The Study Of Felodipine Solid Dispersion Based On Hydroxypropyl Methylcellulose Via Hot Melt Extrusion

More than 50%of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II?BCS class II?,which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability.Therefore,there is a critical need to develop formulations that will enhance the solubility and bioavailability of these compounds.Solid dispersion has been proved to be one of the promising technologies to improve the solubility,dissolution and bioavailability.Hot-melt extrusion?HME?is a promising technology to produce SDs for the production of new chemical entities and for improving products already on the market.Hydroxypropyl methylcellulose?HPMC?is a hydrophilic polymer with the limited application in hot-melt extrusion?HME?due to its high glass transition temperature?T_g191 ^oC?and melt viscosity.The aim of this study is select poorly water-soluble drug felodipine?FLDP?as model drug to explore lower viscosity grade of hydroxypropyl cellulose(HPC_EF)in combination with HPMC_K15M or use HPMC HME_15LV as polymer carrier for fabricating controlled-release or immediate-release SDs via HME.The molten rheological properties of FLDP and HPMC,the mechanical and microstructural characterization and the mechanisms of HPMC on the formation,dissolution and stability were Investigated.FLDP/HPC_EF/HPMC_K15M controlled-release SD prepared via HME by using the rheological,mechanical and microstructural characterization tools.Results indicated30%maximum solubility of FLDP in the molten HPC_EF/HPMC_K15M.FLDP,as a stronger plasticizer than HPC_EF and their combining plasticization on HPMC_K15M,induced the smooth and regularly shaped extrudates loading up to 50%FLDP at 160^oC and torque of 0.1-0.5 N·m.The asymmetric microstructure of the FLDP/HPC_EF/HPMC_K15M extrudates with the dense surface and loose interior were discovered under SEM.The EDX resulted FLDP is homogeneously molecular dispersion in HPC_EF/HPMC_K15M.FT-IR and DSC confirmed hydrogen bonding of FLDP with HPC_EF/HPMC_K15M,and amorphous state with 30%preloaded FLDP.The hot-melt extruded FLDP/HPC_EF/HPMC_K15M?10:45:45 and 30:35:35?matrices showed24 h zero-order controlled release,low moisture absorption,and enhanced stability.HPC_EF/HPMC_K15M provide an alternative potential approach to control release poorly-water soluble drugs via hot melt extrusion.Further,FLDP immediate-release SD was prepared by HME using HPMC HME_15LV as a polymer carrier.The melt rheological properties of FLDP/HPMC HME_15LV5LV were investigated in comparison with HPC_EF/HPMC_K15M.PLM,DSC,PXRD and FT-IR were used to study the crystal form and intermolecular forces of the extrudates.Factors influencing the in vitro dissolution and stability of FLDP/HPMC HME_15LV extrudates were investigated.HPMC HME_15LV was report as an amorphous polymer,however,due to the presence of the microcrystalline domain,it still appeared as a colored bright spot in the PLM,which makes it impossible to identify the FLDP/HPMC HME_15LV by PLM.HPMC HME_15LV is an effective recrystallization inhibitor of FLDP and exhibits superior crystal inhibition performance than conventional HPMC(including HPMC_E3,HPMC_E15,HPMC_k100LV),HPC(including HPC-L,HPC_EF),HEC and PVA.The dissolution rate and the dissolution amount of the SD powder were affected by the particle size of the powder,the same extrudate can further adjust the dissolution rate by controlling the particle size,and usually the powder particle size can be completely dissolved under 80 mesh.The addition of filler,disintegrator and lubricant to compress the SD powder into tablet can increase the dissolution rate and the dissolution amount.However,the stability of the SD can not be increased,and the type of the filler and the disintegrator did not affect the stability of the tablet.The stress tests results showed the stability of SD was greatly affected by temperature.The dissolution was decreased to 40%-50%after 60min when placed at60°C for 10 days.To storage extrudates in strips can improve its stability to some extent because in the strip structure,amorphous drug molecules are incorporated into the complex network structure of the polymer,and the polymer reduced the molecular mobility of amorphous drugs.