The Formability And Stabilization Of Solid Dispersions Prepared By Ball Milling

A considerable proportion(about 40%) of recently discovered drug candidates are poorly water soluble and therefore have limited bioavailability.The solid dispersion technique for water-insoluble drugs developed by Chiou and Reigelman provides an efficient method to improve the dissolution rate of a drug.In this thesis,FLDP solid dispersions were prepared by high-energy ball milling,and three different viscosity of hydroxypropyl cellulose(HPC-L,HPC-SL,HPC-SSL),hydroxypropyl methyl cellulose acetate succinate(HPMCAS-MF)or amphiphilic polymer polyethylene caprolactam-poly(vinyl acetate-polyethylene glycol(peg)graft copolymer(Soluplus ?)as the carriers of FLDP solid dispersions.Detailed characterization was performed using PLM,differential scanning calorimetry,powder FT – IR and in-vitro dissolution testing.Dissolution profiles were evaluated in the presence of sodium dodecyl sulphate.Stability of different solid dispersions was studied stress test and accelerated test.The results of FLDP-HPC SD indicate that when the drug loading ratio is 1:1,the cumulative dissolution in 60 min are 90.4%±1.3%?90.9%±1.7% and 85.4%±2.8%.When the drug loading ratio of 2:1,the cumulative dissolution of solid dispersion declines 10% compared with the drug load ratio of 1:1,especially FLDP-HPC-SSL solid dispersions stripping down more obvious,only had 59.3%±4.0%.PLM observation found that FLDP in the form of amorphous and microcrystalline evenly dispersed within the HPC polymer chain in FLDP-HPC solid dispersions.The result of High temperature 60 ? test demonstrates that FLDP-HPC solid dispersions can remain stable.However,FLDP-HPC SD influenced by strong light and high humidity,under the action of strong light and high humidity,the dissolution of SD were dropped,and with the increase of the viscosity of the HPC,the dissolution drop deeper.In order to improve the stability,solid dispersions using different flexible polymer Soluplus and HPMCAS-MF,were prepared by ball milling method to comparative study.The particle size of FLDP-Soluplus was smaller than FLDP-HPMCAS-MF,two kinds of material in the preparation of the solid dispersions of drugs are distributed in the form of amorphous and microcrystalline by the PLM results.In vitro dissolution test,The cumulative dissolution of FLDP-Soluplus SD was higher than FLDP-HPMCAS SD about 20%,stress test showed that high temperature,high humidity and strong light are not affected on the stability of the two kinds of solid dispersions.Surfactants used as solubilizer in order to improve the solubility of difficult soluble drugs,or add in dissolution medium to promote the dissolution of difficult soluble drug,achieve the correlation between in vivo and in vitro.This research adopts the ball milling to prepare the solid dispersions,and research the influence on the formability,the in vitro dissolution and stability of FLDP SD.Results showed that surfactants(SDS,Poloxamer P407 and P188)were improved the dispersion of FLDP in ball grinding process,FLDP may be in the amorphous and microcrystalline coexist,and improve the dissolution rate of FLDP.FLDP-HPMCAS-SDS ternary solid dispersions can find visible blue opalescence in dissolution process,become a self-assembly nanometer dispersive system.By DSC and Fourier infrared spectroscopic analysis showed that the S=O and C=O can produce hydrogen bonds to felodipine,at the same time,SDS and HPMCAS-MF have intermolecular action,so FLDP,HPMCAS and SDS can be assembled a stable system..Stability of different solid dispersions was studied under accelerated conditions(40°C/75% RH)over 6 months.FLDP-HPMCASMF-SDS(5:15:1)was more stability than then FLDP-HPMCASMF(1:3) binary solid dispersion.