Box-Behnken study design for optimization of bicalutamide-loaded nanostructured lipid carrier: stability assessment.

Bicalutamide (BCM) is an anti-androgen drug used to treat prostate cancer. In this study, nanostructured lipid carriers (NLCs) were chosen as a carrier for delivery of BCM using Box-Behnken (BB) design for optimizing various quality attributes such as particle size and entrapment efficiency which is very critical for efficient drug delivery and high therapeutic efficacy. Stability of formulated NLCs was assessed with respect to storage stability, pH stability, hemolysis, protein stability, serum protein stability and accelerated stability. Hot high-pressure homogenizer was utilized for formulation of BCM-loaded NLCs. In BB response surface methodology, total lipid, % liquid lipid and % soya lecithin was selected as independent variable and particle size and %EE as dependent variables. Scanning electron microscopy (SEM) was done for morphological study of NLCs. Differential scanning calorimeter and X-ray diffraction study were used to study crystalline and amorphous behavior. Analysis of design space showed that process was robust with the particle size less than 200 nm and EE up to 78%. Results of stability studies showed stability of carrier in various storage conditions and in different pH condition. From all the above study, it can be concluded that NLCs may be suitable carrier for the delivery of BCM with respect to stability and quality attributes.

Diastereoselective synthesis of N-(p-tosylsulfonyl)-2-phenylaziridine over a novel magnetically recyclable Cu(II) catalyst accompanied with the N-inversion assessment at DFT.

An experimental and theoretical study has been carried out on diastereoselective aziridation of styrene over a magnetically recyclable copper(II) catalyst: Cu(acac)2/NH2-T/SiO2@Fe3O4NPs. The turnover number (TON) of our heterogeneous catalyst appears considerably higher than that reported for the homogeneous Cu(acac)2. Successive applications of solid Cu(acac)2/NH2-T/SiO2@Fe3O4NPs have a slight effect on its catalytic activity. Between anticipated cis and trans diastereomeric products, formation of only one is suggested by NMR. Even though, the trans-invertomer appears thermodynamically more stable at B3LYP/AUG-cc-pVTZ//B3LYP/6-31+G+G* level, we propose formation of the kinetically more stable cis-invertomer due to π-stacking between the tosyl group and the phenyl of styrene. The possibility of cis-trans conversion is ruled out by the high energy barrier of > 76.9 kcal/mol probed in toluene, CCl4, C7H16, DMSO, CH3CN, and H2O.

Assessment of absorption potential of poorly water-soluble drugs by using the dissolution/permeation system.

This study aims to assess the absorption potential of oral absorption of poorly water-soluble drugs by using the dissolution/permeation system (D/P system). The D/P system can be used to perform analysis of drug permeation under dissolution process and can predict the fraction of absorbed dose in humans. When celecoxib at 1/100 of a clinical dose was applied to the D/P system, percentage of dose dissolved and permeated significantly decreased with an increase in the applied amount, resulting in the oral absorption being predicted to be 22-55%. Whereas similar dissolution and permeation profiles of montelukast sodium were observed, estimated absorption (69-85%) was slightly affected. Zafirlukast absorption (33-36%) was not significantly affected by the dose, although zafirlukast did not show complete dissolution. The relationship between clinical dose and predicted oral absorption of drugs corresponded well to clinical observations. The limiting step of the oral absorption of celecoxib and montelukast sodium was solubility, while that of zafirlukast was dissolution rate. However, due to high permeability of montelukast, oral absorption was not affected by dose. Therefore, the D/P system is a useful tool to assess the absorption potential of poorly water-soluble drugs for oral use.

Monte Carlo studies of drug nucleation 1: formation of crystalline clusters of bicalutamide in water.

A computational method of predicting the effects of the metastability of drug solutions is sought. A simple extension of our in silicio approach to thermodynamic drug solubility is tested on the drug bicalutamide for which we performed vapor pressure measurements complementing earlier measurements of aqueous solubility and crystal-water interfacial tension. The free energy of formation of an N-cluster of the drug molecule is estimated semiempirically by use of an Einstein model of the crystal in which experiment supplies the crystal structure, enthalpy of sublimation, and Einstein frequency of vibration. The rigid drug clusters with N from 2 to 14 are extracted from the bulk crystal by minimization of either cluster energy or radius of gyration. The free energy of hydration is estimated by Monte Carlo simulation combined with simplified response theory based on the OPLS-AA/COMPASS force field for the drug-water interaction and the TIP4P water model. The results have been interpreted in terms of an apparent crystal-water interfacial tension according to classical nucleation theory. The energy-minimal and radius of gyration-minimal clusters seem to give very similar crystal-water interfacial tensions for both the monoclinic and the triclinic polymorph. The interfacial tension of the monoclinic polymorph is significantly higher (by around 20%) than that of the triclinic polymorph in accordance with experiment. For the triclinic polymorph a substantial overestimation of the interfacial tension compared to estimates from crystal nucleation experiments is found, mitigated somewhat by an empirical scaling of the simulated binding energies and free energies of hydration.

Determination of the global fibrinolytic state.

Fibrinolysis consists of a plasmatic part and a cellular part. A rapid global assay for plasmatic fibrinolysis is the fibrinolysis parameters assay (FIPA). Cellular fibrinolysis is measured by testing the clot lysis capacity using the microtitre plate clot lysis assay with polymorphonuclear neutrophils (CLA-PMN). Individual citrated plasma or pooled normal plasma (50 microl) of 232 patients was recalcified, incubated for 90 min at 37 degrees C, oxidized with 0 or 1.5 mmol/l (final concentration) chloramine-T, and supplemented with 50 microl respective polymorphonuclear neutrophil plasma. The turbidity of the clots was measured at 405 nm after 12 h and 60 h (37 degrees C). Plasma (50 microl) was also incubated with 5 microl of 100 IU/ml urokinase, 6 mmol/l tranexamic acid, 6% human albumin for 10 min (37 degrees C). Then 100 microl of 0.5 mmol/l Val-Leu-Lys-pNA in 2.45 mol/l arginine, pH 8.6, was added and the increase in absorbance with time was measured. The different CLA-PMN assay versions correlated with each other with r = 0.543-0.782. Cellular fibrinolysis (34 +/- 30% lysis; normal: 25 +/- 10%) did not correlate with the FIPA (72 +/- 27%; normal: 100 +/- 15%), prothrombin time, activated partial thromboplastin time, fibrinogen, C-reactive protein, or the blood counts of thrombocytes, leukocytes, or polymorphonuclear neutrophils. Chloramine (1.5 mmol/l) oxidation of the microclots favours their fibrinolytic breakdown, especially if lysis-resistant microclots are oxidized. The FIPA and CLA-PMN are new economical tests for the fibrinolytic state in patient blood.

Electrochemical characteristics of zafirlukast and its determination in pharmaceutical formulations by voltammetric methods.

Simple, rapid, reliable and fully validated voltammetric methods were developed for the determination of zafirlukast in pharmaceutical formulations, based on its electrochemical reduction at a hanging mercury drop electrode. Its electrochemical behavior in borate buffer (pH 8.0) was investigated using cyclic voltammetry, linear sweep voltammetry and chronoamperometry. The linear sweep voltammetric study of zafirlukast was carried out using glassy carbon electrode. A well-defined cathodic peak at -1326 mV without the adsorptive accumulation time and at -1312 mV with 20 s of accumulation time versus Ag/AgCl reference electrode in square-wave and square-wave adsorptive stripping voltammetric methods, respectively, was observed. The experimental and instrumental parameters affecting the peak current of zafirlukast were investigated and optimized for the zafirlukast determination. The detection limits of square-wave and square-wave adsorptive stripping voltammetric methods were 50 and 5 ngmL(-1) with R.S.D. of 6.79 and 5.72%, respectively. The methods showed good sensitivity, accuracy, precision, selectivity, robustness and ruggedness. The proposed methods were applied for the determination of zafirlukast in its pharmaceutical formulations. The results obtained from developed methods were compared with a spectrophotometric method reported in the literature and no significant difference was found statistically.