Chapter 10: Liquid–Liquid Extraction for Process Development in the Pharmaceutical Industry

Multi-stage batch pharmaceutical processes can be broken down into the general steps: reaction, ‘drown-out’/extraction into a solvent, separation, isolation and drying. This chapter covers the area of extraction and separation. Liquid extraction is one of the most widely used techniques in the pharmaceutical industry and this chapter outlines the fundamental theory and heuristics of liquid-liquid extraction and shows how, with limited physical property information, it is possible to establish separation strategies for pharmaceutical process development. To aid process development the UNIFAC physical property method is often used; this activity coefficient method estimates non-ideal interactions between components from the structure of the molecules. In the chapter, detailed phase equilibria predictions for liquid-liquid extraction are carried out using UNIFAC for binary and ternary systems for some common solvent systems used in the pharmaceutical industry and these are checked against experimental data. However, several key UNIFAC group interactions are missing and it is not clear when these may be available in the future due to the vast experimental investment required for their determination. Therefore, an a priori method of predicting physical property behavior, COSMO-RS, is proposed as one way forward in the future. The COSMO-RS predictions are also checked against one of the commonly encountered solvent systems in pharmaceutical development. The chapter concludes with a number of case studies where a step by step methodology is outlined for the use of solvents, physical property information (such as azeotropes) and phase equilibria diagrams.