Quality by Design: Design of Experiments Approach Prior to the Validation of a Stability-Indicating HPLC Method for Montelukast

This paper describes a systematic design of experiments (DoE) approach by applying the principle of quality by design (QbD) to determine the design space for a stability-indicating HPLC method prior to validation. By employing DoE, a simultaneous multivariate approach was carried out for mobile phase pH, flow rate, percentage of organic content and column temperature. A two-level fractional factorial design (2⁴⁻¹ + 2 center points = 10 experiments) was employed and statistical analysis of the experimental data uncovered the significant influential chromatographic factors. The experimental data for USP tailing and resolution were analyzed statistically to screen the chromatographic factors. This approach determined the most influential chromatographic factors. During this process, inferences were evaluated from various data tables, for example, analysis of variance, summary of fit, lack of fit, and parameter estimates. The study also explained various plots such as actual vs. predicted plot, Pareto plot, and prediction profiler. The acceptable range of the chromatographic factors was displayed as a Contour plot defining the ‘design space’ of the method. The range of operating conditions that guarantee a satisfactory QbD was deduced to finalize the method prior to validation. The method is simple, rapid, and robust for the determination of montelukast in montelukast sodium oral granules dosage form. The method was validated according to ICH guidelines for accuracy, precision, linearity, range, specificity, ruggedness and robustness (one factor varied at a time). The method has been successfully transferred to the quality control department for quality analysis of manufactured batches and stability samples.

     

Analysis of <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> PAO1 Biofilm Protein Profile After Exposure to <Emphasis Type="Italic">n</Emphasis>-Butanolic <Emphasis Type="Italic">Cyclamen coum</Emphasis> Extract Alone and in Combination with Ciprofloxacin

Pseudomonas aeruginosa biofilm-related infections are the major cause of premature death in cystic fibrosis patients. Strategies to induce biofilm dispersal are of interest, because of their potential in preventing biofilm-related infections. Our previous work demonstrated that n-butanolic Cyclamen coum extract with ciprofloxacin could eliminate 1- and 3-day-old P. aeruginosa PAO1 biofilms. To gain new insights into the role of C. coum extract and its synergistic effect with ciprofloxacin in eliminating P. aeruginosa PAO1 biofilms, two-dimensional gel electrophoresis (2-DE) in combination with mass spectrometry-based protein identification were used. Changes in the bacterial protein expression were analyzed when 3-day-old biofilm cells were exposed to the C. coum extract alone and in combination with ciprofloxacin. Proteins involved in alginate biosynthesis, quorum sensing, adaptation/protection, carbohydrate and amino acid metabolism showed a weaker expression in the C. coum extract-ciprofloxacin-treated biofilm cells compared to those in the untreated cells. Interestingly, the proteome of C. coum extract-ciprofloxacin-treated biofilm revealed more resemblance to the planktonic phenotype than to the biofilm phenotype. It appears that saponin extract in combination with ciprofloxacin causes biofilm disruption due to several mechanisms such as motility induction, cell envelope integrity perturbation, stress protein expression reduction, and more importantly, signal transduction perturbation. In conclusion, exposure to a combination of biofilm dispersal such as saponin extract and antimicrobial agents may offer a novel strategy to control preestablished, persistent P. aeruginosa biofilms and biofilm-related infections.     

Reversed-phase liquid chromatographic separation of antiretroviral drugs on a monolithic column using ionic liquids as mobile phase additives

The use of 3-methylimidazolium cation-based ionic liquids (ILs) was evaluated as mobile phase additives for separation of antiretroviral drugs on a monolithic column by RP-HPLC. Separation of eight commonly used antiretroviral drugs was achieved on a Chromolith Flash, RP-18e column (25 × 4.6 mm, porous material) using water (pH 4.0 adjusted with acetic acid)/methanol v/v as a mobile phase containing ILs in a gradient elution mode. The effects of concentrations of ILs on retention, resolution and peak shape were studied and a regression equation correlating the interactions between stationary phase and the ILs was established. The retention of all the drugs was decreased notably by using 1-butyl-3-methylimidazolium tetrafluoroborate, while 1-ethyl-3-methylimidazolium methylsulfate reduced gradient drift drastically when compared to triethylamine.     

Disposable amperometric sensor for neurotransmitters based on screen-printed electrodes modified with a thin iridium oxide film.

Potential cycling in the range from -0.2 to +1.2 V is used for the electrodeposition of hydrous iridium oxide films onto a screen-printed electrode from a saturated solution of alkaline iridium(III) solution. The iridium oxide redox couple shows a stable and obvious reversible redox, with the formal potential being pH dependent in the range 1-14. The properties, stability and electrochemical properties of iridium oxide films were investigated by cyclic voltammetry. A modified electrode showed excellent catalytic activity toward the oxidation of neurotransmitters (catecholamines) over a wide pH range (2-8). The electrocatalytic behavior is further exploited as a sensitive detection scheme for adrenaline and dopamine by hydrodynamic amperometry. Under the optimized conditions, the calibration curves are linear in the concentration range 0.1-70 and 0.1-15 microM for dopamine and adrenaline determination, respectively. The detection limit and sensitivity are 30 nM and 30 nA/microM for adrenaline and 15 nM and 80 nA/microM for dopamine. Finally, the analytical performance of the modified electrode was demonstrated for the elimination of interference by uric acid in catecholamines determination when present in a 1000-fold concentration excess.     

Selective oxidation of alcohols with hydrogen peroxide catalyzed by tungstate ions (WO4) supported on periodic mesoporous organosilica with imidazolium frameworks (PMO-IL)

Tungstate ions supported on the periodic mesoporous organosilica with ionic liquid frameworks (WO₄⁼@PMO-IL) were found to be a recoverable catalyst system for the highly selective oxidation of various primary or secondary alcohols to the corresponding aldehydes or ketones by 30% H₂O₂ as green oxidant under neutral aqueous reaction conditions. The catalyst can be also recovered and efficiently reused in seven subsequent reaction cycles without any remarkable decreasing in the catalyst activity and selectivity. Moreover, N₂ sorption analysis, transmission electron microscopy (TEM) images, and thermal gravimetric analysis (TGA) showed that the structure regularity and functional groups loaded of the catalyst were not affected during the reaction process.     

Synthesis of α-phthalimido-α′-dithiocarbamato propan-2-ols via a one-pot,three-component epoxide ring-opening in water

Regioselective ring-opening of the N-(2,3-epoxypropyl)phthalimide with in situ prepared dithiocarbamic acid in water is reported for the synthesis of a new family of α-phthalimido-α′-dithiocarbamato propan-2-ols. The present method is simple, EtOAc is used for work-ups and affords excellent yield of products.     

Asymptotic Maslov’s method for shocks of conservation laws systems with quadratic flux

In this work we apply the asymptotic method suggested by Maslov [1] to obtain the Hugoniot–Maslov chain for shock type solutions of conservation laws systems with quadratic flux. Additionally to the ODE infinite system that make up the chain, it was obtained an algebraic compatibility condition that must be satisfied by some of the coefficients of the asymptotic expansion of the shock solution. We give a new geometrical interpretation for this compatibility condition by means of certain singular surface whose projections represent time-dependent Hugoniot locus through the left limit state of the Shock.     

Identification of Voice Disorders Using Long-Time Features and Support Vector Machine With Different Feature Reduction Methods

Identification of voice disorders has a fundamental role in our life nowadays. Therefore, many of these diseases must be diagnosed at early stages of occurrence before they lead to a critical condition. Acoustic analysis can be used to identify voice disorders as a complementary technique with other traditional invasive methods, such as laryngoscopy. In this article, we followed an extensive study in the diagnosis of voice disorders using the statistical pattern recognition techniques. Finally, we proposed a combined scheme of feature reduction methods followed by pattern recognition methods to classify voice disorders. Six classifiers are used to evaluate feature vectors obtained by principal component analysis or linear discriminant analysis (LDA) as feature reduction methods. Furthermore, individual, forward, backward, and branch-and-bound methods are examined as feature selection methods. The performance of each combined scheme is evaluated in terms of the accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). The experimental results denote that LDA along with support vector machine (SVM) has the best performance, with a recognition rate of 94.26% and AUC of 97.94%. Additionally, this structure has the lowest complexity in comparison with other architectures. Among feature selection methods, individual feature selection followed by SVM classifier shows the best recognition rate of 91.55% and AUC of 95.80%.     

A simple route for the synthesis of 3,3,3′,3′-tetramethyl-2,3,3′,4′-tetrahydro-1H,1′H-[4,9′-bixanthene]-1,1′(2′H,9′H)-dione and its derivatives catalyzed by Mn and other transition metal cations

A simple and efficient unusual coupling reaction of 9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one and its derivatives was accomplished in the presence of Mn²⁺, Cu²⁺, Cd²⁺, Hg²⁺, Fe³, or La³⁺. The structure elucidation was accomplished by IR, ¹H NMR, ¹³C NMR, X-ray crystallography, UV-Visible and elemental analysis. A reaction mechanism is proposed.