(612a) Simultaneous Production and Co-Mixing of Itraconazole Nanoflakes with Stabilizers and Excipients by a Supercritical Antisolvent Method, for Dissolution Enhancement

Nanoflakes of itraconazole, an antifungal drug with poor bioavailability, were prepared by supercritical antisolvent (SAS) method and simultaneously deposited on the surface of an excipient, spray dried lactose, to reduce itraconazole particle agglomeration. In this method, termed supercritical antisolvent-drug excipient mixing (SAS-DEM), the itraconazole is precipitated in a high pressure vessel containing supercritical CO2 and suspended excipient particles. Various ratios of drug, stabilizer, and excipient were chosen to determine in which formulations the drug uniformly coated the surface of the excipient, thus reducing agglomeration and increasing drug dissolution. The two stabilizers examined in this work were sodium lauryl sulfate (SLS) and Pluronic F127. The mixtures were characterized for surface morphology by scanning electron microscopy (SEM), crystallinity by X-ray diffraction (XRD), and physicochemical properties by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). Drug content assays and dissolution studies were also carried out for each mixture.

SEM analysis confirms that an intimate mixture of itraconazole and spray dried lactose can be obtained using the SAS-DEM process and demonstrates that when appropriate drug to excipient ratios and stabilizers are selected, drug particle agglomeration is overcome. The XRD results indicate that the crystallinity of the itraconazole was not altered by the SAS process, while the DSC and FTIR results confirm that the physicochemical properties of itraconazole were not significantly impacted either. The dissolution of the itraconazole, Pluronic F127, and spray-dried lactose mixture obtained by SAS-DEM is significantly faster than SAS drug nanoflakes alone or when the nanoflakes were physically mixed with lactose. Through use of SEM, XRD, DSC, FTIR, and dissolution studies, it is shown that the SAS-DEM method is effective in overcoming drug particle agglomeration and increasing drug dissolution rate without altering the crystal structure or chemical properties of itraconazole.