Molecular Indicators of Surface and Bulk Instability of Hot Melt Extruded Amorphous Solid Dispersions

• Published in: Pharmaceutical research Vol. 32; no. 4; pp. 1210 - 1228
• Main Authors: Yang, Ziyi, Nollenberger, Kathrin, Albers, Jessica, Craig, Duncan, Qi, Sheng
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.04.2015; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Calorimetry, Differential Scanning; Chemical Phenomena; Chemistry, Pharmaceutical - methods; Crystallization; Dispersion; Dissolution; Drug Stability; Hot Temperature; Medical Law; Microscopy, Electron, Scanning; Microscopy, Polarization; Pharmaceutical Preparations - chemistry; Pharmacology; Pharmacology/Toxicology; Pharmacy; Polymer solubility; Research Paper; Solubility; Spectroscopy, Fourier Transform Infrared; Surface Properties; Transition Temperature; X-Ray Diffraction; molecular mobility; surface crystallization; physical stability; hot melt extrusion; amorphous molecular dispersions
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-014-1527-8

ABSTRACT Purpose To identify molecular indicators of bulk and surface instabilities of amorphous dispersions prepared by hot melt extrusion. Methods Four model drugs with different physicochemical properties were formulated with EUDRAGIT ® E PO using hot melt extrusion. Samples were aged under a range of conditions for up to 6 months and characterized using SEM, ATR-FTIR, PXRD and MTDSC. The effects of a range of thermodynamic, kinetic and molecular parameters, including glass transition temperature, molecular mobility, the crystallization tendency of the amorphous drug and drug-polymer miscibility, on the bulk and surface stabilities of the solid dispersions were evaluated. Results For all drug-containing systems, a higher degree of instability was observed at the surface of the material in comparison to the bulk. Stressed humidity showed a more profound effect on the dispersions in comparison to stress temperature, reducing both their surface and bulk stabilities. For supersaturated systems the order of the bulk and surface instabilities of the samples was found following the same order of the molecular mobilities of the amorphous model drugs. This was attributed to the presence of phase separation of amorphous drug-rich domains in the supersaturated extrudates. Conclusions The stability of the amorphous drug-rich domains appears to be governed by the physical stabilities of the amorphous drugs. The more commonly used indicators such as T g , fragility of the amorphous drug and the theoretically predicted drug-polymer solubility showed less influence on the bulk and surface stabilities of the extrudates in comparison to the molecular mobility of the amorphous drug.