Alex Joseph

Novel Co-Processed Excipients of Mannitol and Microcrystalline Cellulose for Preparing Fast Dissolving Tablets of Glipizide

Co-processed particles of microcrystalline cellulose and mannitol were fabricated by spray drying technique to be used as a direct compression excipient in fast dissolving tablet formulation. Microcrystalline cellulose passed through sieve no.80, having a volumetric mean diameter (d 50 ) of 28.35 µm, was used to form composite particles with powdered mannitol which was previously passed through sieve no. 80, in various mixing ratios. The composite particles were evaluated for their powder and compression properties. An increase in the microcrystalline cellulose proportion imparted greater compressibility to the composite particles, but the flowability of these mixtures was decreased. Although microcrystalline cellulose and mannitol have been extensively used in the formulation of fast dissolving tablets, the non-wetting property of the hard compact central core may delay the disintegration time. Optimized co-processed formulation containing mannitol and microcrystalline cellulose in the ratio of 1.25:1 was found to have optimized powder and compressibility characteristics with fast disintegrating property (<15 s). Photomicrographs have shown that the mannitol crystals are fine and uniformly distributed in the microcrystalline matrix in spray dried form compared to physical mixture of the same combination. The fast disintegration may be due to the partial amorphization and formation of submicron particles of mannitol. These results indicated that improved fast dissolving tablets could be prepared by the co-processed mixture of microcrystalline cellulose and mannitol. Finally fast dissolving tablets of glipizide were prepared by blending with other excipients and compressed into tablets. Sensory study on disintegration time and mouth feel attributes ranked the present formulation based on grittiness, chalkiness and overall preference as the best.

Design and synthesis of novel 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles as selective COX-2 inhibitors with potent anti-inflammatory activity

A novel series of 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles were designed and synthesized for selective COX-2 inhibition with potent anti-inflammatory activity. Among the compounds tested, 9g (2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazole) was found to be the most potent inhibitor of COX-2 with IC50 of 0.31 μM showing promising degree of anti-inflammatory activity in the carrageenan-induced rat paw edema model with ED50 of 74.3 mg/kg. The lead compound 9g further showed suppression of acetic acid-induced writhes comparable to that of aspirin and gastro-sparing profile superior to the aspirin. Molecular docking analysis displayed higher binding affinity of ligands towards COX-2 than COX-1.

Synthesis and biological evaluation of some novel pyrazolines

Chalcones (2a and 2b) were prepared from 2-acetyl benzofuran (1) and condensed with different aromatic acid hydrazides (3a-o) to get the corresponding pyrazolines (4a-o and 5a-o). The structures of all these compounds have been established on the basis of analytical and spectral data. Compounds have been screened for antiinflammatory, antioxidant and antibacterial studies. Among the 7 compounds that were screened for antiinflammatory activity, compounds 4g and 5m showed 83.4% and 80.5% inhibition of oedema volume, while the standard drug (ibuprofen) showed inhibition of 91.9%. Compounds 4k and 5h showed moderate activity of 72.8% and 59.6% respectively. All the 30 compounds were tested for antioxidant activity at 1000, 500, 250, 100, 50, 25 and 10 mg/ml concentrations against standard drug ascorbic acid. Compounds 4g, 4h, 4k, 4m, 5g, 5h, 5k and 5m showed excellent antioxidant activity as compared with ascorbic acid. Among the 30 compounds that were screened against two Gram +ve ( Staphylococcus aureus and Bacillus subtilis ) and two gram -ve ( Escherichia coli and Pseudomonas aeruginosa ) organisms, compounds possessing p-chloro, p-fluoro, 2-amino-5-bromo, 2-hydroxy-5-nitro and 3,5-dichloro substitutions on the phenyl ring showed good activity against Escherichia coli and Bacillus subtilis . The activity is comparable with that of the standard drug ciprofloxacin.

Simultaneous Estimation of Esomeprazole and Domperidone by UV Spectrophotometric Method.

A novel, simple, sensitive and rapid spectrophotometric method has been developed for simultaneous estimation of esomeprazole and domperidone. The method involved solving simultaneous equations based on measurement of absorbance at two wavelengths, 301 nm and 284 nm, λ max of esomeprazole and domperidone respectively. Beers law was obeyed in the concentration range of 5-20 μg/ml and 8-30 μg/ml for esomeprazole and domperidone respectively. The method was found to be precise, accurate, and specific. The proposed method was successfully applied to estimation of esomeprazole and domperidone in combined solid dosage form.

Synthesis, in vitro anticancer and antioxidant activity of thiadiazole substituted thiazolidin-4-ones

Abstract A series of novel 5-alkyl/aryl thiadiazole substituted thiazolidin-4-ones were synthesized by a two-step process. In the first step, 5-alkyl/aryl substituted 2-aminothiadiazoles were synthesized, which on reaction with substituted aromatic aldehydes and thioglycolic acid in the presence of dicyclohexylcarbodiimide afforded thiazolidin- 4-ones. All the compounds were synthesized in fairly good yields and their structures were confirmed by spectral and physical data. The title compounds were screened for in vitro anti-proliferative activity on human breast adenocarcinoma cells (MCF-7) by MTT assay. Most of the derivatives showed an IC50 less than 150 μmol L-1. Among the compounds tested, 2-(2-nitrophenyl)- 3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3f), 2-(3-fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2- -yl)-thiazolidin-4-one (3b), and 2-(4-chlorophenyl)-3- -(5-methyl-1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3c) were found to be the most active derivatives with IC50 values of 46.34, 66.84, and 60.71 μmol L-1, respectively. Antioxidant studies of all the synthesized compounds were carried out by diphenylpicrylhydrazyl (DPPH) assay. Among the compounds tested, 2-phenyl-3-(5-styryl- -1,3,4-thiadiazol-2-yl)-thiazolidin-4-one (3s) elicited superior antioxidant activity with IC50 of 161.93 μmol L-1.

Development and evaluation of carboplatin-loaded PCL nanoparticles for intranasal delivery

Abstract Context: The study was aimed to develop a polymeric nanoparticle formulation of anticancer drug carboplatin using biodegradable polymer polycaprolactone (PCL). The formulation is intended for intranasal administration to treat glioma anticipating improved brain delivery as nasal route possess direct access to brain and nanoparticles have small size to overcome the mucosal and blood–brain barrier. Objective: Development and evaluation of carboplatin-PCL nanoparticles for brain delivery by nasal route. Methodology: Carboplatin-loaded PCL nanoparticles (CPCs) were prepared by double emulsion-solvent evaporation technique and characterized by particle size, zeta potential, entrapment efficiency, scanning electron microscopy and differential scanning calorimetry. The CPCs were assessed for in vitro release kinetics, ex vivo permeation and in situ nasal perfusion. Cytotoxic potential of CPCs in vitro was evaluated on LN229 human glioblastoma cells. Results and discussion: The optimized formulation of carboplatin-PCL nanoparticle CPC-08 with particle size of 311.6 ± 4.7 nm and zeta potential −16.3 ± 3.7 mV exhibited percentage entrapment efficiency of 27.95 ± 4.21. In vitro drug release showed initial burst release followed by slow and continues release indicating biphasic pattern. The ex vivo permeation pattern through sheep nasal mucosa also exhibited a similar release pattern as for in vitro release studies. In situ nasal perfusion studies in Wistar rats demonstrate that CPCs show better nasal absorption than carboplatin solution. In vitro cytotoxicity studies on LN229 cells showed an enhancement in cytotoxicity by CPCs compared to carboplatin alone. Conclusion: CPC-08 effectively improves nasal absorption of carboplatin and can be used for intranasal administration of carboplatin for improved brain delivery.

Determination of racecadotril by HPLC in capsules

A simple, precise and rapid RP-HPLC method was developed for the determination of racecadotril in a pharmaceutical formulation using gemfibrozil as internal standard. Ratio of the peak area of analyte to internal standard was used for quantification. The chromatographic separation was carried out by using a Reverse Phase C18 column (BDS-Hypersil). The mobile phase consisting of a mixture of 20 mM phosphate buffer (pH 3.5) and acetonitrile in the ratio of (40:60) with detection at 230 nm at a flow rate of 1 ml/min was employed. The method was statistically validated for linearity, accuracy and precision. The elution time was 6.9 min for racecadotril and 9.8 min for gemfibrozil. The simplicity and accuracy of the proposed method ensures its use in routine quality control analysis of pharmaceutical formulations.

Development and validation of stability indicating method for the quantitative determination of venlafaxine hydrochloride in extended release formulation using high performance liquid chromatography

Objective: Venlafaxine,hydrochloride is a structurally novel phenethyl bicyclic antidepressant, and is usually categorized as a serotonin–norepinephrine reuptake inhibitor (SNRI) but it has been referred to as a serotonin–norepinephrine–dopamine reuptake inhibitor. It inhibits the reuptake of dopamine. Venlafaxine HCL is widely prescribed in the form of sustained release formulations. In the current article we are reporting the development and validation of a fast and simple stability indicating, isocratic high performance liquid chromatographic (HPLC) method for the determination of venlafaxine hydrochloride in sustained release formulations. Materials and Methods: The quantitative determination of venlafaxine hydrochloride was performed on a Kromasil C18 analytical column (250 × 4.6 mm i.d., 5 μm particle size) with 0.01 M phosphate buffer (pH 4.5): methanol (40: 60) as a mobile phase, at a flow rate of 1.0 ml/min. For HPLC methods, UV detection was made at 225 nm. Results: During method validation, parameters such as precision, linearity, accuracy, stability, limit of quantification and detection and specificity were evaluated, which remained within acceptable limits. Conclusions: The method has been successfully applied for the quantification and dissolution profiling of Venlafaxine HCL in sustained release formulation. The method presents a simple and reliable solution for the routine quantitative analysis of Venlafaxine HCL.

Design, synthesis, and biological evaluation of oxindole derivatives as antidepressive agents.

The 3-substituted oxindole derivatives were designed, synthesized, and evaluated for antidepressant activity by employing forced swimming test, tail suspension test, and MAO-A inhibition assay. Results of biological studies revealed that the majority of compounds exhibited potent to moderately potent activity and among them, 12 displayed potency comparable to that of the imipramine with %DID of 37.95 and 44.84 in the FST and TST, respectively. At the same time, imipramine showed %DID of 43.62 and 50.64 in the FST and TST, correspondingly. In the MAO-A inhibition assay, 12 showed an IC50 of 18.27 μmol, whereas the reference drug moclobemide displayed an IC50 of 13.1 μmol. The SAR study disclosed that the presence of bromo atom at the phenyl/furanyl or thienyl moiety in the oxindole derivatives was critical for the antidepressant activity.

Synthesis and evaluation of a series of novel imidazolidinone analogues of 6-aminoflavone as anticancer and anti-inflammatory agents

The flavone moiety is a potential pharmacophore known for its diverse range of pharmacological activities. Aminoflavones have recently been the subject of considerable attention as lead molecules in several cancer research projects. Imidazolidinone heterocycles represent another biologically active scaffold with known cytotoxic properties. In an attempt to provide synergistic cytotoxic activity, these two moieties have been combined, and the resulting novel analogues evaluated for their anticancer and anti-inflammatory activities. The results revealed that the cytotoxicities of these compounds were fivefold greater than those of aminoflavone. DNA histograms obtained from cell cycle analysis in the presence of these compounds were apoptotic in their nature. Furthermore, the in vivo screening of these compounds using Ehrlich’s ascites tumour model showed an increase in life span, whereas an in vivo anti-inflammatory study resulted in the enhancement of the anti-inflammatory potential. The results therefore supported the hypothesis that there is a relationship between inflammation and cancer.