Composite Ibuprofen/Lipid Particles By PGSS

Supercritical fluid(SCF) technology for manufacturing fine particles is developing rapidly,while the extention of the technology in producing drug composite particles with controlled release has become another hot research topic in recent years.Particle formation from gas-saturated solutions(PGSS) is a relatively new process,which has revealled its superiority in drug micronization and producing composite particles.In this work,by using the N₂-assisted and CO₂-assisted PGSS processes,ibuprofen/lipid composite particles were investigated on the base of the solid-liquid-gas(SLG) phase equilibria of the single-solid and binary-solid containing ibuprofen or/and lipids in high pressure CO₂ and N₂.PR-UNIFAC model was established for the prediction of the SLG equilibria of ibuprofen,myristic acid,biphenyl,naphthalene,and tripalmitin in CO₂.The model shows good predictions in comparison with experimental data,with the average absolute deviations for meting temperatures(AADT) being less than 5℃.Comparing with our previously reported PR-LCVM model,the two models show good agreement with the experimental data of the ibuprofen/CO₂ and myristic acid/CO₂ systems,but the PR-LCVM model fails to give predictions for the systems containing biphenyl,naphthalene,and tripalmitin.Meanwhile,a new apparatus was constructed for measuring the melting points of solid solutes in high pressure gases.Then the SLG equilibrium data for myristic acid, palmitic acid,stearic acid and tripalmitin in N₂ were determined and caculated by the PR-UNIFAC model with AADT less than 2℃.A simplified PR-UNIFAC was also applied, which provides fairly good predictions,suggesting that this simplication can be used for estimation of the SLG equilibria of solid solutes in high pressure N₂.With the new apparatus,the first and last melting points approach was proposed to determine the SLG equilibrium data of the binay-solid ibuprofen/myristic acid and ibuprofen/tripalmitin in CO₂.The SLG data of the ternary systems determined at atmospheric pressure are in line with those from DSC.At low pressures(0.1MPa and 6MPa),the binary-solid ibuprofen/myrisitc acid shows the simple eutectic phase diagram, while it changes to the solid solution phase diagram at high pressures(10MPa and 15MPa). The content of ibuprofen(in mass) is 50%at the eutectic point.Similarly,it is found that the binary-solid ibuprofen/tripalmitin belongs to the simple eutectic phase diagram at low pressures and solid solution phase diagram at high pressures.The content of ibuprofen increases from 40%to 60%at the eutectic point following the increase of the pressure from 0.1 to 10MPa.Based on the SLG studies of the ibuprofen/myristic acid system,the influence of SCF and ibuprofen's content on particle size and particle size distribution(PSD) on the produced composite particles was investigated by using PGSS.Fastest dissolution of ibuprofen from the composite particles is shown when the content of ibuprofen at the eutectic point(0.5). Infrared analysis shows that hydrogen bond between ibuprofen and myristic acid exisits, explaining why the dissolution of ibuprofen is enhanced at its molar fraction of 0.5.The composite particles show similar particle sizes to that of pure myrstic acid from the N₂-assisted PGSS process,while the composite particles have a large average particle size and wide PSD,compared to that of pure myristic acid from the CO₂-assisted PGSS process.By using the CO₂-assisted and N₂-assisted PGSS processes,tripalmitn particles were generated.Results show that spherical particles with some needle-like particles or plates can be found from the CO₂-assisted PGSS with the average particle sizes between 1-5μm; in the investigated ranges,a high pre-expansion pressure favors to produce small particles with narrow PSD,and the nozzle size and the pre-expansion temperature show no evident effect on the particle size and PSD.Spherical particles can be obtained from the N₂-assisted PGSS with the average particle sizes between 1-5μm;in the investigated ranges,a high pre-expansion pressure favors to produce small particles with narrow PSD,and a high pre-expansion temperature favors to produce large particles,and the 100μm-nozzle provides small particles with narrow PSDs.Based on the conditions for generating pure tripalmitin particles and the SLG of ibuprofen/tripalmitin,the ibuprofen/tripalmitin composite particles were investigated using both the CO₂-assisted and N₂-assisted processes.The produced particles with different contents of ibuprofen can evidently show controlled drug releases.The dissolution of ibuprofen from the composite particles decreases with the decrease of the ibuprofen's content.The obtained composite particles containing 20%(in mass) ibuprofen show similar particle morphology to,while have a larger average particle size than,that of the pure tripalmitin in the case of the N₂-assisted process.Nevertheless,the particles from the CO₂-assisted process have small average particle sizes with narrow PSDs,compared to that of the pure tripalmitin.