Spectrophotometric stability-indicating methods for the determination of leflunomide in the presence of its degradates

Five simple and sensitive methods were developed for the determination of leflunomide (I) in the presence of its degradates 4-trifluoromethyl aniline (II) and 3-methyl-4-carboxy isoxazole (III). Method A was based on differential derivative spectrophotometry by measuring the delta(1)D value at 279.5 nm. Beer's law was obeyed in the concentration range of 2.00-20.00 microg/mL with mean percentage accuracy of 100.07 +/- 1.32. Method B depended on first-derivative spectrophotometry and measuring the amplitude at 253.4 nm. Beer's law was obeyed in the concentration range of 2.00-16.00 microg/mL with mean percentage accuracy of 98.42 +/- 1.61. Method C was based on the reaction of degradate (II) with 2,6-dichloroquinone-4-chloroimide (Gibbs reagent). The colored product was measured at 469 nm. Method D depended on the reaction of degradate (II) with para-dimethyl aminocinnamaldehyde (p-DAC). The absorbance of the colored product was measured at 533.4 nm. Method E utilized 3-methyl-2-benzothiazolinone hydrazone in the presence of cerric ammonium sulfate with degradate (II). The green colored product was measured at 605.5 nm. The linearity range was 40.00-280.00, 2.40-24.00, and 30-250 microg/mL with mean percentage accuracy of 100.75 +/- 1.21, 100.13 +/- 1.45, and 99.74 +/- 1.39 for Methods C-E, respectively. All variables were studied to optimize the reaction conditions. The proposed methods have been successfully applied to the analysis of leflunomide in pharmaceutical dosage forms and the results were statistically compared with that previously reported.     

Quantum Laplacian and Applications

In this paper, we give an explicit solution of some linear quantum white noise differential equations by applying the convolution calculus on a suitable distribution space. In particular, we give an integral representation for the solution of the quantum heat equation.     

An Efficient Synthesis and Antibacterial Activity of Pyrido[2,3‐d]Pyrimidine,Chromeno[3,4‐c]Pyridine,Pyridine, Pyrimido[2,3‐c]Pyridazine,Enediamines, and Pyridazine Derivatives

A series of Pyrido[2,3‐d]pyrimidine have been synthesized through a reaction of cyanoacetylurea derivatives with aromatic aldehydes or Arylidines. Reaction of compound 1 with aromatic arylidine derivatives or arylhydrazones gave Chromeno[3,4‐c]pyridine, Pyridine, Pyrimido[2,3‐c]pyridazine, Enediamines, and Pyridazine derivatives. All the synthesized compounds were confirmed by spectral studies and screened for their in antibacterial activity against Staphylococcus aureus (Gram positive) and Escherichia coli (Gram negative) bacterial strains. All the compounds were weak to good active against the tested bacterial strains on comparing with the standard drug gentamicin.     

A "classical" tetrahydroxycalix[4]arene adopting the 1,2-alternate conformation

The first example of a "classical" tetrahydroxycalixarene, which adopts the 1,2-alternate conformation both in solution and in the crystal, is described. Calixarene derivatives with two distal methylene groups substituted in a trans fashion by phenyl (5a) or mesityl (5b) groups were synthesized via addition of PhMgBr/CuCN or MesMgBr/CuCN to the bis(spirodiene) derivative 3. Whereas the phenyl-substituted calixarene derivative 5a adopts the usual "cone" conformation, solution NMR data and X-ray crystallography indicate that the more crowded mesityl derivative 5b adopts a 1,2-alternate conformation with the two mesityl groups located at isoclinal positions of the macrocycle.     

Conformational analysis of p-tert-butylcalix[4]arene derivatives with trans-alkyl substituents on opposite methylene bridges: destabilization of the cone form by axial alkyl substituents

The stereochemistry of calix[4]arenes substituted by a pair of identical alkyl substituents in a trans fashion at two distal bridges is analyzed. MM3 calculations suggest that increasing the bulk of the alkyl group at the bridges destabilizes those conformations possessing an axial disposition of the substituent. In contrast to the 1,3-dimethyl ether of p-tert-butylcalix[4]arene, which adopts a cone conformation, solution NMR data indicate that the 1,2-alternate conformation is preferred in the dimethyl ether derivatives 5b (alkyl = i-Pr) and 5c (alkyl = t-Bu). In the derivative substituted by the less bulky methyl substituent (5a), both the cone and 1,2-alternate forms coexist in CDCl3. Increasing the polarity of the solvent increases the relative population of the cone form of 5a and 5b. The steric destabilization ensuing from the presence of the axial substituent is so large in the cone conformation of 5c that the 1,2-alternate conformer is the major form even in polar solvents. The cone --> 1,2-alternate interconversion barrier of 5a is 18.2 kcal mol(-1), indicating that the presence of an axial methyl group both destabilizes the cone conformation and decreases its rigidity.     

A Reliable Electrochemical Sensor Based on Functionalized Magnetite Nanoparticles for Over-the-counter Allergy Medication Abuse Sensing in Biological Fluids

Diphenhydramine (DIPH) has become one of the world‘s most widely abused over-the-counter medications. In addition to relieving allergy symptoms, it is also recognized for causing elevated energy and mild euphoric effects. The U.S. Food and Drug Administration (FDA) has recently warned about serious problems at high doses including heart problems, seizures, coma or even death among addicted teenagers. Herein, a simple, cost-effective, and reliable nanocomposite based electrochemical sensor was designed for DIPH quantification in biological fluids. Introducing the functionalized Fe₃O₄ nanoparticles (NPs) into the inner-filling solution and the PVC-based ion sensing membrane has been employed and compared to the classical potentiometric approach. The nanoparticles were incorporated to endorse in situ cooperative ion-pairing interaction between the ionophore and DIPH, and to improve the selectivity and detection limit (9.5×10⁻⁸ M). Nernstian potentiometric response was achieved for DIPH over the concentration range of 1.0×10⁻⁷ to 1.0×10⁻² M with a slope of 59.0±0.2 mV/decade. Inherent merits of the proposed sensor include fast response time (6 s), superior stability (60 days) with higher sensitivity and selectivity towards DIPH without interference from co-formulated drugs and several ions commonly found in biological matrices. The proposed sensor was successfully applied to the potentiometric determination of DIPH in different biological fluids (plasma and human milk) with an average recovery of 99.06±1.95 % and 100.34±1.92 %, respectively. As a consequence, the developed ISE might be the ideal choice for in-line DIPH measurements in plasma samples to identify overdose ingestion and its related symptoms, as well as for quality-control laboratories without prior treatments.     

Sensitive and selective LC-MS/MS for the determination of tolperisone and etodolac in human plasma and application to a pharmacokinetic study

Tolperisone and etodolac were proven to have synergistic effect for patients of acute low back pain associated with musculoskeletal spasm. In this work, a specific, highly sensitive and reproducible analytical method was developed and validated for the simultaneous determination of tolperisone and etodolac in human plasma using liquid chromatography-tandem mass spectrometric technique. Liquid–liquid extraction was optimized for sample preparation. Zorbax C₈ column (3.5 μm, 50 × 4.6 mm) was used, carrying a mobile phase mixture of 10.0 mM ammonium formate:acetonitrile (40:60, v/v) pH 3.8, running in an isocratic mode. Chlorzoxazone acted as an internal standard. Sample volume of injection was 5.0 μL, and analysis was achieved within 2.5 min. Detection and quantitation were performed by electrospray ionization mass spectrometry using the multiple-reaction monitoring mode. The proposed method could determine the analytes in the range of concentration 0.5–200.0 ng mL⁻¹ for tolperisone and 0.05–20.0 μg mL⁻¹ for etodolac. Findings of inter- and intraday precisions were ≤12.3% with accuracy of ±5.0%. Pharmacokinetics study for the two drugs after oral administration of healthy human volunteers was achieved with the aid of application of the developed study.     

Simultaneous determination of phenylephrine hydrochloride, guaifenesin, and chlorpheniramine maleate in cough syrup by gradient liquid chromatography

A simple and reliable high-performance liquid chromatographic method was developed for the simultaneous determination of mixture of phenylephrine hydrochloride (PHENYL), guaifenesin (GUAIF), and chlorpheniramine maleate (CHLO) either in pure form or in the presence of methylparaben and propylparaben in a commercial cough syrup dosage form. Separation was achieved on a C8 column using 0.005 M heptane sulfonic acid sodium salt (pH 3.4 +/- 0.1) and acetonitrile as a mobile phase by gradient elution at different flow rates, and detection was done spectrophotometrically at 210 nm. A linear relationship in the range of 30-180, 120-1800, and 10-60 microg/mL was obtained for PHENYL, GUAIF, and CHLO, respectively. The results were statistically analyzed and compared with those obtained by applying the British Pharmacopoeia (2002) method and showed that the proposed method is precise, accurate, and can be easily applied for the determination of the drugs under investigation in pure form and in cough syrup formulations.