Supercritical fluid chromatography tandem mass spectrometry employed with evaporation-free liquid–liquid extraction for the rapid analysis of cinnarizine in rat plasma

Cinnarizine is a weak base, which can produce supersaturation and precipitation during gastrointestinal transit, affecting its absorption in vivo. Therefore, it is necessary to investigate whether the oral bioavailability of cinnarizine can be improved after co-administration with precipitation inhibitors or not. In order to evaluate the pharmacokinetic behavior of cinnarizine in rats, a simple, rapid, sensitive, and environmentally friendly supercritical fluid chromatography-tandem mass spectrometric method was established and validated. In this method, flunarizine, a structural analogue of cinnarizine, was selected as the internal standard, and cinnarizine was extracted from rat plasma using evaporation-free liquid–liquid extraction method. The analytes were separated on a Torus 1-AA column (3.0 mm × 100 mm, 1.7 μm) within 2.0 min, using a gradient elution procedure. The transitions of cinnarizine and flunarizine were m/z 369.1 → 167.1 and m/z 405.1 → 203.1, respectively. Cinnarizine showed good linear correlation in the range of 1–500 ng/ml with a lower limit of quantification of 1 ng/ml. The intra- and interday precision and accuracy of all quality control samples were within ±15%. This high-throughput, accurate, sensitive, and reproducible method has been successfully applied to study the effects of the precipitation inhibitor cinnarizine on the pharmacokinetics in rats.     

Phase stabilization in cinnarizine complexes using X-ray profile analysis

Characterization of cobalt(II), cadmium(II), copper(II) and tin(II) cinnarizine complexes have been carried out using conductivity, electronic spectra, infrared, nmr, thermogravimetric and X-ray analyses to establish the nature of phase stabilization in these materials. Also, the intrinsic strain components present in these materials during the formation have been computed using wide-angle X-ray scattering analysis. The variation of the crystallite shape ellipsoid in these materials has been discussed on the basis of Hosemann’s paracrystalline model.     

Voltammetric Behavior and Determination of Cinnarizine in Pharmaceutical Formulations and Serum

Abstract

The electrochemical reduction of cinnarizine was investigated by cyclic and linear sweep adsorptive voltammetry at glassy carbon electrode in Britton-Robinson buffers over the pH range 2.5–11.5. For analytical purposes, a well-defined adsorption-controlled cathodic peak was obtained at pH 2.5. By cathodic adsorptive linear sweep voltammetry, a linear calibration plot was obtained in the range of 2.0 × 10^?7 to 5.0 × 10^?6 mol L^?1 with detection limit of 9.0 × 10^?9 mol L^?1. The method was successfully applied to the determination of cinnarizine in commercial formulations with mean recovery and relative standard deviation of 100.24% and 1.46, respectively. The proposed method was also applied for drug determination in spiked serum samples by applying the standard addition method with a mean recovery of 97.80% and standard deviation of 3.06.     

Stereoselective Synthesis of (Z)-1-Benzhydryl-4-cinnamylpiperazines via the Wittig Reaction

A synthetic method of producing (E)- and (Z)-isomers of 1-benzhydryl-4-cinnamylpiperazines in a specific ratio from corresponding benzhydrylpiperazine is described. Of the three compounds synthesized (5a–c), the ratio of E/Z-isomers remained around 15:85. The key intermediates, 1-benzhydryl-4-(2,2-dimethoxyethyl)piperazine derivatives (3a–c), were prepared by nucleophilic substitution reaction of benzhydrylpiperazines (2a–c) with chloroacetaldehyde dimethylacetal in good yield (up to 88%). Hydrolysis of 3a–c gave the corresponding aldehydes 4a–c, which when subjected to the Wittig reaction followed by column purification to afford 1a–c (E-isomers) and 6a–c (Z-isomers) in pure form. The isolated compounds were characterized by NMR and mass spectral analysis.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

A New Sensitive Spectrophotometry Method for the Analysis of Some Antihistamines

A simple and sensitive spectrophotometric method is developed for the assay of some antihistamines. The method is based on the interaction of these basic compounds with picrolonic acid in chloroform to give a yellow color exhibiting maximum absorption at 359 nm.

The drugs determined are astemizoie, cinnarizine, mequitazine and terfenadine. Beer's Law is valid for the investigated antihistamines.

The drugs are determined either in pure form or in their pharmaceutical formulations. The sensitivity of the proposed procedure is discussed and the results are compared with reported ones.     

Solubility of Cinnarizine in (Transcutol + Water) Mixtures: Determination,Hansen Solubility Parameters,Correlation, and Thermodynamics

Between 293.2 and 313.2 K and at 0.1 MPa, the solubility of the weak base, cinnarizine (CNZ) (3), in various {Transcutol-P (TP) (1) + water (2)} combinations is reported. The Hansen solubility parameters (HSP) of CNZ and various {(TP) (1) + water (2)} mixtures free of CNZ were also predicted using HSPiP software. Five distinct cosolvency-based mathematical models were used to link the experimentally determined solubility data of CNZ. The solubility of CNZ in mole fraction was increased with elevated temperature and TP mass fraction in {(TP) (1) + water (2)} combinations. The maximum solubility of CNZ in mole fraction was achieved in neat TP (5.83 × 10⁻² at 313.2 K) followed by the minimum in neat water (3.91 × 10⁻⁸ at 293.2 K). The values of mean percent deviation (MPD) were estimated as 2.27%, 5.15%, 27.76%, 1.24% and 1.52% for the “Apelblat, van’t Hoff, Yalkowsky–Roseman, Jouyban–Acree, and Jouyban–Acree–van’t Hoff models”, respectively, indicating good correlations. The HSP value of CNZ was closed with that of neat TP, suggesting the maximum solubilization of CNZ in TP compared with neat water and other aqueous mixtures of TP and water. The outcomes of the apparent thermodynamic analysis revealed that CNZ dissolution was endothermic and entropy-driven in all of the {(TP) (1) + water (2)} systems investigated. For {(TP) (1) + water (2)} mixtures, the enthalpy-driven mechanism was determined to be the driven mechanism for CNZ solvation. TP has great potential for solubilizing the weak base, CNZ, in water, as demonstrated by these results.     

Determination of cinnarizine in pharmaceutical preparations by spectrophotometry, atomic absorption spectrometry and potentiometry

New methods are developed for the determination of cinnarizine in various dosage forms. They are based on the reaction of cinnarizinium cation with cobalt tetrathiocyanate anion, whereby a sparingly soluble blue 21 drug: reagent ion-pair complex is quantitatively formed. The complex is (a) extracted with nitrobenzene and spectrophotometrically measured at 622 nm; (b) extracted with nitrobenzene and nebulized in an air-acetylene flame for atomic absorption spectrometric monitoring of cobalt at 242.5 nm; and (c) dispersed in a PVC membrane plasticized with 2-nitrophenyloctyl ether and used as a sensor for direct potentiometric determination of the drug. Optimum reaction conditions and performances of the three analytical techniques are evaluated and compared. At the 25 mg level of cinnarizine, the three methods give results with equal accuracy and precision. The average recovery is 98–99% of the nominal and the mean standard deviation is 0.7%. No significant interferences are caused by drug excipients and diluents.