selectivity with the addition of nine common organic or inorganic compounds in living organisms and revealing the potential for in vivo pharmacokinetics. Besides providing a satisfactory surrogate for studying the transmembrane mechanism of antihistamines, this work also sheds light on micro- and nano L/L interfacial sensors for in vivo analysis of pharmacokinetics at a single-cell or single-organelle level.

Separation and identification of cetirizine enantiomers in human urine by capillary electrophoresis and circular dichroism independent of their standards.

Enantioseparation and determination of chiral drugs are of vital importance in biochemical and pharmaceutical research due to the different biological activity, mechanism, and toxicity of individual enantiomers. As a second-generation H(1)-antagonist, cetirizine's pharmaceutical activity is mainly derived from the levocetirizine while the dextro-enantiomer is ineffective and even associated with side effects. Herein, the enantiomers of cetirizine were separated by capillary electrophoresis and identified by electronic circular dichroism. Satisfactory linear relationship was found between the circular dichroism signal at λmax and the electrophoretic peak area difference in the nonracemic mixture of enantiomers. It made possible identification and quantification of cetirizine enantiomers independent of single enantiomer standards. The method's feasibility was demonstrated on the enantiomeric excess experiments of oral drugs measured in human blank urine. Additionally, the separation and determination of cetirizine in human urine after administration were also realized by capillary electrophoresis, indicating the method was sensitive enough for pharmacokinetic study.

Comparison of Carbon Dots Prepared in Deep Eutectic Solvent and Water/Deep Eutectic Solvent: Study of Fluorescent Detection of Fe3+ and Cetirizine and their Photocatalytic Antibacterial Activity.

In this study, two solvents (deep eutectic and water/deep eutectic solvents) were used for N-doped carbon dots (N-CDs) preparation by microwave irradiation. The solvent can influence surface chemical composition, quantum yield, morphology, and fluorescence of CDs. N-CDs synthesized in water/deep eutectic solvent (DES) had better quantum yield (24.5%) with respect to N-CDs synthesized in deep eutectic solvent (17.4%). These carbon dots were used as a rapid and high sensitive "off-on" fluorescent probe for the determination of Fe3+ ion and cetirizine. Morphology and structure of the N-CDs were characterized by FT-IR, UV-Vis, XRD and TEM. Linear range and detection limit for N-CDs synthesis in deep eutectic solvent for cetirizine were 0.08-48 µM and 15 nM, respectively and for N-CDs synthesis in water/deep eutectic solvent were 0.03-50 µM and 10 nM, respectively. Applicability of this nanoprobe was tested in cetirizine determination in serum sample. Antibacterial activities of the two synthesized N-CDs were also investigated using agar disk diffusion method.

Rapid and sensitive method for simultaneous determination of citalopram with antihistamines by liquid chromatography.

A highly sensitive liquid chromatographic method with UV detection has been developed for simultaneous determination of citalopram, levocetirizine and loratadine in bulk drug, pharmaceutical formulation and human serum at 230nm employing 80:20 v/v methanol-water as mobile phase with pH3.5, adjusting flow rate of 1.0mL.min-1. Separation was achieved on Shimadzu Shim-pack CLC-ODS (M) 25M column within the linear range of 0.4-12.5, 0.8-25 and 0.8-25µg.mL-1 with R2 >0.998 and detection limit 7.75, 3.35 and 10.26ng.mL-1respectively. ICH guidelines were followed for validation showing 0.22-1.76, 0.06-1.83 and 0.22-2.11% RSD. The recovery of analytes in tablets and serum was found to be in acceptable range. The method was fruitfully employed for the determination of studied analyte in pharmaceutical formulation and human serum.

Analysis of cocaine adulterants in human brain in cases of drug-related death.

For different reasons, street cocaine is often diluted with pharmacologically active substances, the so-called adulterants such as levamisole or hydroxyzine. A controversial debate exists currently on the uptake of adulterants from cocaine preparations and drug-related death. Previous research convincingly argues that serious adverse side effects that affect the central nervous and cardiovascular systems can be a consequence of adulterated cocaine. AIMS: Having identified the presence of adulterants in lung tissue and blood, the concentrations of these substances in brain, an important target location, was of interest. This provides an opportunity to assess their role in cases of drug-related deaths. MATERIALS AND METHODS: We developed and validated a method for the analysis of cocaine, two cocaine metabolites and six adulterants, which can typically be found in cocaine preparations, and one adulterant metabolite in brain tissue by gas chromatography-mass spectrometry (GC-MS)1. Ten brain samples which were tested positive for cocaine were analyzed. The homogenized brain tissue was embedded into drying paper for protein precipitation. During a subsequent solid-phase extraction (SPE), the eluate and one of the wash fractions were collected. After derivatization with N-Methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) in pyridine and isooctane, the extracts were analyzed by GC-MS. RESULTS AND DISCUSSION: The method was fully validated for cocaine (COC), benzoylecgonine (BZE), ecgonine methyl ester (EME), diltiazem (DIL), hydroxyzine (HYD), and levamisole (LEV) and partly validated for cetirizine (CET), lidocaine (LID), phenacetin (PHE), and procaine (PRO) in brain material. By analyzing post-mortem brain tissue of ten cocaine users, LEV, LID, and HYD as well as PHE were identified in contrast to DIL, PRO, and the HYD metabolite CET. HYD and LEV were found in moderate to high concentrations in some cases. Therefore, it cannot be excluded that they have caused adverse side effects. CONCLUSION: Because adulterants can potentially affect the central nervous and cardiac systems, it is likely that they enhance COC toxicity.

Estimation of simvastatin and cetirizine by RP-LC method: Application to freeze and thaw (FT) stability studies.

Sensitive, simple, reliable and rapid HPLC technique for the estimation of simvastatin (SMV) and cetirizine has been designed in this study. The chromatographic conditions were set using Shimadzu LC-10 AT VP pump, with UV detector (SPD-10 AV-VP). System integration was performed with CBM-102 (Bus Module). Partitioning of components was attained with pre-packed C-18 column of Purospher Star (5 µm, 250 x 4.6 mm) at ambient conditions. Injected volume of sample was 10 µl. Mobile phase was composed of 50:50 v/v ratio of Acetonitrile/water (pH 3.0 adjusted with ortho-phosphoric acid) having 2 ml/minutes rate of flow. Compounds were detected in UV region at 225 nm. Percent Recovery of simvastatin was observed in the range of 98-102%. All results were found in accept table range of specification. The projected method is consistent, specific, precise, and rapid, that can be employed to quantitate the SMV along with cetirizine HCl. It was estimated by 3 successive cycles of freeze and thaw stability. Results of FT samples were found within accept table limits the method was developed and validated in raw materials, bulk formulations and final drug products.

In vitro drug interaction of levocetirizine and diclofenac: Theoretical and spectroscopic studies.

Levocetirizine dihydrochloride is known to interact with some anti-inflammatory drugs. We report here a comprehensive integrated theoretical and experimental study for the in vitro drug interaction between levocetirizine dihydrochloride (LEV) and diclofenac sodium (DIC). The interaction of the two drugs was confirmed by the molecular ion peak obtained from the mass spectrum of the product. Moreover, FTIR and 1HNMR spectra of the individual drugs and their interaction product were inspected to allocate the possible sites of interaction. In addition, quantum mechanical DFT calculations were performed to search for the interaction sites and to verify the types of interactions deduced from the spectroscopic studies such as charge-transfer and non-bonding π-π interactions. It was found that the studied drugs interact with each other in aqueous solution via four types of interactions, namely, ion-pair formation, three weak hydrogen bonds, non-bonding π-π interactions and charge-transfer from DIC to LEV.

Non-target impurity profiling of marketplace Cetirizine using high-resolution mass spectrometry and multivariate data analysis.

RATIONALE: As always, drug impurity is the first concern of medication safety. The quality of pre- and post-marketed drugs is estimated through systematic analysis of potential hazardous substances by impurity profiling. Impurity profile is the general name of all unwanted materials which may affect the purity of an active pharmaceutical ingredient (API). The safety of original drugs is guaranteed by an enormous amount of animal experiments and clinical research while the safety of generic drugs should also be ensured by comparative analysis for consistency evaluation. The significantly differential impurities between them should be focused on and the toxicity should be further estimated if necessary. Herein, we take a marketplace drug named Cetirizine as an example to investigate if there was a method which could effectively discover the potential markers among Cetirizine tablets with different brands and describe specific impurity profiling which makes the unknown brand of Cetirizine tablets predictable. METHODS: Liquid chromatography coupled with high-resolution mass spectrometry (LC/HRMS) was applied to capture the characteristic features of the impurity profile for three brands of marketplace Cetirizine tablets using full scan data-dependent MS/MS scan mode (FS-ddMS(2) ). RESULTS: Unsupervised learning: principal component analysis (PCA) and supervised learning: consensus orthogonal partial least squares discriminant analysis (OPLS-DA) were utilized to reveal the essential character of Cetirizine impurity profile; 16 differential impurities were finally found, their structures were speculated by HRMS(2) data. CONCLUSIONS: The cause of formation was further elucidated which gave a suggestion for production process optimization. Copyright © 2016 John Wiley & Sons, Ltd.

Experimental and quantum mechanical studies on the ion-pair of levocetirizine and bromocresol green in aqueous solutions.

In the present work, levocetirizine dihydrochloride (LEV) was found to interact with bromocresol green (BCG) via ion-pair formation. UV-vis and FTIR spectroscopy were used to validate the data obtained from quantum mechanical calculations (QMC). The electrostatic potential maps show that the reaction is preferred through the interaction of the sulfonic acid group of BCG and the quaternary ammonium group of LEV. The optimized geometry of the product shows that there are six different intermolecular hydrogen bonds between the studied molecules resulting from the ionic attraction between the oppositely charged groups. The UV-vis spectra suggest the formation of an ion-pair. This finding is contradicting with the previous charge-transfer hypothesis.

Validated derivative and ratio derivative spectrophotometric methods for the simultaneous determination of levocetirizine dihydrochloride and ambroxol hydrochloride in pharmaceutical dosage form.

Three simple, precise, accurate and validated derivative spectrophotometric methods have been developed for the simultaneous determination of levocetirizine dihydrochloride (LCD) and ambroxol hydrochloride (ABH) in bulk powder and in pharmaceutical formulations. The first method is a first derivative spectrophotometric method ((1)D) using a zero-crossing technique of measurement at 210.4 nm for LCD and at 220.0 nm for ABH. The second method employs a second derivative spectrophotometry ((2)D) where the measurements were carried out at 242.0 and 224.4 nm for LCD and ABH, respectively. In the third method, the first derivative of the ratio spectra was calculated and the first derivative of the ratio amplitudes at 222.8 and 247.2 nm was selected for the determination of LCD and ABH, respectively. Calibration graphs were established in the ranges of 1.0-20.0 µg mL(-1) for LCD and 4.0-20.0 µg mL(-1) for ABH using derivative and ratio first derivative spectrophotometric methods with good correlation coefficients. The developed methods have been successfully applied to the simultaneous determination of both drugs in commercial tablet dosage form.

Strategy for design NIR calibration sets based on process spectrum and model space: An innovative approach for process analytical technology.

The pharmaceutical industry is under stringent regulations on quality control of their products because is critical for both, productive process and consumer safety. According to the framework of "process analytical technology" (PAT), a complete understanding of the process and a stepwise monitoring of manufacturing are required. Near infrared spectroscopy (NIRS) combined with chemometrics have lately performed efficient, useful and robust for pharmaceutical analysis. One crucial step in developing effective NIRS-based methodologies is selecting an appropriate calibration set to construct models affording accurate predictions. In this work, we developed calibration models for a pharmaceutical formulation during its three manufacturing stages: blending, compaction and coating. A novel methodology is proposed for selecting the calibration set -"process spectrum"-, into which physical changes in the samples at each stage are algebraically incorporated. Also, we established a "model space" defined by Hotelling's T(2) and Q-residuals statistics for outlier identification - inside/outside the defined space - in order to select objectively the factors to be used in calibration set construction. The results obtained confirm the efficacy of the proposed methodology for stepwise pharmaceutical quality control, and the relevance of the study as a guideline for the implementation of this easy and fast methodology in the pharma industry.

Photodegradation of the antihistamine cetirizine in natural waters.

The photodegradation rate of the anti-histamine cetirizine (Zyrtec®) was investigated in various water matrices. The average observed first-order photodegradation rate coefficient (kobs ), obtained by linear regression of the logarithmic-transformed cetirizine concentrations versus irradiation time in simulated sunlight, was 0.024 h(-1) (n = 6; standard deviation ± 0.004) in deionized water corresponding to a half-life of approximately 30 h. There was no statistical difference in the kobs of cetirizine photodegradation in coastal seawater compared with deionized water or deionized water amended with dissolved chromophoric organic matter. The quantum yield of cetirizine photodegradation decreased dramatically with increasing wavelength and decreasing energy of incoming radiation, with the average value ranging from 5.28 × 10(-4) to 6.40 × 10(-3) in the ultraviolet wavelength range (280-366 nm). The activation energy of cetirizine photodegradation was 10.3 kJ mol(-1) with an observed increase in cetirizine photodegradation as temperature increased. This is a significant environmental factor influencing half-life and an important consideration, given that cetirizine has been detected in wastewater and receiving waters from different locations globally.

[Determination of enantiomeric impurity in levocetirizine tablets by capillary electrophoresis].

OBJECTIVE: To determine enantiomeric impurity in levocetirizine tablets by using capillary electrophoresis. METHODS: The effects of pH and the concentrations of sulfated-Β-cyclodextrin (S-Β-CD) and buffer salt on chiral resolution were examined with S-Β-CD as chiral selector. RESULTS: A good enantioseparation of cetirizine was achieved with 30 mmol/L NaH2PO4 buffer solution (pH 7.0) containing 20 g/L of S-Β-CD. CONCLUSION: The method developed in the study is sensitive and reliable for determination of enantiomeric impurity in levocetirizine tablets.

Development of a CZE method for the quantification of pseudoephedrine and cetirizine.

Pseudoephedrine and cetirizine have been combined in dosage forms with more therapeutic benefits when compared with single-drug treatment. The current manuscript reports the development of the first capillary zone electrophoresis (CZE) assay method for that combination. The effects of pH and buffer concentration on resolution, noise, migration time and peak area were examined employing experimental design approach. The analytes were electropherographed into a 50.2 cm-long and 50 µm i.d. fused-silica capillary column using 10 mmol/L borate at pH 8.3 with a potential of 25 kV at 25°C and UV detection at 214 nm. The method was successfully validated in order to verify its suitability for pharmaceutical analysis for the purposes of quality control. Over previous high-performance liquid chromatographic methods, the current CZE method features the benefits of the use of cost-effective electrolyte, besides high sample throughput (11 samples/h). Furthermore, other analytical results including linear dynamic ranges, recovery (96.9-98.1%), intra- and interday precision (relative standard deviation ≤ 1.70%) as well as the limits of detection and quantification (≤2.65 µg/mL) were all satisfactory for the intended purpose.

Identification and determination of selected histamine antagonists by densitometric method.

The conditions for identification were determined for four histamine antagonists: clemastine fumarate, loratadine, cetirizine dihydrochloride and desloratadine by TLC (thin-layer chromatography) method. The selected chromatographic conditions were used to develop a densitometric method for the content determination of the histamine antagonists in medicinal products and substances. The statistical data showed adequate accuracy and precision of the developed methods.

Immunoassays as high-throughput tools: monitoring spatial and temporal variations of carbamazepine, caffeine and cetirizine in surface and wastewaters.

Carbamazepine (CBZ), caffeine and cetirizine were monitored by enzyme-linked immunosorbent assays (ELISAs) in surface and wastewaters from Berlin, Germany. This fast and cost-efficient method enabled to assess the spatial and temporal variation of these anthropogenic markers in a high-throughput screening. CBZ and cetirizine were detected by the same antibody, which selectively discriminates between both compounds depending on the pH value used in the incubation step. To our best knowledge, this is the first dual-analyte immunoassay working with a single antibody. The frequent sampling with 487 samples being processed allowed for the repeated detection of unusually high concentrations of CBZ and caffeine. ELISA results correlate well with the ones obtained by liquid chromatography tandem mass spectrometry (LC-MS/MS). Caffeine concentrations found in surface waters were elevated by combined sewer overflows after stormwater events. During the hay fever season, the concentrations of the antihistamine drug cetirizine increased in both surface and wastewaters. Caffeine was almost completely removed during wastewater treatment, while CBZ and cetirizine were found to be more persistent. The maximum concentrations of caffeine, CBZ and cetirizine found in influent wastewater by LC-MS/MS were 470, 5.0 and 0.49 µg L(-1), while in effluent wastewater the concentrations were 0.22, 4.5 and 0.51 µg L(-1), respectively. For surface waters, concentrations up to 3.3, 4.5 and 0.72 µg L(-1) were found, respectively.

Development of a validated capillary electrophoresis method for enantiomeric purity control and quality control of levocetirizine in a pharmaceutical formulation.

A chiral capillary electrophoresis method has been developed for the quantification of 0.1% of the enantiomeric impurity (dextrocetirizine) in levocetirizine and determination of both in pharmaceuticals using sulfated-ß-cyclodextrins (CDs) as chiral selector. Several parameters affecting the separation were studied such as the type and concentration of chiral selectors, buffer composition and pH, organic modifier, mixtures of two CDs in a dual system, voltage, and temperature. The optimal separation conditions were obtained using a 50 mM tetraborate buffer (pH 8.2) containing 1% (w/v) sulfated-ß-CDs on a fused-silica capillary. Under these conditions, the resolution of two enantiomers was higher than 3. To validate the method, the stability of the solutions, robustness (two level half fraction factorial design for 5 factors using 19 experiments [2(n-1)+3]), precision, linearity (dextrocetirizine 0.25-2.5 µg/ml, R(2) = 0.9994, y = 0.0375x + 0.0008; levocetirizine 15-100 µg/ml, R(2) = 0.9996, y = 0.0213x + 0.0339), limit of detection (0.075 µg/ml, 0.03% m/m), limit of quantification (0.25 µg/ml, 0.1% m/m), accuracy (dextrocetirizine 84-109%, levocetirizine 97.3-103.1%), filter effect, and different CD batches were examined. The validated method was further applied to bulk drug and tablets of levocetirizine.

High throughput method for the analysis of cetrizine hydrochloride in pharmaceutical formulations and in biological fluids using a tris(2,2'-bipyridyl)ruthenium(II)-peroxydisulphate chemiluminescence system in a two-chip device.

A fast, economic and sensitive chemiluminescence (CL) method has been developed for the analysis of cetrizine hydrochloride (CET) in pharmaceutical formulations and in biological fluids. The CL method is based on the oxidation of tris(2,2'-bipyridyl)ruthenium(II) (Ru (bipy)(3)(2+)) by peroxydisulphate in a two-chip device. Up to 180 samples can be analysed per hour, consuming only minute quantities of reagents. Three instrumental setups were tested to find the most economical, sensitive and high throughput setup. In the first setup, a continuous flow of sample and CL reagents was used, whereas in the second setup, a fixed volume (2 µL) of (Ru (bipy)(3)(2+)) was introduced into a continuous infusion of peroxydisulphate and the sample. In the third design, a fixed volume of sample (2 µL) was injected while the CL reagents were continuously infused. Compared to the first setup, a 200% signal enhancement was observed in the third setup. Various parameters that influence the CL signal intensity, including pH, flow rates and reagent concentrations, were optimized. A linear response was observed over the range of 50 µg L(-1) to 6400 µg L(-1) (R(2)=0.9959) with RSD values of 1.1% (n=15) for 1000 µg L(-1). The detection limit was found to be 15 µg L(-1) (S/N=3). The amount of consumed sample was only 2 µL, from which the detected amount of CET was found to be 6.5 × 10(-14)mol. This procedure was successfully applied to the analysis of CET in pharmaceutical formulations and biological fluids.

Cetirizine as pH-dependent cross-reactant in a carbamazepine-specific immunoassay.

High performance liquid chromatography (HPLC) was hyphenated with a previously reported carbamazepine-specific enzyme-linked immunosorbent assay (ELISA) as a screening approach to water analysis in order to identify possible interferences from transformation products. Treated wastewater was analysed and three substances were recognized by the antibody besides carbamazepine: the metabolites 10,11-dihydro-10,11-epoxycarbamazepine and 2-hydroxycarbamazepine plus the structurally not obviously related antihistamine cetirizine. The molar cross-reactivity against cetirizine was found to be pH-dependent and assessed to be 400% at pH 4.5 and 22% at pH 10.5. Performing the ELISA at pH 10.5 greatly improved the accuracy when carbamazepine was determined in surface and wastewater samples.