SOLUBILITY ENHANCEMENT OF KETOCONAZOLE VIA SALT AND COCRYSTAL FORMATION

Objective: Pharmaceutical salt and cocrystal is a promising alternative method for improving the solubility and dissolution rate of active pharmaceutical ingredients. In this work, an attempt was made to improve solubility of ketoconazole (KTZ) using salt formation and cocrystallization technique.Methods: Salt and cocrystal were prepared using oxalic acid (OXA) and fumaric acid (FUMA) via slurry conversion method. Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC) and Scanning Electron Microscope (SEM) techniques were employed to investigate the crystallinity, melting point and morphology of salt and cocrystal respectively. KTZ salt and cocrystal were evaluated further for their solubility, stability and antifungal activities.Results: Synthesis of KTZ OXA salt and KTZ FUMA cocrystal were successfully carried out using slurry conversion method using ethyl acetate solvent. The result from PXRD, DSC and SEM analysis confirms the formation of salt and cocrystal of KTZ with OXA and FUMA. Saturation solubility studies in water at 25 °C exhibited a remarkable improvement in the drug solubility. KTZ FUMA and KTZ OXA were considered to be stable over the period of 1 month confirmed by the stability study. In vitro antifungal activity study revealed that the formation of KTZ OXA and KTZ FUMA did not alter the therapeutic activity as an antifungal agent.Conclusion: Salt and cocrystal of KTZ (KTZ OXA and KTZ FUMA) exhibit enhanced solubility compare the pure drug. In vitro antifungal study revealed that both salt and cocrystal of KTZ retained their antifungal activities

SIMULTANEOUS COCRYSTALLIZATION AND MICRONIZATION OF PARACETAMOL-DIPICOLINIC ACID COCRYSTAL BY SUPERCRITICAL ANTISOLVENT (SAS)

Objective: This present study aims to produce cocrystal of paracetamol (PCA)-dipicolinic acid (DPA) using supercritical antisolvent (SAS) cocrystallization process in order to improve tabletability profile of PCA.Methods: The PCA-DPA cocrystal prepared by SAS cocrystallization were compared to those produced using a traditional solvent evaporation. The cocrystals produced were characterized using Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Polarized Light Microscopy (PLM), Fourier Transform Infrared (FTIR) spectroscopy, particle size analysis, Scanning Electron Microscopy (SEM) and High Performance Liquid Chromatography (HPLC). Analysis of flowability, drug content, solubility, dissolution, stability and powder compaction were performed to evaluate the cocrystals.Results: Cocrystal particles with mean diameter of 4.18 µm were produced from SAS process, smaller than those produced by traditional solvent evaporation method (mean diameter of 64.93 μm). The PCA-DPA cocrystal from SAS process showed an enhanced dissolution rate by 2.45 times compared to PCA, higher than cocrystal from traditional solvent evaporation (enhanced dissolution rate by 1.72 times compared to PCA). Tabletability study revealed superior tableting performance of both cocrystals compared to PCA.Conclusion: This study showed the utility of PCA-DPA cocrystal to improve mechanical properties of PCA while also demonstrating that simultaneous micronization and cocrystallization process can be obtained using SAS process.Â

Simultaneous micronization and purification of bioactive fraction by supercritical antisolvent technology

Simultaneous micronization and purification of DLBS3233 bioactive fraction, a combination of two Indonesian herbals Lagerstroemia speciosa and Cinnamomum burmannii has been successfully performed via supercritical anti-solvent (SAS) technology. The objective of the present study was to investigate the effectiveness of SAS technology to micronize and reduce coumarin content of DLBS3233. The effects of four SAS process parameters, i.e. pressure, temperature, concentration and solution flow rate on particle formation were investigated. In SAS process, DLBS3233 was dissolved in dimethylformamide (DMF) as the liquid solvent. The solution was then pumped through a nozzle into a chamber simultaneously with supercritical carbon dioxide (SC-CO2) which acts as the anti-solvent, resulting in DLBS3233 precipitation. Physicochemical properties of unprocessed DLBS3233 and SAS-processed DLBS3233 particles were analyzed using scanning electron microscopy (SEM) and high pressure liquid chromatography (HPLC). Total polyphenol content (TPC) was also analyzed.Particles with mean particle size ranging from 0.107±0.028 μm to 0.298±0.138 μm were obtained by varying the process parameters. SAS-processed DLBS3233 particles showed no coumarin content in all experiments studied in this work. Results of TPC analysis revealed no significant change in SAS-processed DLBS3233 particles compared to unprocessed DLBS3233. Nano-sized DLBS3233 particles with no coumarin content have been successfully produced using SAS process. This study demonstrates the ability of SAS for processing herbal medicine in single step process