Rheological Characterization of Molten Polymer-Drug Dispersions as a Predictive Tool for Pharmaceutical Hot-Melt Extrusion Processability.

PURPOSE: The aim of this study was to investigate (i) the influence of drug solid-state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests. METHODS: Poly (ethylene oxide) (PEO) (100.000 g/mol) and physical mixtures (PM) containing 10-20-30-40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized. Rheological tests were performed (frequency and temperature sweeps in oscillatory shear as well as shear-induced crystallization experiments) to obtain a thorough understanding of the flow behaviour and crystallization of PEO-drug dispersions. RESULTS: Theophylline did not dissolve in PEO as the complex viscosity (η*) of the drug-polymer mixture increased as compared to that of neat PEO. In contrast, ketoprofen dissolved in PEO and acted as a plasticizer, decreasing η*. Acting as a nucleating agent, theophylline induced the crystallization of PEO upon cooling from the melt. On the other hand, ketoprofen inhibited crystallization upon cooling. Moreover, higher concentrations of ketoprofen in the drug-polymer mixture increasingly inhibited polymer crystallization. However, shear-induced crystallization was observed for all tested mixtures containing ketoprofen. CONCLUSION: The obtained rheological results are relevant for understanding and predicting HME processability (e.g., barrel temperature selection) and downstream processing such as injection moulding (e.g., mold temperature selection).