Melt Extrusion of High-Dose Co-Amorphous Drug-Drug Combinations

TY - JOUR

T1 - Melt Extrusion of High-Dose Co-Amorphous Drug-Drug Combinations

AU - Arnfast, Lærke

AU - Kamruzzaman, Md

AU - Löbmann, Korbinian

AU - Aho, Johanna

AU - Baldursdottir, Stefania

AU - Rades, Thomas

AU - Rantanen, Jukka

PY - 2017/12

Y1 - 2017/12

N2 - PURPOSE: Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated.METHODS: Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% (w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry. Extrudates containing a co-amorphous glass solution were produced and the solid-state composition of these was studied with DSC.RESULTS: Rheological analysis indicated that the studied systems display viscosities higher than expected for small molecule melts and addition of PEO decreased the viscosity of the melt. Extrudates of indomethacin-cimetidine alone displayed amorphous-amorphous phase separation after 4 weeks of storage, whereas no phase separation was observed during the 16 week storage of the indomethacin-cimetidine extrudates containing 5% (w/w) PEO.CONCLUSIONS: Melt extrusion of co-amorphous extrudates with low amounts of polymer was found to be a feasible manufacturing technique. Addition of 5% (w/w) polymer reduced melt viscosity and prevented phase separation.

AB - PURPOSE: Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated.METHODS: Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% (w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry. Extrudates containing a co-amorphous glass solution were produced and the solid-state composition of these was studied with DSC.RESULTS: Rheological analysis indicated that the studied systems display viscosities higher than expected for small molecule melts and addition of PEO decreased the viscosity of the melt. Extrudates of indomethacin-cimetidine alone displayed amorphous-amorphous phase separation after 4 weeks of storage, whereas no phase separation was observed during the 16 week storage of the indomethacin-cimetidine extrudates containing 5% (w/w) PEO.CONCLUSIONS: Melt extrusion of co-amorphous extrudates with low amounts of polymer was found to be a feasible manufacturing technique. Addition of 5% (w/w) polymer reduced melt viscosity and prevented phase separation.

KW - Journal Article

U2 - 10.1007/s11095-017-2254-8

DO - 10.1007/s11095-017-2254-8

M3 - Journal article

C2 - 28929263

SN - 0724-8741

VL - 34

SP - 2689

EP - 2697

JO - Pharmaceutical Research

JF - Pharmaceutical Research

IS - 12

ER -