Development of Two Charge-Transfer Complex Spectrophotometric Methods for Determination of Tofisopam in Tablet Dosage Form

Purpose: To develop an easy, fast and sensible spectrophotometric method for determination of tofisopam in tablet dosage form.Methods: Tofisopam as n-electron donor is react with two π-acceptors namely: chloranilic acid (ChA), and 7,7,8,8 tetracyanoquinodimethane (TCNQ) to form charge-transfer complexes. The obtained complexes were tested spectrophotometrically at 520 and 824 nm for ChA and TCNQ, respectively. The optimal conditions affecting the reaction status were surveyed and optimized, and the results compared with Japanese Pharmacopeia method.Results: The calibration curve were obeyed Beer`s low in the ranges 25 – 125 and 30 – 150 μg/mL for ChA and TCNQ, respectively. The lower limit of detection was 8.0 and 10.0 μg/m for ChA and TCNQ, respectively. The slope and intercept of the calibration graphs were 0.0025 and 0.011, and 0.0115 and -0.237 for ChA and TCNQ, respectivelyConclusion: The proposed methods have successfully been applied to determination of tofisopam with good accuracy and precision. The methods are accurate as the Japanese pharmacopeial method amd may be applied for routine analysis in quality control laboratories.Keywords: Charge-transfer complex, Tofisopam, Chloranilic acid, Tetracyanoquinodimethane, Spectrophotometr

Ionophore-based potentiometric PVC membrane sensors for determination of phenobarbitone in its pharmaceutical formulations

The fabrication and development of two polyvinyl chloride (PVC) membrane sensors for assaying phenobarbitone sodium are described. Sensors 1 and 2 were fabricated utilizing - or -cyclodextrin as ionophore in the presence of tridodecylmethylammonium chloride as a membrane additive, and PVC and dioctyl phthalate as plasticizer. The analytical parameters of both sensors were evaluated according to the IUPAC guidelines. The proposed sensors showed rapid, stable anionic response (–59.1 and –62.0 mV per decade) over a relatively wide phenobarbitone concentration range (5.0×10–6–1×10–2 and 8×10–6–1×10–2 mol L–1) in the pH range of 9–11. The limit of detection was 3.5×10–6 and 7.0×10–6 mol L–1 for sensors 1 and 2, respectively. The fabricated sensors showed high selectivity for phenobarbitone over the investigated foreign species. An average recovery of 2.54 µg mL–1 phenobarbitone sodium was 97.4 and 101.1 %, while the mean relative standard deviation was 3.0 and 2.1 %, for sensors 1 and 2, respectively. The results acquired for determination of phenobarbitone in its dosage forms utilizing the proposed sensors are in good agreement with those obtained by the British Pharmacopoeial method

Multiple metabolomics of uropathogenic E. coli reveal different information content in terms of metabolic potential compared to virulence factors.

No single analytical method can cover the whole metabolome and the choice of which platform to use may inadvertently introduce chemical selectivity. In order to investigate this we analysed a collection of uropathogenic Escherichia coli. The selected strains had previously undergone extensive characterisation using classical microbiological methods for a variety of metabolic tests and virulence factors. These bacteria were analysed using Fourier transform infrared (FT-IR) spectroscopy; gas chromatography mass spectrometry (GC-MS) after derivatisation of polar non-volatile analytes; as well as reversed-phase liquid chromatography mass spectrometry in both positive (LC-MS(+ve)) and negative (LC-MS(-ve)) electrospray ionisation modes. A comparison of the discriminatory ability of these four methods with the metabolic test and virulence factors was made using Procrustes transformations to ascertain which methods produce congruent results. We found that FT-IR and LC-MS(-ve), but not LC-MS(+ve), were comparable with each other and gave highly similar clustering compared with the virulence factors tests. By contrast, FT-IR and LC-MS(-ve) were not comparable to the metabolic tests, and we found that the GC-MS profiles were significantly more congruent with the metabolic tests than the virulence determinants. We conclude that metabolomics investigations may be biased to the analytical platform that is used and reflects the chemistry employed by the methods. We therefore consider that multiple platforms should be employed where possible and that the analyst should consider that there is a danger of false correlations between the analytical data and the biological characteristics of interest if the full metabolome has not been measured

Cyclodextrin potentiometric sensors based on selective recognition sites for procainamide: Comparative and theoretical study

Polyvinyl chloride (PVC) membrane sensors were constructed and developed for the determination of procainamide HCl (PR). Three membrane sensors incorporating α-, β- and γ- cyclodextrin (CD) as ionophores with potassium tetrakis (4-chlorophenyl) borate (KTpClPB) as the ion additive, o-nitro phenyl ether (o-NPOE) as the plasticizer and a PVC matrix. The reaction mechanisms were based on inclusion complexes. The developed α- and β- CD sensors exhibited near-Nernstian profile, whereas γ- CD showed a non-Nernstian response. At pH 4 -8, the sensors exhibited a calibration range for PR of 10-3 to 10−6, and the detection limits were 2.40 × 10-6, 2.12 × 10-6, 2.40 × 10-6 for α-, β- and γ- CD sensors, respectively. Interference was investigated by studying the selectivity coefficient values of the test sensors, which indicated that the methods were free from interference from investigated species. The determination of PR exhibited high recovery and favorable relative standard deviation using the investigated sensors. The sensors were subsequently used for the quantification of PR in a pharmaceutical formulation and the potentiometric results agreed with those of a spectrophotometric method. A molecular docking (MD) study was used to predict the structure of the inclusion complexes of PR (guest) and α- or β- or γ-CD (host). The study results indicated that the formed complexes were stable with sufficient binding energy

Ionophore-based potentiometric PVC membrane sensors for determination of phenobarbitone in pharmaceutical formulations

The fabrication and development of two polyvinyl chloride (PVC) membrane sensors for assaying phenobarbitone sodium are described. Sensors 1 and 2 were fabricated utilizing β- or γ-cyclodextrin as ionophore in the presence of tridodecylmethylammonium chloride as a membrane additive, and PVC and dioctyl phthalate as plasticizer. The analytical parameters of both sensors were evaluated according to the IUPAC guidelines. The proposed sensors showed rapid, stable anionic response (-59.1 and -62.0 mV per decade) over a relatively wide phenobarbitone concentration range (5.0 × 10-6-1 × 10-2 and 8 × 10-6-1 × 10-2 mol L-1) in the pH range of 9-11. The limit of detection was 3.5 × 10-6 and 7.0 × 10-6 mol L-1 for sensors 1 and 2, respectively. The fabricated sensors showed high selectivity for phenobarbitone over the investigated foreign species. An average recovery of 2.54 μg mL-1 phenobarbitone sodium was 97.4 and 101.1 %, while the mean relative standard deviation was 3.0 and 2.1 %, for sensors 1 and 2, respectively. The results acquired for determination of phenobarbitone in its dosage forms utilizing the proposed sensors are in good agreement with those obtained by the British Pharmacopoeial method

A new selective, and sensitive method for the determination of lixivaptan, a vasopressin 2 (V2)-receptor antagonist, in mouse plasma and its application in a pharmacokinetic study

A new, selective and sensitive HPLC method for the determination of lixivaptan, an oral selective vasopressin 2 (V2)-receptor antagonist, was investigated and validated. A Waters symmetry C18 column was used as a stationary phase in isocratic elution mode using a mobile phase composed of KH2PO4 (100 mM)-acetonitrile (40: 60, v/v) at a flow rate of 1.5 mL min-1. Diclofenac was used as the internal standard (IS). Lixivaptan and the IS were extracted from plasma by protein precipitation and were detected at 260 nm. Lixivaptan and diclofenac were eluted at 3.6 and 6.2 min, respectively. The developed method showed good linearity over the calibration range of 50 -1000 ng mL-1 with a lower limit of detection of 16.5 ng mL-1. The extraction percentage of lixivaptan in the mouse plasma was in the range of 88.88 - 114.43%, which indicates acceptable extraction. The aforementioned method was validated according to guidelines of the International Council on Harmonization (ICH). The intra- and inter-day coefficients of variation did not exceed 5.5%. This method was presented to be simple, sensitive, and accurate and was successfully adapted in a pharmacokinetic study of the profile of lixivaptan in mouse plasma. A mean maximum plasma concentration of lixivaptan of 113.82 ng mL-1 was achieved in 0.5 h after oral administration of a 10 mg kg-1 dose in mouse as determined using the developed method

Charge Transfer Complexes of Ketotifen with 2,3-Dichloro-5,6-dicyano-p-benzoquinone and 7,7,8,8-Tetracyanoquodimethane: Spectroscopic Characterization Studies

The reactions of ketotifen fumarate (KT) with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as π acceptors to form charge transfer (CT) complexes were evaluated in this study. Experimental and theoretical approaches, including density function theory (DFT), were used to obtain the comprehensive, reliable, and accurate structure elucidation of the developed CT complexes. The CT complexes (KT-DDQ and KT-TCNQ) were monitored at 485 and 843 nm, respectively, and the calibration curve ranged from 10 to 100 ppm for KT-DDQ and 2.5 to 40 ppm for KT-TCNQ. The spectrophotometric methods were validated for the determination of KT, and the stability of the CT complexes was assessed by studying the corresponding spectroscopic physical parameters. The molar ratio of KT:DDQ and KT:TCNQ was estimated at 1:1 using Job’s method, which was compatible with the results obtained using the Benesi–Hildebrand equation. Using these complexes, the quantitative determination of KT in its dosage form was successful

Validated LC-MS/MS assay for quantification of the newly approved tyrosine kinase inhibitor, dacomitinib, and application to investigating its metabolic stability.

Dacomitinib (DMB) is a second-generation irreversible tyrosine kinase inhibitor (TKI) that is claimed to overcome the disadvantages of the resistance reported for first-line epidermal growth factor receptor (EGFR) TKIs. Towards the end of 2018, the US Food and Drug Administration approved DMB in the form of VIZIMPRO tablets. In the current study, a validated LC-MS/MS assay was established for DMB quantification in rat liver microsomes (RLMs) with application to the drug metabolic stability assessment. Chromatographic resolution of DMB and lapatinib (internal standard) was achieved using an isocratic mobile phase and a reversed-phase C18 column. The linearity of the established LC-MS/MS assay ranged from 2 to 500 ng/mL with r2 ≥ 0.9999. The limit of detection (LOD) and limit of quantification (LOQ) were 0.35 and 1.1 ng/mL, respectively. The precision and accuracy (both intra-day and inter-day) were 0.84-3.58% and 92.2-100.32%, respectively. The metabolic stability of DMB in the RLM matrix was estimated by calculating two parameters, in vitro t1/2 (0.97 mL/min/kg) and intrinsic clearance (157.5 min). Such values infer that DMB would be excreted very slowly from the human body, which might lead to possible bioaccumulation. To the best of our knowledge, this is the first method for DMB analysis in RLMs with metabolic stability estimation

An LC–MS/MS Analytical Method for Quantifying Tepotinib in Human Liver Microsomes: Application to In Vitro and In Silico Metabolic Stability Estimation

Tepotinib (MSC2156119) is a potent mesenchymal–epithelial transition (MET) factor inhibitor, a receptor tyrosine kinase that plays a crucial role in promoting cancer cell malignant progression. Adverse effects of tepotinib (TEP), such as peripheral edema, interstitial lung disease, nausea and diarrhea, occur due to drug accumulation and lead to termination of therapy. Therefore, the in silico and experimental metabolic susceptibility of TEP was investigated. In the current work, an LC-MS/MS analytical method was developed for TEP estimation with metabolic stability assessment. TEP and lapatinib (LTP) used as internal standards (ISs) were separated on a reversed-phase C18 column using the isocratic mobile phase. Protein precipitation steps were used to extract TEP from the human liver microsome (HLM) matrix. An electrospray ionization multi-reaction monitoring (MRM) acquisition was conducted at m/z 493→112 for TEP, at m/z 581→350, and 581→365 for the IS. Calibration was in the range of 5 to 500 ng/mL (R2 = 0.999). The limit of detection (LOD) was 0.4759 ng/mL, whereas the limit of quantification (LOQ) was 1.4421 ng/mL. The reproducibility of the developed analytical method (inter- and intra-day precision and accuracy) was within 4.39%. The metabolic stability of TEP in HLM was successfully assessed using the LC-MS/MS method. The metabolic stability assessment of TEP showed intermediate Clint (35.79 mL/min/kg) and a moderate in vitro t1/2 (22.65 min), proposing the good bioavailability and moderate extraction ratio of TEP. The in silico results revealed that the N-methyl piperidine group is the main reason of TEP metabolic lability. The in silico Star Drop software program could be used in an effective protocol to confirm and propose the practical in vitro metabolic experiments to spare resources and time, especially during the first stages for designing new drugs. The established analytical method is considered the first LC-MS/MS method for TEP estimation in the HLM matrix with its application to metabolic stability assessment