Design and synthesis of S-citalopram-imprinted polymeric sorbent: Characterization and application in enantioselective separation.

The current work describes the efficient creation and employment of a new S-citalopram selective polymeric sorbent, made from poly(divinylbenzene-maleic anhydride-styrene). The process began by using suspension polymerization technique in the synthesis of poly(styrene-maleic anhydride-divinylbenzene) microparticles. These were then modified with ethylenediamine, developing an amido-succinic acid-based polymer derivative. The S-citalopram, a cationic molecule, was loaded onto these developed anionic polymer particles. Subsequently, the particles were post-crosslinked using glyoxal, which reacts with the amino group residues of ethylenediamine. S-citalopram was extracted from this matrix using an acidic solution, which also left behind stereo-selective cavities in the S-citalopram imprinted polymer, allowing for the selective re-adsorption of S-citalopram. The attributes of the polymer were examined through methods such as 13C NMR, FTIR, thermogravemetric and elemental analyses. SEM was used to observe the shapes and structures of the particles. The imprinted polymers demonstrated a significant ability to adsorb S-citalopram, achieving a capacity of 878 mmol/g at a preferred pH level of 8. It proved efficient in separating enantiomers of (±)-citalopram via column methods, achieving an enantiomeric purity of 97 % for R-citalopram upon introduction and 92 % for S-citalopram upon release.

Gelatin microsphere coated Fe3O4@graphene quantum dots nanoparticles as a novel magnetic sorbent for ultrasound-assisted dispersive magnetic solid-phase extraction of tricyclic antidepressants in biological samples.

Gelatin microsphere-coated Fe3O4@graphene quantum dots (Fe3O4@GQD@GM) were designed and synthesized as a novel sorbent via ultrasonic-assisted dispersive magnetic solid-phase extraction (UA-DMSPE) method. The synthesized sorbent was identified and confirmed by FT-IR, XRD, VSM, and SEM techniques. UA-DMSPE was combined with corona discharge ion mobility spectrometry for trace determination of desipramine, sertraline, and citalopram. Effective parameters were considered and optimized. The proposed method, under optimal conditions, showed excellent linearity in different concentration ranges (2-700 ng mL-1, R2 > 0.995), repeatability (RSD < 5.1%), good sensitivity (LODs in the range 0.6-1.5 ng mL-1), high preconcentration factor (PF = 207-218), and acceptable relative recoveries (93.5-101.8%). Eventually, this method was used to determine tricyclic antidepressants in various biological samples. Schematic presentation of the microextraction and monitoring of TCAs by ultrasonic-assisted dispersive magnetic solid phase microextraction-ion mobility spectrometry producer.

Application of LC-ESI-MS/MS Method for Analysis of Escitalopram Oxalate in Human Urine and Pharmaceutical Dosage Forms.

An effective and sensitive liquid chromatographic-electrospray ionization tandem mass-spectrometric (LC-ESI-MS/MS) method was developed and validated for quantification of escitalopram oxalate (ESC-OX), antidepressant drug in spiked human urine and pharmaceutical formulations. In this work, simple liquid-liquid extraction was optimized and used for extraction of cited drug from urine samples. The chromatographic separation was attained within 6 min including re-equilibration time by using gradient elution with 0.1% formic acid in acetonitrile and 0.1% formic acid in water as mobile phase, Zorbax Eclipse RP C18 (50 × 2.1 mm) column was used with a particle size of 1.8 µm; the flow-rate was 0.35 mL min-1. Ion signal m/z 262.0 and 109.0 for ESC-OX product ions were monitored at positive ESI mode. Validation of the method was carried out according to the ICH Q2 (R1) guidelines and EMEA criteria. The method was linear over 79-196,450 pg mL-1 with a regression of 0.9999 and 0.9993 for both standard and urine samples. The LOD was 3.88 and 10.66 pg mL-1 for standard and urine samples, respectively, while lower limit of quantification was 79 pg mL-1.

Maltodextrin-modified graphene oxide for improved enantiomeric separation of six basic chiral drugs by open-tubular capillary electrochromatography.

An electrochromatographic capillary was modified with graphene oxide (GO), and the coating was characterized by scanning electron microscopy, energy dispersive X-ray spectrometry, and Fourier transform infrared spectra. By utilizing maltodextrin (MD) as the chiral selector, the basic chiral drugs nefopam (NEF), amlodipine (AML), citalopram hydrobromide (CIT), econazole (ECO), ketoconazole (KET) and cetirizine hydrochloride (CET) can be enantiomerically separated on this CEC. Compared with an uncoated silica capillary, the resolutions are markedly improved (AML: 0.32 → 1.45; ECO: 0.55 → 1.89; KET: 0.88 → 4.77; CET: 0.81 → 2.46; NEF: 1.46 → 2.83; CIT: 1.77 → 4.38). Molecular modeling was applied to demonstrate the mechanism of enantioseparation, which showed a good agreement with the experimental results. Graphical abstractSchematic representation of the preparation of graphene oxide-modified capillary (GO@capillary) for enantioseparation of drug enantiomers. The monolayered GO was used as the coating of the GO@capillary. Then the capillary was applied to construct capillary electrochromatography system with maltodextrin for separation of basic chiral drugs.

Dendrimer-reinforced sol-gel based hollow fiber solid-phase microextraction for citalopram determination using response surface methodology.

The inclusion of a polyamidoamine dendrimer in a silica sol-gel yielded a solid nanosorbent that was used for the preconcentration, extraction, and determination of citalopram in hospital waste water, hemodialysis solution, and some drinking water. The method was developed by applying a novel nanosorbent for the solid-phase microextraction of citalopram, containing a silica sol-gel reinforced by polyamidoamine second-generation dendrimer, which was protected by a polypropylene hollow fiber. Plackett-Burman design and central composite design were utilized to evaluate the significance of several factors on the extraction efficiency. The adsorption mechanism and thermodynamic and kinetic aspects were studied. The adsorption process was exothermic and well fitted to the Bangham equation kinetic model. Under optimal conditions, the presented method was liner in the range of 0.05-100 µg/mL. The limits of detection of quantification of citalopram were 0.0095 and 0.031 µg m/L, respectively.

Enantioselective analysis of citalopram and demethylcitalopram in human whole blood by chiral LC-MS/MS and application in forensic cases.

Citalopram is one of the most frequently used antidepressants in Denmark. It is marketed as a racemic mixture (50:50) of S- and R-enantiomers as well as of the S-enantiomer alone, which is the active enantiomer named escitalopram that processes the inhibitory effects. In this study, a chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is developed for the measurement of citalopram and demethylcitalopram enantiomers in whole blood and is applied to forensic cases. Whole blood samples (0.10 g) were extracted with butyl acetate after adjusting the pH with 2 M NaOH. The analytes were separated on a 250 × 4.6 mm Chirobiotic V, 5 µm column by isocratic elution with methanol:ammonia:acetic acid (1000:1:1) using an ultra-high-pressure liquid chromatography (UHPLC) system. Quantification was performed by tandem mass spectrometry (MS/MS) using multiple reaction monitoring (MRM) in the positive mode. The total chromatographic run time was 20 min. The limit of detection (LOD) and quantification (LOQ) were 0.001 and 0.005 mg/kg of all four enantiomers, respectively. Linear behaviour was obtained for all four enantiomers from LOQ to 0.50 mg/kg blood with absolute recoveries from 71 to 80%. The method showed an acceptable precision and accuracy as the obtained coefficient of variation, and bias values were ≤16% for all enantiomers. After the validation of the method, a correlation with the racemic method was assessed and found to be acceptable. Then, the method was successfully applied to authentic blood samples from forensic investigations demonstrating that escitalopram was less frequent than citalopram among all forensic cases. Copyright © 2017 John Wiley & Sons, Ltd.

Application of tandem dispersive liquid-liquid microextraction for the determination of doxepin, citalopram, and fluvoxamine in complicated samples.

A new type of dispersive liquid-liquid microextraction is used for the determination of doxepin, citalopram, and fluvoxamine in aqueous matrices. This method is based upon the tandem utilization of dispersive liquid-liquid microextraction, and by providing a high sample clean-up, it efficiently improves the applicability of the method in complicated matrices. For this purpose, in the first step, the analytes contained in an aqueous sample solution (8.0 mL) were extracted into an organic solvent, and then these analytes were simply back-extracted into an aqueous acceptor phase (50 µL). The overall extraction time was 7 min, and very simple tools were required for this aim. Optimization of the variables affecting the method such as the type and volume of the organic solvent used and effect of ionic strength was carried out to achieve the best extraction efficiency. Under the optimized experimental conditions, tandem dispersive liquid-liquid microextraction with high-performance liquid chromatography and UV detection showed a good linearity in the range of 10-5000 ng/mL. The limits of detection were in the range of 3-10 ng/mL. The Intra-day precisions (relative standard deviation) were 9.2, 4.5, and 4.8, and the recoveries were 58.5, 52.9, and 39.3% for citalopram, doxepin, and fluvoxamine, respectively.

Enantiomer separations of basic chiral compounds by capillary electrochromatography on a phosphated ß-cyclodextrin-modified zirconia monolith.

Phosphated ß-cyclodextrin (PCD)-coated zirconia monolith was used as the chiral stationary phase in capillary electrochromatography (CEC) for separation of four basic chiral compounds including metoprolol (MET), sertraline (SER), citalopram (CIT) and atenolol (ATE). Migration, chiral selectivity and resolution data were measured in reversed-phase mobile phases of varying pH, buffer and organic modifier compositions. Optimum mobile phase conditions for CEC separation of the compounds studied were found to be a 15-mM aqueous buffer of pH 5.0 with 5mM PCD. Baseline separations of enantiomers of CIT, MET and SER, and partial separation for ATE were achieved with the optimal mobile phase.

Enantiomeric separation of citalopram base by supercritical fluid chromatography.

The chiral separation of citalopram base by supercritical fluid chromatography on a semipreparative Chiralpak AD column was studied with the use of three alcohol-type modifiers (methanol, ethanol, and 2-propanol) with different volume percentages (5, 10, and 15%). The best separation was achieved when 10% 2-propanol was used in the presence of 0.1% diethylamine as additive. Under these conditions, the resolution reached 2.15 and the selectivity was 1.388. In addition, other parameters that affected the retention and separation properties, i.e. temperature, pressure, and density, were studied in detail. At the same pressure, a decrease in the temperature improved the enantioselectivity as the experimental temperature range was below the isoelution temperature. However, the temperature dependence of the retention factor was complicated. As a rule, the retention factor decreased when the temperature increased at the same density. A satisfactory regression of the logarithm of the retention factor versus density and temperature was obtained using a simplified lattice-fluid model. Surprisingly, the relationship between the Henry constant and density can be accurately correlated by using the same quadratic equation.

Rapid determination of letrozole, citalopram and their metabolites by high performance liquid chromatography-fluorescence detection in urine: Method validation and application to real samples.

This work reports the validation of a high precision and accuracy method for the simultaneous determination of letrozole, citalopram and their metabolites in urine by high performance liquid chromatography with fluorescence detection. Dilution (urine:mobile phase, 1:2, v/v) was the only sample preparation step. The separation was carried out in a Kromasil C(18) (150mm×4.6mm) column, and the mobile phase was phosphate buffer 80mM (pH 3.0) and acetonitrile (65:35, v/v) at a flow rate of 1.0mL/min. The analytes were detected at 295nm after excitation at 230nm. Linearity was observed in the range of 1.0-1000ng/mL for letrozole and its metabolite and 2.5-1000ng/mL for citalopram and their metabolites, with limits of detection and quantification between 0.09-1.0 and 0.27-1.65ng/mL, respectively. The precisions were satisfactory with RSDs between 0.17 and 5.71%. The accuracy was studied by spiking three urines from healthy female volunteers, and the recoveries were from 85 to 103%. The method was applied to urine samples from women under treatment for breast cancer and depression diseases.

Fate of citalopram during water treatment with O3, ClO2, UV and Fenton oxidation.

In the present study we investigate the fate of citalopram (CIT) at neutral pH using advanced water treatment technologies that include O(3), ClO(2) oxidation, UV irradiation and Fenton oxidation. The ozonation resulted in 80% reduction after 30 min treatment. Oxidation with ClO(2) removed>90% CIT at a dosage of 0.1 mg L(-1). During UV irradiation 85% reduction was achieved after 5 min, while Fenton with addition of 14 mg L(-1) (Fe(2+)) resulted in 90% reduction of CIT. During these treatment experiments transformation products (TPs) were formed from CIT, where five compounds were identified by using high resolution and tandem mass spectrometry. Among these desmethyl-citalopram and citalopram N-oxide have been previously identified as human metabolites, while three are novel and published here for the first time. The three TPs are a hydroxylated dimethylamino-side chain derivative, a butyrolactone derivative and a defluorinated derivative of CIT.

Electrosynthesis of polypyrrole on steel fiber for solid-phase microextraction of citalopram in serum.

A solid-phase microextraction (SPME) technique using steel fiber coated with polypyrrole (PPY) was developed for UV-Vis determination of citalopram in blood serum. The coating was prepared using a three-electrode electrochemical system from an acetonitrile/aqueous (ACN/H(2)O) oxalic acid solution containing 0.01 M of pyrrole monomer by applying a potential range (0-1.3 V) for 25 min. In order to obtain an efficient film of PPY, experimental parameters related to the coating process were optimized, specifically deposition potential, concentration of monomer, and number of cycles. The effects of various parameters on the efficiency of the SPME process such as extraction time, stirring speed, adsorption and desorption temperature, desorption solvent, and pH of desorption solution were also studied. The coating was stable and adhered to the surface of the steel fiber. The method was linear over about three orders of magnitude with an average correlation coefficient of 0.97. Spiking of blank samples with 0.2 µg/mL citalopram afforded a recovery of 84% with a precision of 10.2%. A limit of detection of 0.046 µg/mL (based on S/N = 3) was obtained in the linear dynamic range of 0.046-2.0 µg/mL. The proposed method was applied to monitor citalopram in serum samples.

Fast separation of selective serotonin reuptake inhibitors antidepressants in plasma sample by nonaqueous capillary electrophoresis.

A simple, fast, and sensitive liquid-liquid extraction method followed by nonaqueous capillary electrophoresis (LLE/NACE) was developed and validated for simultaneous determination of four antidepressants (fluoxetine, sertraline, citalopram and paroxetine) in human plasma. Several experimental separation conditions using aqueous and nonaqueous media separation were tested by varying the electrolyte pH value (for aqueous medium) and the ionic strength concentration considering the similar mobility of the compounds. High-resolution separation was achieved with a mixture of 1.25 mol L(-1) of phosphoric acid in acetonitrile. The quantification limits of the LLE/CE method varied between 15 and 30 ng mL(-1), with a relative standard deviation (RSD) lower than 10.3%. The method was successfully applied in therapeutic drug monitoring and should be employed in the evaluation of plasma levels in urgent toxicological analysis.

Column liquid chromatography-ultraviolet and column liquid chromatography/mass spectrometry evaluation of stress degradation behavior of escitalopram oxalate.

The objective of this work was to study the degradation behavior of escitalopram oxalate under different International Conference on Harmonization (ICH)-recommended stress conditions by column liquid chromatography (LC)-UV and LC/mass spectrometry (LC/MS) and to establish a validated stability-indicating LC assay method. Escitalopram oxalate was subjected to stress conditions of hydrolysis, oxidation, photolysis, and thermal decomposition. Extensive degradation was found to occur in alkaline medium. Mild degradation was observed in acidic and oxidative conditions. Escitalopram oxalate was stable to neutral, photolytic, and thermal stress. Successful separation of the drug from degradation products formed under stress conditions was achieved on a PerfectSil-100 ODS-3 column [C18 (5 microm, 25 cm x 4.6 mm id)] using methanol-0.01 M acetate buffer pH 3.8 adjusted with acetic acid (45 + 55) as the mobile phase. The flow rate was 1 ml/min, and the detection wavelength was 239 nm. The method was validated according to ICH guidelines. Major degradation products formed in hydrolysis and oxidative conditions were isolated, and structural elucidation of degradation products was done by LCIMS and infrared spectrometry studies. The major hydrolysis degradation product was confirmed as 1-(3-dimethylaminopropyl)-1-(4-fluoro- phenyl)-1,3dihydroisobenzofuran-5-carboxylic acid, and the major oxidative degradation product was confirmed as 1-{[3-dimethylamino(oxide)- propyl]-1-(4-fluro-phenyl)}-1,3-dihydro-isobenzofuran- 5-carbonitrile.

Isolation and characterization of degradation products of citalopram and process-related impurities using RP-HPLC.

A reversed-phase high-performance liquid chromatographic method for simultaneous separation and determination of citalopram hydrobromide and its process impurities in bulk drugs and pharmaceutical formulations was developed. The separation was accomplished on an Inertsil ODS 3V (250x4.6 mm; particle size 5 mum) column using 0.3% diethylamine (pH = 4.70) and methanol/acetonitrile (55:45 v/v) as mobile phase in a gradient elution mode. The eluents were monitored by a photodiode array detector set at 225 nm. The chromatographic behavior of all the related substances was examined under variable conditions of different solvents, buffer concentrations, and pH. The method was validated in terms of accuracy, precision, and linearity. The method could be of use not only for rapid and routine evaluation of the quality of citalopram in bulk drug manufacturing units but also for the detection of its impurities in pharmaceutical formulations. Three unknown impurities were consistently observed during the analysis of different batches of citalopram. Forced degradation of citalopram was carried out under thermal, photo, acidic, alkaline, and peroxide conditions. The degradation products and unknown impurities were isolated and characterized by ESI-MS/MS, (1)H NMR, and FT-IR spectroscopy.

Liquid-phase microextraction with porous hollow fibers, a miniaturized and highly flexible format for liquid-liquid extraction.

Since 1999, substantial research has been devoted to the development of liquid-phase microextraction (LPME) based on porous hollow fibers. With this technology, target analytes are extracted from aqueous samples, through a thin supported liquid membrane (SLM) sustained in the pores in the wall of a porous hollow fiber, and further into a microL volume of acceptor solution placed inside the lumen of the hollow fiber. After extraction, the acceptor solution is directly subjected to a final chemical analysis by liquid chromatography (HPLC), gas chromatography (GC), capillary electrophoresis (CE), or mass spectrometry (MS). In this review, LPME will be discussed with focus on extraction principles, historical development, fundamental theory, and performance. Also, major applications have been compiled, and recent forefront developments will be discussed.

Enantiomeric separation of citalopram and its metabolites by capillary electrophoresis.

A simple and fast capillary electrophoretic method has been developed for the enantioselective separation of citalopram and its main metabolites, namely N-desmethylcitalopram and N,N-didesmethylcitalopram, using beta-cyclodextrin (beta-CD) sulfate as the chiral selector. For method optimisation several parameters were investigated, such as CD and buffer concentration, buffer pH, and capillary temperature. Baseline enantioseparation of the racemic compounds was achieved in less than 6 min using a fused-silica capillary, filled with a background electrolyte consisting of a 35 mM phosphate buffer at pH 2.5 supplemented with 1% w/v beta-CD sulfate and 0.05% w/v beta-CD at 25 degrees C and applying a voltage of -20 kV. A fast separation method for citalopram was also optimized and applied to the analysis of pharmaceutical formulations. Racemic citalopram was resolved in its enantiomers in less than 1.5 min using short-end injection (8.5 cm, effective length) running the experiments in a background electrolyte composed of a 25 mM citrate buffer at pH 5.5 and 0.04% w/v beta-CD sulfate at a temperature of 10 degrees C.