Supercritical carbon dioxide-based technologies for the production of drug nanoparticles/nanocrystals - A comprehensive review.

Low drug bioavailability, which is mostly a result of poor aqueous drug solubilities and of inadequate drug dissolution rates, is one of the most significant challenges that pharmaceutical companies are currently facing, since this may limit the therapeutic efficacy of marketed drugs, or even result in the discard of potential highly effective drug candidates during developmental stages. Two of the main approaches that have been implemented in recent years to overcome poor drug solubility/dissolution issues have frequently involved drug particle size reduction (i.e., micronization/nanonization) and/or the modification of some of the physicochemical and structural properties of poorly water soluble drugs. A large number of particle engineering methodologies have been developed, tested, and applied in the synthesis and control of particle size/particle-size distributions, crystallinities, and polymorphic purities of drug micro- and nano-particles/crystals. In recent years pharmaceutical processing using supercritical fluids (SCF), in general, and supercritical carbon dioxide (scCO2), in particular, have attracted a great attention from the pharmaceutical industry. This is mostly due to the several well-known advantageous technical features of these processes, as well as to other increasingly important subjects for the pharmaceutical industry, namely their "green", sustainable, safe and "environmentally-friendly" intrinsic characteristics. In this work, it is presented a comprehensive state-of-the-art review on scCO2-based processes focused on the formation and on the control of the physicochemical, structural and morphological properties of amorphous/crystalline pure drug nanoparticles. It is presented and discussed the most relevant scCO2, scCO2-based fluids and drug physicochemical properties that are pertinent for the development of successful pharmaceutical products, namely those that are critical in the selection of an adequate scCO2-based method to produce pure drug nanoparticles/nanocrystals. scCO2-based nanoparticle formation methodologies are classified in three main families, and in terms of the most important role played by scCO2 in particle formation processes: as a solvent; as an antisolvent or a co-antisolvent; and as a "high mobility" additive (a solute, a co-solute, or a co-solvent). Specific particle formation methods belonging to each one of these families are presented, discussed and compared. Some selected amorphous/crystalline drug nanoparticles that were prepared by these methods are compiled and presented, namely those studied in the last 10-15 years. A special emphasis is given to the formation of drug cocrystals. It is also discussed the fundamental knowledge and the main mechanisms in which the scCO2-based particle formation methods rely on, as well as the current status and urgent needs in terms of reliable experimental data and of robust modeling approaches. Other addressed and discussed topics include the currently available and the most adequate physicochemical, morphological and biological characterization methods required for pure drug nanoparticles/nanocrystals, some of the current nanometrology and regulatory issues associated to the use of these methods, as well as some scale-up, post-processing and pharmaceutical regulatory subjects related to the industrial implementation of these scCO2-based processes. Finally, it is also discussed the current status of these techniques, as well as their future major perspectives and opportunities for industrial implementation in the upcoming years.