Effects of Surfactants on Itraconazole-HPMCAS Solid Dispersion Prepared by Hot-Melt Extrusion I: Miscibility and Drug Release

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been widely investigated as a carrier for amorphous solid dispersion (ASD) of poorly water-soluble drugs. However, its use has mostly been limited to ASDs prepared by spray drying using organic solvents, and the solvent-free method, hot-melt extrusion (HME), has only limited use because it requires high processing temperature where the polymer and drug may degrade. In this investigation, surfactants were used as plasticizers to reduce the processing temperature. Their effects on drug release were also determined. To determine suitability of using surfactants, the miscibility of HPMCAS with 3 surfactants (poloxamer 188, poloxamer 407, and d-alpha tocopheryl polyethylene glycol 1000 succinate) and a model drug, itraconazole (ITZ), was studied by film casting. HPMCAS was miscible with ITZ (>30%) and each surfactant (>20%), and in ternary HPMCAS-ITZ-surfactant (60:20:20) system. ASDs prepared by HME of HPMCAS-ITZ-surfactant mixtures (70:20:10 and 65:20:15) at 160°C were physically stable after exposure to 40°C and 75% relative humidity for 1 month. The presence of 15% w/w surfactant provided up to 50% drug release at pH 1 as compared to only 8% from ASDs with HPMCAS alone. On changing the pH of the dissolution medium from 1 to 6.8 in a step-dissolution process, complete drug release (90%-100%) and extremely high apparent supersaturation (∼75,000 times) of ITZ were observed when the solutions were filtered through 0.45 μm filters. The apparently supersaturated solutions consisted of colloidal particles of ∼300 nm size. The present study demonstrates that stable ASDs with improved processability and drug release may be prepared by HME.