| The production process of active pharmaceutical ingredients (API) involves many unit operations at the end of the synthesis to obtain a dry pure crystalline product. Many of these steps require a significant quantity of various solvents and increase the risks of operator exposure and product contamination. Supercritical antisolvent precipitation offers significant advantages over the traditional processes as it allows an API solution to be converted to a dry end product of specified granulometry and purity, by-passing several unit steps like cooling crystallization, centrifugation, drying and powder milling/homogenisation in one contained process. The impact of the various process parameters on the dryness, purity and crystallinity of the products was studied on a lab-scale system. From these results the economical aspect of scale-up of the SCF-process was considered and compared to conventional technologies. These results show that SCF technology is a viable technique for the production of highly potent pharmaceuticals.
The advent of high through-put screening has led to the development of new drug candidates that tend to have poorer oral bioavailability. In addition, new pharmaceutical entities are characterized by higher activity to such an extent that their viability and commercial interest is often jeopardized by the limitations of the current chemical and pharmaceutical production facilities. Indeed, the production of a new API involves many standard unit operations and powder handling steps before a dry and pure crystalline product is obtained that can be formulated into a suitable dosage form (Figure 58). In this process, risks for operator exposure and product contamination are high (red squares). In addition, solvent use (cleaning) and the corresponding environmental impact is high. One approach to reduce these risks is to combine various unit operations into one contained step by using supercritical fluids. Indeed, supercritical antisolvent precipitation has been successfully applied to the precipitation of many model API’s. The process is contained and offers the possibility to tune properties of the final product such as particle size, polymorphic form, purity, surface charge and dissolution properties, activities that are often split between chemical and pharmaceutical production facilities. The economical impact of the technology will then be compared to that of the conventional technology.
Figure 58: Impact of SCF process on standard API processing.
Characterization of the SCF processed material showed that the physicochemical properties of the compounds do not change during SCF processing. Thermal and IR analysis of the SCF treated powders showed that both compounds were crystalline and that no polymorphic changes occurred during precipitation. SEM analysis of the compound B before and after precipitation with SC-CO2 showed that the shape of the crystals did not change but that the particle size was reduced after processing. This may be beneficial for many pharmaceutical formulation processes in which a fine powder is needed to improve dissolution and bioavailability.
Comparison of the costs related to a conventional crystallisation process with the SCF process (Table 19) shows that the conventional process contains many unit operations implying high contamination and operator exposure risks. In addition, cleaning and environmental costs are important for such a process. The SCF process is a fully contained in 1 piece of equipment reducing not only exposure risks but also costs related to maintenance, cleaning etc. As SCF technology is not yet widespread in the pharmaceutical industry, cost of design and manufacture of a production scale unit may be high. A fully contained equipment train for conventional precipitation of potent compounds or parenterals is very costly.
The process can be immediately applied to concentrated solutions coming out of the synthesis process. The crystallization occurs with a high yield and does not modify the physicochemical properties of the compounds. Particle size reduction was observed and this may be beneficial for many downstream formulation processes. Comparing the economical impact of the SCF technology with the fully contained conventional production process shows that the SCF technology is a viable platform technology for the production of highly potent pharmaceuticals.
Table 19: Economic feasibility of SCF process
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