Characterization and Antiproliferative Activity of a Novel 2-Aminothiophene Derivative-β-Cyclodextrin Binary System

The novel 2-aminothiophene derivative 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (6CN) has shown potential anti-proliferative activity in human cancer cell lines. However, the poor aqueous solubility of 6CN impairs its clinical use. This work aimed to develop binary 6CN-β-cyclodextrin (βCD) systems with the purpose of increasing 6CN solubility in water and therefore, to improve its pharmacological activity. The 6CN-βCD binary systems were prepared by physical mixing, kneading and rotary evaporation methods and further characterized by FTIR, XRD, DSC, TG and SEM. In addition, molecular modeling and phase solubility studies were performed. Finally, MTT assays were performed to investigate the cytostatic and anti-proliferative effects of 6CN-βCD binary systems. The characterization results show evident changes in the physicochemical properties of 6CN after the formation of the binary systems with βCD. In addition, 6CN was associated with βCD in aqueous solution and the solid state, which was confirmed by molecular modeling and the aforementioned characterization techniques. Phase solubility studies indicated that βCD forms stable 1:1 complexes with 6CN. The MTT assay demonstrated the cytostatic and anti-proliferative activities of 6CN-βCD binary systems and therefore, these might be considered as promising candidates for new anticancer drugs.

COMPARATIVE STUDIES WITH DIFFERENT CYCLODEXTRIN DERIVATIVES IN IMPROVING THE SOLUBILITY AND DISSOLUTION OF SAQUINAVIR

Objective: The present study was aimed to perform comparative studies with different cyclodextrin (CD) derivatives and to study the effect of different methods of preparation in improving the solubility and dissolution of saquinavir (SQV).Methods: Phase solubility studies were performed with beta CD (βCD), hydroxypropyl βCD, randomly methylated βCD, and sulfobutyl ether βCD (SBE7βCD). Complexes were prepared using physical mixture, coevaporation, kneading, spray drying, and freeze-drying techniques. For complexes prepared by spray drying, process parameters were optimized based on percentage yield. The prepared complexes were characterized using Fourier-transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction studies, nuclear magnetic resonance spectroscopy, and scanning electron microscopy. In vitro drug release study was conducted in phosphate buffer pH 6.8 and mean dissolution time (MDT) was calculated for all freeze-dried complexes.Results: Phase solubility studies showed a linear relationship with an increase in CD concentration and phase diagrams were of AL type. Highest stability constant was observed with SQV-SBE7βCD (8281.28/M). All characterization studies proved complexation. Among four CD derivatives, SQV complexed with SBE7βCD by freeze-drying showed maximum drug release and low MDT of 20.67.Conclusion: Among different CDs, SBE7βCD proved as ideal CD derivative, and among different methods of preparations, freeze-drying method was found to be useful in improving the solubility and dissolution of SQV.

PHASE SOLUBILITY STUDIES OF ONDANSETRON -2- HYDROXYPROPYL BETACYCLODEXTRIN FOR DEVELOPMENT OF ONDANSETRON ORODISPERSIBLE FILMS

The present research work was aimed to formulate transparent mouth dissolving films of ondansetron. Ondansetron is poorly soluble in aqueous solvents (less than 5 mg/mL) and thus improvisation in solubility was crucial. The phase solubility studies were carried in order to study the formation of inclusion complex with Hydroxy Propyl Beta cyclodextrin. The phase solubility diagrams revealed the formation of stable inclusion complex and apparent stability constants were evaluated. The calculated apparent stability constant, Kc was found to be 288.5 mol-1. The shape of solubility graph indicated that there is probability of the formation of 1:1complex with respect to HP-b-CD concentration (Slope of less than 1). The Scanning Electron Microscopy study of plain ondansetron and ondansetron orodispersible film revealed the formation of stable inclusion complex, which renders the complete solubilisation of ondansetron, yielding the formation of transparent mouth dissolving films.

Preparation and Cyclodextrin Solubilization of the Antibacterial Agent Benzoyl Metronidazole

A one-pot method for the preparation of benzoyl metronidazole was achieved by usingN,N′-carbonyldiimidazole as a coupling reagent. Moreover, it was found that the byproduct imidazole as the catalyst promoted the reaction. In addition, theβ-cyclodextrin solubilization of benzoyl metronidazole was investigated by phase-solubility method. The phase-solubility studies indicated that the solubility of benzoyl metronidazole (S=0.1435 g/L) was substantially increased 9.7-fold (S′=1.3881 g/L) by formation of 1 : 1 benzoyl metronidazole/β-cyclodextrin complexes in water, and the association constantKavalue was determined to be 251 (±23) dm3/mol. Therefore,β-cyclodextrin can work as a pharmaceutical solubilizer for benzoyl metronidazole and may improve its oral bioavailability.