Research progress in the preparation of pharmaceutical formulations based on supercritical fluid technology

Supercritical fluid is a fluid whose temperature and pressure are both higher than its critical value (P_c and T_c). At the critical point, the physical and chemical properties of the fluid are very sensitive to slight changes in temperature or pressure. At present, supercritical fluid is widely used in various fields of healthcare, from which supercritical extraction technology, supercritical fluid microparticle technology, chemical reaction in supercritical fluid and so on are derived. CO₂ is the most widely used supercritical fluid due to its low price, stable chemical properties and mild operating conditions. The critical pressure P_c of CO₂ is 7.37 MPa, which has low requirements for equipment conditions. The critical temperature T_c is 304.2 K, which can realize supercritical fluid operation at room temperature and save energy. This paper reviews the application of supercritical fluid technology in the preparation of pharmaceutical formulations, focusing on the problems of pharmaceutical research and clinical translation. Compared with the traditional pharmaceutical methods, the preparation of pharmaceutical formulations by supercritical fluid technology has the inherent characteristics of high biological activity, high purity, less impurities, green and safe, environmentally friendly. It is a promising new process in the pharmaceutical industry and also attracts the interest of scientific researchers. This review also summarizes the latest research achievements in the preparation of pharmaceutical nanoparticles, nano-drug carriers, nano-enzymes and super-stable pharmaceutical compounds based on supercritical fluid technology, introduces its basic principles and advantages, and looks forward to the development prospect of supercritical fluid technology in the field of nano-medicine. The main challenges in the field of pharmaceuticals are low solubility and poor stability in vivo. In order to solve these problems, supercritical technology is used to prepare nano-drugs, such as gambogic acid particles and curcumin particles, featuring improved solubility and bioavailability. Reducing drug particles to the nanoscale can increase the surface area of pure drug particles, thus increasing their solubility and bioavailability of active substances. In addition, small-scale drug delivery systems could be prepared by using supercritical fluid antisolvent method, which effectively improved the stability and solubility of active drugs and basically produced no organic solvent residue. More recently, a new superstable homogeneous iodinated formulation technology (SHIFT) was proposed and developed to improve the stability of drugs in lipiodol for lipiodol-based transcatheter arterial embolization (TAE) in hepatocellular carcinoma interventional therapy. By controlling temperature and pressure to make CO₂ in a supercritical state, the lipiodol and indocyanine green (ICG) were mixed to obtain a uniformly stable medicine-iodized formulation. It was found that the lipiodol-ICG formulation had long-term fluorescence stability, improved the optical performance of ICG, and retained the embolization performance of lipiodol-ICG. With the application of SHIFT, embolization preparations and small-molecule drugs are combined to achieve better tumor treatment efficiency than single therapy. As a green, efficient and widely applicable technology platform, SHIFT is expected to combine various commonly used fluorescent drugs, chemotherapy drugs and radionuclide drugs with embolization agents, thus playing a greater application value in the future clinical anticancer treatment. In summary, supercritical fluid technology is in line with the principle of green chemistry, which overcomes the problems of toxic organic solvents and high energy in the traditional technology, and has shown great potential and advantages in the field of medicine. Despite the growing success of supercritical fluid technology, there are still some challenges in the preparation process, such as the lack of reliable experimental data and models, and the large-scale application in the pharmaceutical industry. With the increasing emphasis on personalized medicine, this green technology will continue to develop, and it is expected to achieve large-scale use from laboratory scale to industrialization in the future.