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. 2016 Feb;17(1):133-47.
doi: 10.1208/s12249-015-0425-7. Epub 2015 Oct 20.

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

Anjali M Agrawal  1 , Mayur S Dudhedia  2 , Ewa Zimny  2
Affiliations

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

Anjali M Agrawal et al. AAPS PharmSciTech. 2016 Feb.

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.

Keywords: amorphous solid dispersion; bioavailability; dissolution; hot melt extrusion; process scale up.

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Figures

Fig. 1
Fig. 1
Screw profile of Leistritz’s a micro 18-mm and b nano 16-mm extruder
Fig. 2
Fig. 2
Flowchart to develop amorphous dispersions for compound X by HME process using material-sparing approaches
Fig. 3
Fig. 3
Generic structure of compound X
Fig. 4
Fig. 4
Polarized light microscopy images during hot stage microscopy evaluation of a compound X:PVP VA64 (1:2), b compound X:PVP K12 (1:3), c compound X:HPMC (1:2), and d compound X:HPMCAS LF (1:2) blends
Fig. 5
Fig. 5
DSC thermograms of compound X and blends of compound X and HME polymers
Fig. 6
Fig. 6
Dissolution of compound X:PVP VA64 amorphous solid dispersion a with and without SDS and b with and without tartaric acid
Fig. 7
Fig. 7
Amorphous and crystalline formulations of compound X tested in dogs at 100 mg dose. a Dissolution profiles. b Mean plasma profiles
Fig. 8
Fig. 8
PLM images of stability samples of HME amorphous solid dispersions of compound X
Fig. 9
Fig. 9
Compound X:PVP VA64 (1:2) ASD samples packaged in aluminum blister—evaluation on long-term ICH stability study by a XRPD and b dissolution profiles
Fig. 10
Fig. 10
HME process—scale-independent scale up approach
Fig. 11
Fig. 11
Solid-state and performance assessment of compound X:PVP VA64 (1:2) ASD from 9- to 18-mm hot melt extruders. a PLM images. b XRPD patterns. c Dissolution profiles
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