Experimental measurement - correlation of solubility and dissolution thermodynamics study of itraconazole in pure monosolvents at various temperatures.

The information about the solubility and thermodynamic properties of solution is important for pharmaceutically important processes, formulation development, and further theoretical studies. In the present study, the solid-liquid equilibrium (solubility) for itraconazole (ITC) was determined experimentally in 14 monosolvents at temperatures between 293.15 K and 318.15 K under pressure of 0.1 MPa. The mole fraction solubilities were found to increase with increasing temperatures and followed inverse trend with the polarity of selected solvents. Besides, KAT-LSER analysis was performed to study the effect of solvent. The results revealed that the solute-solvent interaction (43.94%) was much higher than that of solvent-solvent interaction (16.59%). Thermodynamic based models like van't Hoff equation, modified Apelblat equation, Buchowski-Ksiazaczak equation, and polynomial empirical equation were applied to fit and correlate the experimental solubilities. Overall relative average deviation (RAD) and overall root-mean square deviation (104×RMSD) were observed to be minimum with the empirical polynomial equation and attained the values of 0.0033 and 0.0047, respectively. Furthermore, theoretical ideal solubilities, activity coefficients, and thermodynamic properties of dissolution including molar enthalpy, molar entropy, molar Gibbs free energy, and excess enthalpy were estimated. Ideal solubilities were projected considerably higher than experimental solubilities at each studied temperature. Thermodynamic properties of dissolution indicated that the dissolution was not a spontaneous process; observed to be endothermic (ΔH0soln>0) and enthalpy driven (ΔS0soln>0). Such solid-liquid equilibrium data of ITC will be of immense help in process and formulation development in pharmaceutical sciences.

Extended Hildebrand Solubility Approach: Prediction and Correlation of the Solubility of Itraconazole in Triacetin: Water Mixtures at 298.15°K.

OBJECTIVES: The aim of the study is to explore the suitability of an empirical approach for the extended Hildebrand solubility approach (EHSA) to predict and correlate the solubility of the crystalline drug itraconazole (ITRA) in triacetin: water mixtures. MATERIALS AND METHODS: The physicochemical properties of ITRA like fusion enthalpy, solubility parameter, and ideal mole fraction solubility were estimated. The solubilities of ITRA in mixed solvent blends comprising triacetin: water were determined at 298.15°K. Theoretical solubilities were back calculated using a polynomial regression equation of the interaction energy parameter W as a function of the solubility parameter (δ1) of the solvent mixture. Similarly, the solubilities were predicted by direct method based on the use of logarithmic experimental solubilities (logX2 ) against the solubility parameter (δ1) of the solvent mixture. The predictive capabilities of both EHSA and the direct method were compared using mean percent deviations. RESULTS: The solubility of ITRA was increased in all the triacetin: water blends and was highest in the blend in which the solubility parameter of ITRA equaled that of the solvent mixture. The prediction capacities of the direct method (mean % deviation was -1.89%) were better than those of EHSA (mean % deviation was 9.76%) in the fifth order polynomial. CONCLUSION: The results indicated that the solubility of any crystalline solute can be adequately predicted and correlated with the mere knowledge of physicochemical properties and EHSA. The information could be of help in process and formulation development.

Solubilization and determination of solution thermodynamic properties of itraconazole in different solvents at different temperatures.

The solubility of itraconazole (ITRA) in thirteen pure solvents including water, dimethyl sulphoxide, acetonitrile, methanol, 1,4-butanediol, ethanol, isopropyl alcohol, n-butanol, octanol, ethyl acetate, toluene, benzene, 1,4-dioxane were estimated at the temperatures ranging from 293.15 K to 318.15 K under atmospheric pressure (0.1 MPa). The results reflected that the solubility of ITRA was a function of temperature and was increased with a rise in temperature in each solvent. Moreover, the solubility in polar solvents was less and found to be increased in non-polar solvents. Furthermore, the results of solubilization were correlated by the Van't Hoff equation, the modified Apelblat equation, the Buchowski - Ksiazaczak λh equation, and the polynomial empirical equation. The polynomial empirical equation proved to be more accurate and suitable for the correlation of solubilities of ITRA in studied solvents at various temperatures. Besides, theoretical ideal solubilities, activity coefficients, and thermodynamic properties of the solution process including standard molar enthalpy, entropy, Gibbs free energy, and excess enthalpy were calculated from the experimental solubility data. These thermodynamic parameters indicated that the solubilization process was not spontaneous, endothermic, and enthalpy driven. Such thermodynamic based solubility data of ITRA will be of immense help in solubilization, synthesis, process development, preformualtion, and dosage form development in pharmaceuticals.

Ethanolic extract of Amaranthus paniculatus Linn. ameliorates diabetes-associated complications in alloxan-induced diabetic rats.

BACKGROUND: The aim of this study was to evaluate the hypoglycemic, hypolipidemic, and anti-inflammatory potentials of ethanolic extract of leaves of Amaranthus paniculatus linn. (EEAP) on alloxan-induced diabetic rats scientifically. Hyperglycemia induces the generation of free radicals which can affect antioxidant defenses, thus leading to the disruption of beta cellular functions, oxidative damage to membranes, leading to the release of C-reactive protein and altered lipid metabolism. METHODS: Diabetes was induced by intraperitoneal injection of ice-cold aqueous alloxan monohydrate at the dose of 150 mg/kg body weight. RESULTS: After a daily single oral administration of the EEAP for 28 days starting from the study protocol, the blood glucose, serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), total cholesterol (TC), triglyceride (TG), and C-reactive protein (CRP) levels were assessed. The results obtained from the study administration of daily dose of EEAP significantly reduced the blood glucose, SGPT, SGOT, TC, TG, and CRP in a dose-dependent manner. The results obtained were comparable to those of glibenclamide. The serum levels of TC, TG, and CRP were significantly altered in the diabetic control group, but it was significantly decreased in the extract-treated group and standard glibenclamide-treated group, except at a dose of 100 mg/kg where there was no significant effect on the TG level. The finding obtained suggests that EEAP acts through molecular level, modifying the altered pathways in diabetes and associated complications. CONCLUSION: The results obtained suggest that EEAP possesses a potential for the management of diabetes and associated complications in experimentally-induced diabetic rats.

Synthesis and Pharmacological Evaluation of Tetrazolobenzimidazoles as Novel Anti-inflammatory Agents.

BACKGROUND: Currently used anti-inflammatory drugs are associated with some severe side effects such as gastric irritation, which may range from simple discomfort to ulcer formation. Therefore, the development of potent anti-inflammatory drugs with fewer side effects is important. Benzimidazole, tetrazole and its various derivatives have been used in the synthesis of numerous heterocyclic compounds. In the past few decades, these compounds received much attention due to their diverse array of biological activities. As these heterocycles are known to possess anti-inflammatory activity individually, we thought it worthwhile to link these heterocycles, synthesize them and evaluate for possible changes in this anti-inflammatory activity. METHODS: Novel benzimidazole linked tetrazole compound 2-{[2-(1H-tetrazole-5-yl)ethyl] sulfanyl}-1,3-benzimidazole (3) was synthesized by cyclization of 3-(1,3-benzimidazol-2-ylsulfanyl) propanenitrile in presence of sodium azide. A series of tetrazolobenzimidazole derivatives (3a-h) were synthesized by the reaction of compound (3) with acid chlorides. All the synthesized compounds were subjected to structural elucidation by IR, 1H-NMR spectroscopy, Mass spectrometry and elemental analyses. The newly synthesized compounds were screened for anti-inflammatory activity by carrageenan-induced paw oedema method in albino rats. RESULTS: Compounds (3a, 3c, 3g) which contain acetyl, benzoyl and benzoyl moieties; respectively at N-1of tetrazole exhibited anti-inflammatory activities comparable with standard drug diclofenac. Other compounds exhibited anti-inflammatory activity less than the standard. The differences between control and treatment group were tested using one way ANOVA followed by Dunnett's test. A probability value less than 0.01 was considered to be statistically significant. The GraphPad Instat 3.0 version was used for statistical analysis. CONCLUSION: Synthesized compounds having anti-inflammatory activity better than standard were found to be 1-{5-[2-(benzimidazol-2-yl-sulfanyl)ethyl]-2H-tetrazol-2yl}methanone (3c) and 1-{5-[5-methoxy-2-(benzimidazol-2-yl-sulfanyl)ethyl]-2H-tetrazol-2yl}methanone (3g) and the compounds (3a, 3e, 3f) were found to exhibit anti-inflammatory activity comparable to that of standard. All the compounds were found to cause less gastric ulceration than the standard drug diclofenac.

Zinc-aceclofenac complex: synthesis, hydrolysis study and antiinflammatory studies.

Aceclofenac, a nonsteroidal anti-inflammatory drug, has a propensity to cause gastric ulcers, while zinc ions are known to possess anti-ulcer and anti-inflammatory activities. With a view to reduce the gastroenteropathies associated with aceclofenac, its zinc complex was prepared and characterized using spectroscopy and differential scanning calorimetry. In vitro hydrolysis study showed that zinc complex of aceclofenac is more stable in HCl buffer (pH 1.2) than in phosphate buffer (pH 7.4) indicating the stability of the complex in stomach. In silico testing of the aceclofenac and its complex using PASS (Prediction of activity spectra of substances) software revealed that the complex might possess antiinflammatory activity which was confirmed by carrageenan-induced rat paw edema test. It has been found that antiinflammatory activity of this complex is comparable with that of parent drug along with reduction in ulcer index. Thus, the use of complex is suggested to be more preferable than aceclofenac alone.

Stability-Indicating LC Method for the Determination of Prasugrel Hydrochloride in Pharmaceutical Dosage Form.

A simple, rapid and precise method was developed for the quantitative estimation of prasugrel hydrochloride in pharmaceutical dosage form. A chromatographic separation of prasugrel and its degradants was achieved with Zorbax XDB C(8), 150 × 4.6 mm, 3.5µm analytical column using aqueous solution of 0.05 M ammonium acetate pH 4.5 with acetic acid-acetonitrile (40:60 v/v). The instrumental settings include flow rate of 1.0 ml/min, column temperature at 30°C and detector wavelength of 254 nm using a photodiode array detector. Theoretical plates for prasugrel were 7023. Tailing factor for prasugrel was 1.11. Prasugrel was exposed to thermal, photolytic, hydrolytic and oxidative stress conditions, and the stressed samples were analyzed by the proposed method. Peak homogeneity data of prasugrel was obtained using photodiode array detector in the stressed sample chromatograms, which demonstrated the specificity of the method for the estimation in presence of degradants. The described method showed excellent linearity over a range of 10-300 µg/ml for prasugrel. The correlation coefficient is 0.999. The relative standard deviation of peak area for six measurements is always less than 2%. Overall, the proposed method was found to be suitable and accurate for quantitative determination and stability study of prasugrel in pharmaceutical dosage form.