Learn more about drug formulation by using supercritical fluid technology


Supercritical fluid (SCF) technology has been applied to drug product development over the last thirty years and drug particle generation using SCFs appears to be an efficient way to carry out drug formulation which will form end-products meeting targeted specifications. This article presents an overview of drug particle design using SCFs from a rather different perspective than usual, more focused on chemical and process engineering aspects. The main types of existing processes are described in a concise way and a focus is put on how to choose the right operating conditions considering both thermodynamic and hydrodynamic aspects.

It is shown that the operating conditions and parameters can be easily optimized so as to facilitate the further process scale-up. Furthermore, the new trends in particle generation using SCFs are introduced, related either to new types of drug medicines that are treated or new ways of process implementation methods.


Future Directions / Perspectives

Now that these different drug particle generation processes have been mastered, it is of interest to explore a coupling with conventional methods or with other processes using SCF. For example, supercritical extraction of a compound of interest from a dry natural product can be easily coupled with a particle generation process that could be implemented subsequently to extraction, in a separation vessel. Integrated process can thus be implemented, avoiding or limiting the use of organic solvent and allowing a good control of the end-product characteristics.

Another application of SC CO2 currently studied, either at lab-scale or for industrial applications, is SC CO2 sterilization. Indeed, depending on operating conditions, SC CO2 allows complete inactivation or at least significant bioburden reduction. It is thus worth noting here, that the conditions used for particle generation may correspond to conditions ensuring a significant bioburden reduction, with an efficiency that will depend (in addition to the operating conditions) on the initial bioburden and the type of contamination. It is then of great interest to exploit this specific property of SC CO2.

Furthermore, as a general rule, the current trend in the industry is to focus on optimization and intensification aspects. In the particular case of supercritical technology, this approach can provide a solution for reducing energy consumption. Other advantages like the reduction of the unit’s size and thus of the space occupied by the facilities, the decrease of the production costs and in addition a higher security of the plants are also strengths of these methods. The development in recent years of supercritical microfluidic equipment applied to different SCF applications will allow progress in this path. The currently progressing modeling approaches applied to these specific media will allow a better control of the processes in general and of the intensification in particular. All the different phenomena that have to be further studied for a better control of the different processes will then also have to be tackled at this lower scale.

As concerns the development of the SCF technology in the pharmaceutical industry, it is still in the early stages. Although particle generation processes using SCFs have been widely studied over the last three decades, there are only a few industrial units. Several reasons can be given to explain this. First of all, the processes described have not all been mature for a long time. Several scale-up issues have been the consequences of an improper choice of operating conditions at industrial scale. For example, as previously mentioned, the duration of the precipitation step for anti-solvent processes is of great importance. End-products with different characteristics are obtained if the precipitation step durations are not the same at lab-scale and at industrial scale. The different particle design processes using SCFs are now much more mature and useful results are now available for more reliable scale-ups. Furthermore, some economic data are now available in the literature [63]. A second reason may be that the products elaborated using these processes did not all fit a market. Indeed, the market for products elaborated using environmentally friendly processes is rather recent. Moreover, the majority of current legislation all over the world still allows the use of conventional liquid organic solvents.

Lastly, an important change in recent years is that several companies used as service providers can now ensure the scale-up study, the production of clinical batches (required for clinical studies) and even the production of commercial batches. This allows a product development without necessarily requiring investment costs. For all these reasons and because SCF technology can be considered as environmentally friendly, it seems inevitable that its development will grow in the pharmaceutical industry in the near future.



Microscope photos of particles created by Supercritical fluid technology