Application of hot-melt extrusion in the manufacturing of amorphous solid dispersions containing thermally labile drugs

Hot-melt extrusion has gained favor over traditional pharmaceutical formulation techniques in bioavailability/solubility enhancement because it is a solvent-free and continuous operation process that does not require major downstream processing. However, the thermal and mechanical energy applied during the extrusion process can cause chemical degradation of drugs and polymeric carriers In Chapter 1, different methods of preparing amorphous solid dispersions were reviewed. The amorphous solid dispersions generated by different methodologies were compared in terms of physical stability, chemical stability, and the in vivo/in vitro performance. In Chapter 2, the solubility advantage of amorphous solid dispersions was investigated through the heterogeneous phase equilibria analysis. A thermodynamic model for the quantitative assessment of solubility advantage of amorphous solid dispersions was then presented. The thermodynamic model accounted for the chemical potential change as a result of (a) amorphization, (b) ASD formation, and (c) water partition. Experimental solubility advantages of amorphous solid dispersions containing indomethacin was studied by means of intrinsic dissolution measurement. The thermodynamic model allowed predicting the solubility advantage of amorphous solid dispersions. In Chapters 3 and 4, the strategies used in hot-melt extrusion to facilitate manufacture of amorphous solid dispersions containing thermally labile drugs were investigated. Formulation screening based on Flory-Huggins theory, and the utilization of polymer designed for the extrusion process was evaluated in Chapter 3. With the selection of proper formulations, amorphous solid dispersions containing 30% (w/w) carbamazepine were manufactured without any degradation. Improved dissolution properties were also revealed with the final formulations. In Chapter 4, gliclazide was identified as a thermally labile drug with severe degradation by hydrolysis at elevated temperatures, especially when it existed in amorphous or solution form. After optimization of the hot-melt extrusion process, including improved screw design, machine setup, and processing conditions, gliclazide amorphous solid dispersion with ~95% drug recovery was achieved. This study demonstrated the importance of the following factors on drug degradation: (a) changing screw design to facilitate shorter amorphous (melt) residence time, (b) lowering processing temperature to avoid excess thermal exposure, and (c) minimizing processing parameters to reduce unnecessary mechanical energy input.