SOLID-STATE PROPERTIES AND SOLUBILITY STUDIES OF NOVEL PHARMACEUTICAL COCRYSTAL OF ITRACONAZOLE

Objective: Pharmaceutical cocrystal is a promising method to improve the solubility of active pharmaceutical ingredients (APIs). Itraconazole (ITZ) is a BCS class II antifungal drug with poor aqueous solubility, therefore an attempt was made to improve the solubility of ITZ using cocrystallization technique. In this work, six novel pharmaceutical cocrystals of ITZ with various coformers, including 4-hydroxybenzoic acid (4HBA), trans-cinnamic acid (TCA), suberic acid (SUB), sebacic acid (SBC), 1-hydroxy-2-naphthoic acid (1H2N), and benzamide (BZD) were prepared.Methods: ITZ cocrystals was prepared by solvent evaporation process. The cocrystals produced were characterized using powder x-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and fourier transform infrared (FTIR) spectroscopy. Solubility analysis was performed to evaluate the cocrystals.Results: PXRD and DSC analysis revealed that the pattern of all ITZ cocrystals was distinguishable from the individual compounds which indicates the formation of new phase. The solubility of ITZ and its cocrystals from highest to lowest after 24 h in 0.1 N HCl solution (pH 1.2) follows the order ITZ-TCA (1.97-fold), ITZ-SBC (1.09-fold), ITZ, ITZ-1H2N (0.58-fold) and ITZ-4HBA (0.46-fold).Conclusion: This study demonstrates that the selection of coformers has pronounced an impact on the physicochemical properties of ITZ. Based on this study, it can be concluded that cocrystallization offers a valuable way to improve the solubility of ITZ

PROCESSING PARACETAMOL-5-NITROISOPHTHALIC ACID COCRYSTAL USING SUPERCRITICAL CO2 AS AN ANTI-SOLVENT

Objective: A new method of cocrystallization based on the use of supercritical carbon dioxide (CO2) as an anti-solvent was explored. In the present study, we investigate and analyze paracetamol (PCA)-5-nitroisophthalic acid (5NIP) cocrystal produced using supercritical anti-solvent (SAS) process. Methods: PCA-5NIP cocrystals prepared by SAS cocrystallization were compared to those produced using traditional solvent evaporation by rapid evaporation (RE) process. 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 and scanning electron microscopy (SEM). Results: The products obtained from SAS and RE process exhibited identical PXRD spectra and were distinguishable from the individual compounds, indicating the formation of a new phase. DSC analysis revealed that PCA-5NIP cocrystals from each method possess similar melting point which lies between the melting points of the parent compounds. Cocrystal particles with a mean diameter of 4.66 µm were produced from SAS process, which was smaller than those produced by traditional solvent evaporation method with a mean diameter of 38.09 μm. Conclusion: This study demonstrates the ability of SAS process to produce the submicron size of PCA-5NIP cocrystal with altered physicochemical properties in a single step process

SUPERCRITICAL CARBON DIOXIDE EXTRACTION OF CITRONELLA OIL FROM CYMBOPOGON WINTERIANUS USING TAGUCHI ORTHOGONAL ARRAY DESIGN

Objective: Optimum condition for the extraction of citronella oil from citronella (Cymbopogon winterianus) using supercritical carbon dioxide (SC-CO2) was investigated.Methods: In order to determine the optimum extraction condition, a Taguchi experiment with L9 orthogonal array design was used. Effects of pressure, temperature and dynamic extraction time on citronella oil yield were investigated at levels ranging between 10-15 MPa, 35-45 °C and 60-180 min, respectively.Results: The highest citronella oil yield (3.206%) was achieved at a factor combination of 15 MPa, 50 °C and 180 min. The obtained citronella oil yield from SC-CO2 extraction was higher than that of percolation as the solvent extraction method using ethanol, which gave a citronella oil yield of 1.4%. The experimental oil yield at optimum condition was in accordance to the values predicted by a computational process using Taguchi method. Analysis of variance (ANOVA) with 95% confidence interval indicates that extraction temperature is the most significant factor in maximizing citronella oil yield, followed by dynamic extraction time and pressure.Conclusion: Optimization process for oil yield from SC-CO2extraction of citronella (Cymbopogon winterianus) was successfully performed using Taguchi L9 orthogonal array design. This study demonstrates that Taguchi method was able to simplify the experimental procedure of SC-CO2 process.Â

SUPERCRITICAL CARBON DIOXIDE EXTRACTION OF MANGO GINGER (CURCUMA MANGGA ROXB.): PROCESS OPTIMIZATION USING TAGUCHI METHOD

Objective: Extraction of Curcuma mangga (C. mangga) using supercritical carbon dioxide (SC-CO2) was investigated to provide information about the optimum extraction condition. Methods: A Taguchi method with L9 orthogonal array design was used to determine the optimum extraction conditions. Effects of extraction pressure, temperature, CO2 flow rate and dynamic extraction time on C. mangga oil yield were investigated at levels ranging between 150-350 bar, 40-60 °C, 10-20 g/min and 120-240 min, respectively. Results: The highest C. mangga oil yield (5.223%) from SC-CO2 extraction was obtained at a pressure of 350 bar, temperature of 60 °C, CO2 flow rate of 20 g/min and dynamic extraction time of 240 min. The experimental C. mangga oil yield at optimum condition was in a good agreement with the values predicted by computational process using Taguchi method. Based on S/N ratio calculation, the most influencing parameters in maximizing C. mangga oil yield is extraction temperature, followed by extraction pressure, dynamic extraction time and CO2 flow rate. Conclusion: In this study, Taguchi method was successfully applied to optimize SC-CO2 extraction of C. mangga. Taguchi method was able to simplify the experimental procedure of SC-CO2 extraction

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