Volume 59 (2009): Issue 3 (September 2009)

Identification and characterization of different forms of methotrexate were carried out by crystallization from different solvents. Five different forms of the drug were obtained. Appearance of a desolvation endotherm in the DSC accompanied by mass loss in TGA for forms I, II, IV and V showed these forms to be acetonitrile solvate hydrate (form I), trihydrate (forms II and IV) and dimethylformamide solvate (form V), respectively. However, the desolvation peak was absent in form III (obtained from methanol) indicating the absence of any solvent of crystallization. This form was found to be partially crystalline by its XRPD pattern. Solution calorimetry was further used to differentiate between the forms as they differ in lattice energy, resulting in different enthalpies of solution. The dissolution and solubility profiles were correlated with the enthalpy of solution and subsequently with crystallinity of all the forms; the least endothermic form (form III) had the highest dissolution rate.

Novel organometallic compounds have been prepared by complexing the fluoroquinolones, norfloxacin, ofloxacin, ciprofloxacin, sparfloxacin, lomefloxacin, pefloxacin and gatifloxacin, with bismuth. The complexes were characterized by UV, IR, atomic absorption spectroscopy, elemental analysis, differential scanning calorimetry, thermogravimetric analysis and mass spectrometry. Their antibacterial potential against Helicobacter pylori and other microorganisms was investigated. These compounds were found to possess strong activity against Helicobacter pylori with a minimum inhibitory concentration of 0.5 mg L^-1. They also exhibited moderate activity against Escherichia coli, Staphylococcus aureus, Bacillus pumilus and Staphylococcus epidermidis. These bismuth-fluoroquinolone complexes have the potential to be developed as drugs against H. pylori related ailments.

The purpose of the present investigation was to produce a quick/slow biphasic delivery system for metoclopramide hydrochloride using the superdisintegrant Ac-di-sol for the fast release layer and hydroxypropyl methylcellulose K100M and Ucarflock 302 to modulate the release of the drug. A dual component tablet made up of a sustained release and an immediate release layer was prepared by direct compression. A 3² full factorial design was applied to systematically optimize the drug release profile of the sustained release layer. The results of the full factorial design indicate that a small amount of HPMC K100M and a large amount of Ucarflock 302 favor sustained release of the metoclopramide hydrochloride vaginal dual component system. The ex vivo residence time reveals that the formulation was retained for more than 10 h. The formulation gave an initial burst effect to provide the loading dose of the drug followed by sustained release for 12 h, thus solving the problem of repeated administration, especially in pregnancy.

The essential oil of air-dried Illicium anisatum (Illiciaceae), obtained by hydrodistillation was analyzed by gas chromatography-mass spectrometry (GC-MS). Fifty-two components were identified in the essential oil and the main component was eucalyptol (21.8 %). The antioxidant and anti-elastase activities of the essential oil were also investigated; the essential oil exhibited moderate DPPH scavenging and anti-elastase activities. To clarify the mechanism of the anti-inflammatory activities of I. anisatum essential oil (IAE), we evaluated whether it could modulate the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂) by activated macrophages. The results indicate that IAE is an effective inhibitor of LPS-induced NO and PGE₂ production in RAW 264.7 cells. These inhibitory activities were accompanied by dose-dependent decreases in the expression of iNOS and COX-2 proteins and iNOS and COX-2 mRNA. In order to determine whether IAE can be safely applied to human skin, the cytotoxic effects of IAE were determined by colorimetric MTT assays in human dermal fibroblast and keratinocyte HaCaT cells. IAE exhibited low cytotoxicity at 100 μg mL^-1. Based on these results, we suggest that IAE may be considered an anti-aging and anti-inflammatory candidate for cosmetic materials, but additional in vitro and in vivo tests have to be performed to prove its safety and efficacy.

This study is aimed to design and optimize a sublingual tablet formulation of physostigmine salicylate, an effective drug in Alzheimer's disease and nerve gas poisoning, by means of the D-optimal experimental design methodology. Polyvinyl pyrrolidone, lactose, starch 1500 and sodium starch glycolate were used in the formulations as independent variables. Tablets were prepared by the direct compression method and evaluated for their physical properties (tablet hardness, disintegration time and friability), which were regarded as responses in a D-optimal design. Due to the significance of the special cubic model for data fitted, compared to other models, it was used to examine the obtained results. Response surface plots were plotted to study the tablet properties and the optimized overlay plot was generated based on the results and targets considered for the responses. After verification of the optimum checkpoint formulations, an optimized formulation was chosen due to its desirable physical properties and closely observed and predicted values. Drug assay, content uniformity of the dosage unit, drug dissolution and accelerated stability studies were done on the optimum formulation as further experiments. All the obtained results complied with the requirements of a sublingual tablet formulation.

The purpose of the present research work was to observe the effects of drug solubility on their release kinetics of water soluble verpamil hydrochloride and insoluble aceclofenac from hydrophilic polymer based matrix formulations. Matrix formulations were prepared by the direct compression method. The formulations were evaluated for various physical parameters. Along with the dynamics of water uptake and erosion, SEM and in vitro drug release of the tablets were studied. Applying an exponential equation, it was found that the kinetics of soluble drug release followed anomalous non-Fickian diffusion transport whereas insoluble drug showed zero-order release. SEM study showed pore formation on the tablet surface that differed depending on drug solubility. t-Test pointed to a significant difference in amount of both drugs released due to the difference in solubility. Solubility of the drug effects kinetics and the mechanism of drug release.

Sterodin® is a novel non-specific immunostimulating drug produced by a combination of bile lipids and bacterial metabolites. In the present study, we investigated some of its (i) toxicological and (ii) pharmacological properties in vivo, and (iii) drug-lipid interaction (lipid peroxidation) in vitro. We also evaluated the possible (iv) Sterodin®-induced lipid peroxidation as well as the effect of ascorbic acid on this peroxidation. We found LD₅₀ of Sterodin® to be 31.50 mL kg^-1 body mass. In male albino mice, Sterodin® increased the total white blood cells and neutrophils count by 59 and 26%, respectively, on the 6^th day, compared to day 0 after injection and stimulated phagocytic activity in vivo. We used goat liver as lipid source in drug-lipid interaction studies in vitro. Our experiments show that Sterodin® induces lipid peroxidation, which was prevented by ascorbic acid.

Pharmacosomes are amphiphilic lipid vesicular systems that have shown their potential in improving the bioavailability of poorly water soluble as well as poorly lipophilic drugs. Diclofenac is a poorly water soluble drug and also causes gastrointestinal toxicity. To improve the water solublity of diclofenac, its pharmacosomes (phospholipid complex) have been prepared and evaluated for physicochemical analysis. Diclofenac was complexed with phosphatidylcholine (80%) in equimolar ratio, in the presence of dichloromethane, by the conventional solvent evaporation technique. Pharmacosomes thus prepared were evaluated for drug solubility, drug content, surface morphology (by scanning electron microscopy), phase transition behaviour (by differential scanning calorimetry), crystallinity (by X-ray powder diffraction) and in vitro dissolution. Pharmacosomes of diclofenac were found to be irregular or disc shaped with rough surfaces in SEM. Drug content was found to be 96.2 ± 1.1%. DSC thermograms and XRPD data confirmed the formation of the phospholipid complex. Water solubility of the prepared complex was found to be 22.1 μg mL^-1 as compared to 10.5 μg mL^-1 of diclofenac. This improvement in water solubility in prepared pharmacosomes may result in improved dissolution and lower gastrointestinal toxicity. Pharmacosomes showed 87.8% while the free diclofenac acid showed a total of only 60.4% drug release at the end of 10 h of dissolution study.

In the present work, a gastroretentive in situ gelling liquid formulation for controlled delivery of ranitidine was formulated using sodium alginate (low, medium and high viscosity grades), calcium carbonate (source of cations) and ranitidine. Prepared formulations were evaluated for viscosity, buoyancy lag time and buoyancy duration, drug content and in vitro drug release. Formulation variables such as concentration of sodium alginate, calcium carbonate and drug significantly affected the formulation viscosity, floating behavior and in vitro drug release. Analysis of the release pattern showed that the drug release from in situ gel followed a diffusion mechanism.

Eight novel 1-[2-(1H-tetrazol-5-yl)ethyl]-1H-benzo[d][1,2,3]triazoles (3a-h) have been synthesized in order to obtain new compounds with potential anti-nociceptive and anti-inflammatory activity. The titled compounds were synthesized by the condensation of 1-[2-(1H-tetrazol-5-yl) ethyl]-1H-benzotriazole (2) and appropriate acid chlorides. Compound 2 was synthesized by reacting 3-(1H-benzo[d][1,2,3]triazol-1-yl)propanonitrile (1) with sodium azide and ammonium chloride in the presence of dimethylformamide. The synthesized compounds were characterized by spectroscopic methods (IR, ¹H NMR, mass spectroscopy) and elemental analysis. The titled compounds were evaluated for anti-nociceptive activity by the hot plate method and the writhing response method, and anti-inflammatory activity was evaluated by the carragenean induced paw edema method. 5-(2-(1H-benzo[d][1,2,3]triazo-1-yl)ethyl)-1H-tetrazol-1-yl)(4-aminophenyl)methanone (3d) and 5-(2-(1H-benzo[d][1,2,3]triazo-1-yl)ethyl)-1H-tetrazol-1-yl)(2-hydroxyphenyl)methanone (3g) exhibited significant anti-nociceptive activity. 1-(2-(1-Tosyl-1H-tetrazol-5-yl)ethyl)-1H-benzo[d][1,2,3]triazole (3c) and 4,5-(2-(1H-benzo[d][1,2,3]triazo-1-yl)ethyl)-1H-tetrazol-1-yl sulfonyl)benzenamine (3f) elicited superior anti-inflammatory activity compared to other synthesized compounds. Further investigations are needed to discern the mechanism of action.