Supercritical fluid (SCF)-assisted fabrication of carrier-free drugs: An eco-friendly welcome to active pharmaceutical ingredients (APIs).

Despite the success in developing various pharmaceutical formulations, most of the active pharmaceutical ingredients (APIs)/drugs, according to the Biopharmaceutics Classification System (BCS), often suffer from various intrinsic limitations of solubility and permeability, substantially hindering their bioavailability in vivo. Regardless of the fact that the availability of different particle fabrication approaches (top-down and bottom-up) towards pharmaceutical manufacturing, the supercritical fluid (SCF) technology has emerged as one of the highly effective substitutes due to the environmentally benign nature and processing convenience, as well as the economically promising character of SCFs. The exceptional features of SCFs have endowed the fabrication of various APIs either solely or in combination with the compatible supramolecular species towards achieving improved drug delivery. Operating such APIs in high-pressure conditions often results in arbitrary-sized particulate forms, ranging from micron-sized to sub-micron/nano-sized particles. Comparatively, these SCF-processed particles offer enhanced tailorable physicochemical and morphological properties (size, shape, and surface), as well as improved performance efficacy (bioavailability and therapy) over the unprocessed APIs. Although the "carrier-based" delivery is practical among diverse delivery systems, the direct fabrication of APIs into suitable particulate forms, referred to as "carrier-free" delivery, has increased attention towards improving the bioavailability and conveying a high payload of the APIs. This review gives a comprehensive emphasis on the SCF-assisted fabrication of diverse APIs towards exploring their great potential in drug delivery. Initially, we discuss various challenges of drug delivery and particle fabrication approaches. Further, different supercritical carbon dioxide (SC-CO2)-based fabrication approaches depending on the character of SCFs are explicitly described, highlighting their advantages and suitability in processing diverse APIs. Then, we provide detailed insights on various processing factors affecting the properties and morphology of SCF-processed APIs and their pharmaceutical applications, emphasizing their performance efficacy when administered through multiple routes of administration. Finally, we summarize this compilation with exciting perspectives based on the lessons learned so far and moving forward in terms of challenges and opportunities in the scale-up and clinical translation of these drugs using this innovative technology.