(T1130-12-80) Hot-Melt Extrusion of Simvastatin-Based Amorphous Solid Dispersions with PVP-VA and HPMC-AS

Purpose: Hot-melt extrusion (HME) is a popular technology for preparing amorphous solid dispersions (ASDs). Simvastatin (SIM), which belongs to an important class of lipid-lowering drugs used to lower blood cholesterol and prevent cardiovascular disease, was selected as a model drug for this study. Two key challenges with HME are poor physical stability of the amorphous drug and thermal degradation during processing. Polymeric excipients are employed in HME to stabilize the drug in its amorphous form, to minimize chemical degradation, and to improve overall manufacturability. Poly(vinylpyrrolidone) vinyl acetate (PVP-VA), a neutral, aprotic polymer, and hydroxypropyl methylcellulose acetate succinate (HPMC-AS), an anionic, protic polymer were selected as the excipients for this study. The objective of this study is to prepare and characterize HME ASDs with varying SIM/polymer ratios.

Methods: ASD Preparation. ASDs of SIM/PVP-VA and SIM/HPMC-AS were prepared at varying ratios of 0/100, 25/75, 50/50, 75/25, 100/0 %w/w SIM/polymer using twin-screw hot melt extrusion. Physical blends of SIM and polymer were prepared by a 1-min trituration, followed by a 10-min blending step. Each blend was fed into the hot-melt extruder with a thin-slit die at 150°C. The extrudate was collected and milled to a powder using a tube mill at 15,000 RPM for 1 min. Physical form characterization. The physical form of SIM in the ASDs was identified using powder X-ray diffraction (PXRD). Samples were scanned in reflection mode over a 2.0000 – 39.9990 °2θ range with a Cu Kα1 radiation source and a detector at 45 kV and 40 mA. The step size was 0.0131 °2θ and the scan rate was 0.08 sec/step. Modulated differential scanning calorimetry (mDSC) was used to determine the glass transition temperature Tg, with a nitrogen purge flow of 50 mL/min and a 3°C/min ramp rate with a modulation cycle of ±1°C every 60 seconds. Water content. Thermogravimetric analysis (TGA) was performed on the ASDs, with a nitrogen purge flow of 50 mL/min and a 10°C/min ramp rate from 25°C to 150°C. Weight loss was attributed to water content. Chemical purity. Chemical purity was evaluated using ultra performance liquid chromatography (UPLC). A gradient method using water with 0.1% trifluoroacetic acid (TFA) and acetonitrile with 0.1% TFA was employed for separation, and the chromatogram at 236 nm was used for analysis.

Results: This study determined the suitability of preparing SIM/polymer ASDs with HME. All ASDs demonstrated the amorphous nature of the drug, indicated by an amorphous halo using PXRD. A single glass transition temperature was observed, indicating a homogenous solid solution. The composite Tg of the ASDs decreased as the SIM-loading was increased. Weight loss by TGA was relatively low across all ASDs, indicating moisture content ranging from 0.3% to 3.8%. Thermal degradation was minimal, with purity >97% across all ASDs relative to starting SIM purity, although purity seemed slightly higher with PVP-VA.

Conclusion: ASDs of SIM/PVP-VA and SIM/HPMC-AS were successfully prepared by hot melt extrusion. Simvastatin was demonstrated to be in an amorphous state with both polymeric excipients, and exhibited good chemical stability during the hot melt extrusion process.

PXRD Diffractograms for SIM/PVP-VA and SIM/HPMC-AS ASDs, Neat SIM

DSC Thermograms for SIM/PVP-VA, SIM/HPMC-AS ASDs

Water Content, Glass Transition Temperature, and Simvastatin Purity of SIM/PVP-VA, SIM/HPMC-AS ASDs