Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

Abstract

Abstract. The objective of the study was to develop an amorphous solid dispersion (ASD) for an insoluble compound X by hot melt extrusion (HME) process. The focus was to identify material-sparing approaches to develop bioavailable and stable ASD including scale up of HME process using minimal drug. Mixtures of compound X and polymers with and without surfactants or pH modifiers were evaluated by hot stage microscopy (HSM), polarized light microscopy (PLM), and modulated differential scanning calorimetry (mDSC), which enabled systematic selection of ASD components. Formulation blends of compound X with PVP K12 and PVP VA64 polymers were extruded through a 9-mm twin screw mini-extruder. Physical characterization of extrudates by PLM, XRPD, and mDSC indicated formation of single-phase ASD's. Accelerated stability testing was performed that allowed rapid selection of stable ASD's and suitable packaging configurations. Dissolution testing by a discriminating two-step non-sink dissolution method showed 70-80% drug release from prototype ASD's, which was around twofold higher compared to crystalline tablet formulations. The in vivo pharmacokinetic study in dogs showed that bioavailability from ASD of compound X with PVP VA64 was four times higher compared to crystalline tablet formulations. The HME process was scaled up from lab scale to clinical scale using volumetric scale up approach and scale-independent-specific energy parameter. The present study demonstrated systematic development of ASD dosage form and scale up of HME process to clinical scale using minimal drug (∼500 g), which allowed successful clinical batch manufacture of enabled formulation within 7 months.

The Effect of Cooling on the Degree of Crystallinity, Solid-State Properties, and Dissolution Rate of Multi-Component Hot-Melt Extruded Solid Dispersions

“…During dissolution the carrier traps the dispersed API in a high energy state, maintaining supersaturation in the medium over time and preventing crystallization [3]. Bravo et al (2004) reported that HME has many significant benefits such as the elimination of solvents, good content uniformity due to the low drug loading used, dosage forms of a desired shape, including tablets, pellets and implants can be easily manufactured by this process; HME is 2 of 24 also a continuous process and can be scaled up [4] and finally, HME allows conversion of crystalline drugs to amorphous form or dispersion of API into very small particles, enhancing bioavailability and improving patient compliance.…”

Development of Tablet Formulation of Amorphous Solid Dispersions Prepared by Hot Melt Extrusion Using Quality by Design Approach

“…HME has been successfully applied to enhance solubility of poorly soluble drug substance through formation of an amorphous solid dispersion of drug substance in a polymeric (or lipid) carrier matrix (10,11). Proper selection of polymeric carrier, thorough evaluation of physicochemical properties, stability, and performance assessment of an amorphous solid dispersion are key aspects that should be evaluated to ensure successful development of bioavailable dispersion by HME process (12,13). However, to develop a commercial dosage form the solid dispersion needs to be converted to a final dosage form such as tablets or capsules.…”

Solid Dispersions: Resuscitating Oral Delivery of Hydrophobic Drugs

“…SD formulation of antiulcer drug lafutidine was successfully formulated using hot melt extrusion (HME) technique, and it was demonstrated that the SD of lafutidine performed better with immediate drug release as compared with pure lafutidine [19]. Agrawal et al developed SDs using HME technology with a scale up from mini scale to clinical scale [20].…”