Purpose: Hot-melt extrusion (HME) is a commonly used method to prepare solid dispersions to improve dissolution rate and bioavailability of poorly water-soluble drugs. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is widely evaluated to prepare solid dispersion of weakly basic drugs due to its interaction with acetyl and succinoyl group. It also provides good physical stability due to higher glass transition temperature (Tg) and lower moisture absorption. However, high melt viscosity and Tg limit its use to formulate solid dispersion by HME. Thus, most of the commercial solid dispersion products containing HPMCAS as a carrier were prepared by spray drying. Also, HPMCAS based solid dispersions exhibit pH dependent drug release as it is soluble pH >5.5. Addition of surfactants may plasticize HPMCAS and reduces processing temperature, and also improve the drug release at low stomach pH. The objectives of this study were a) evaluate miscibility of HPMCAS with itraconazole and surfactants (poloxamer 188, poloxamer 407 and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS)) using film casting technique, b) its effect on melt viscosity and processability by HME c) evaluate the effect of surfactants on drug release.
Methods: The physical mixtures containing drug-polymer or drug-surfactant-polymer were extruded using Process 11 twin screw extruder at 160˚C.The drug-polymer, polymer-surfactant and polymer-drug-surfactant miscibility testing was performed using the film casting, where the films examined initially after exposing to 40˚C/75%RH for 30 days. In addition, the physical stability of crushed exudates was conducted after extrusion and upon exposure to 40˚C/75% RH on day 30. Differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD) were carried out to evaluate crystallinity in the films and crushed exudates. The effect of drug and surfactant on viscosity of HPMCAS was evaluated conducting oscillation temperature sweep and frequency sweep using Discovery HR-2 rheometer. The drug release study was carried out in USP dissolution apparatus II using crushed extrudates (< 212 µm) particle size containing 100-mg equivalent of itraconazole in 250 mL of 0.1N HCl (pH 1) for 2 hours and additional 5 hours after adjusting the pH to 6.8 at 75 RPM and 37 ± 0.5°C.
Results: The mixtures of itraconazole-HPMCAS (20:80 w/w), surfactant-HPMCAS (20:80) and surfactant-drug-HPMCAS (15:20:65) was found to be miscible for a month at 40˚C/75% RH. Crushed filaments containing surfactant-drug-polymer (10:20:70 and 15:20:65 w/w) were found to be stable at 40˚C/75% RH for a month. The presence of surfactant and/or the dissolved drug reduced the melt viscosity of HPMCAS drastically and enabled extrusion at low temperature of 130˚C, without surfactant and drug, a temperature 160˚C was necessary for extrusion. The binary mixtures containing surfactant-polymer (10:90 and 15:85 w/w) were also extrudable at 130˚C with ~80% of torque. The drug-polymer solid dispersion showed ~8% of drug release at pH 1. However, incorporation of surfactant improved drug release, and about 50% of drug release was observed with 15% of poloxamer 407 and TPGS at pH 1. Further, complete dispersion of itraconazole was observed upon changing pH to 6.8, and supersaturation was maintained for 5 hours (Fig 1 and 2).
Conclusion: The ternary solid dispersions containing surfactant-drug-polymer were miscible up to 15%, 20% and 65% w/w. The processability of HPMCAS was improved by presence of surfactant and drug, and the drug release was improved by the presence of surfactant.
Kyle Lam– Albert Nerken School of Engineering, The Cooper Union for the Advancement of Science and Art, 41 Cooper Square, NY 10003
Md Tahsin– St. John's University
Suhas Gumaste– St. John's University
Ankita Shah– Post Doctoral Research fellow, St. John's University
Abu Serajuddin– Professor, St Johns University, New York