Hot-Melt extrusion coupled with pressurized carbon dioxide for enhanced processability of pharmaceutical polymers and drug delivery applications - An integrated review.

Hot-melt extrusion (HME) technology is one of the primary approaches that has been implemented in recent years to overcome poor drug solubility/dissolution issues through the development of solid dispersion systems. Carbon dioxide (CO) either in supercritical (SupC) or subcritical (SubC) forms has been introduced to HME as a temporary plasticizer, reducing the operating temperature and eventually processing heat-sensitive molecules more efficiently. In this paper, a comprehensive review of CO-HME processes focused on pharmaceutical polymers and applications is presented. The steps and requirements for the setup of experimental devices are demonstrated, with a detailed influence of CO characteristics on HME processes. The most relevant physical and chemical properties of pharmaceutical grade polymers subjected to the CO- HME process are described. The basic knowledge and main mechanisms of HME process parameters in conjunction with CO concentration with regard to process feasibility and final product formation are discussed. HME coupled with CO is extensively reviewed to provide a complete understanding of how to optimize the process parameters and conditions to reach optimized characteristics of final outcomes, as well as the sequential relationship between those outcomes (foaming → porosity → milling → tableting). Pharmaceutical applications of CO-based HME are presented in detailed case studies, including extrusion feasibility, solubility, dissolution rate enhancement, and gastroretentive or floating drug delivery. Finally, the current status of general CO-based techniques, as well as future perspectives and opportunities for promising applications through the integration of CO with HME is presented.