CONTEXT: Solubility limitation of BCS class II drugs pose challenges to in vitro release. OBJECTIVE: To investigate the miscibility of Aprepitant (APR) and Soluplus(®) (SOL) for hot melt extrusion (HME) viability and improved in vitro release of APR. METHODS: Solubility parameters of APR and SOL from group contribution methods were evaluated. Heat-cool-heat differential scanning calorimetry (DSC) scans were assessed for determining the glass forming ability (GFA) and glass stability (GS) of APR. An optimum HME temperature was selected based on melting point depression in physical mixtures. Moisture sorption isotherms were collected using a dynamic vapor sorption (DVS) analyzer at 25 °C. A 1:4 APR:SOL physical mixture was extruded in a co-rotating 12 mm twin screw extruder and in vitro release was assessed in fasted state simulated intestinal fluid (FaSSIF) with 0.25% SLS. Extrudates were analyzed using TGA, DSC, XRD and FTIR. RESULTS: APR was classified as a class II glass former. APR and SOL had composition dependent miscibility based on Gibb's free energy of mixing. Extrudate prepared using HME had an amorphous as well as a crystalline phase that showed good stability in accelerated stability conditions. Smaller particle size extrudates exhibited a higher % moisture uptake and in vitro release compared to larger particle size extrudates. Enhanced in vitro release of APR from extrudates was attributed to amorphization of APR, solubilization as well as crystal growth inhibition effect of SOL due to H-bond formation with APR. CONCLUSIONS: A solid dispersion of APR with improved in vitro release was successfully developed using HME technology.
CONTEXT: Solubility limitation of BCS class II drugs pose challenges to in vitro release. OBJECTIVE: To investigate the miscibility of Aprepitant (APR) and Soluplus(®) (SOL) for hot melt extrusion (HME) viability and improved in vitro release of APR. METHODS: Solubility parameters of APR and SOL from group contribution methods were evaluated. Heat-cool-heat differential scanning calorimetry (DSC) scans were assessed for determining the glass forming ability (GFA) and glass stability (GS) of APR. An optimum HME temperature was selected based on melting point depression in physical mixtures. Moisture sorption isotherms were collected using a dynamic vapor sorption (DVS) analyzer at 25 °C. A 1:4 APR:SOL physical mixture was extruded in a co-rotating 12 mm twin screw extruder and in vitro release was assessed in fasted state simulated intestinal fluid (FaSSIF) with 0.25% SLS. Extrudates were analyzed using TGA, DSC, XRD and FTIR. RESULTS: APR was classified as a class II glass former. APR and SOL had composition dependent miscibility based on Gibb's free energy of mixing. Extrudate prepared using HME had an amorphous as well as a crystalline phase that showed good stability in accelerated stability conditions. Smaller particle size extrudates exhibited a higher % moisture uptake and in vitro release compared to larger particle size extrudates. Enhanced in vitro release of APR from extrudates was attributed to amorphization of APR, solubilization as well as crystal growth inhibition effect of SOL due to H-bond formation with APR. CONCLUSIONS: A solid dispersion of APR with improved in vitro release was successfully developed using HME technology.
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Keywords:
Hot melt extrusion; in vitro release; intermolecular interactions; moisture sorption isotherm; solubility parameter