A greener pharmaceutical industry

Purification

In chemical processes, there is typically significant emphasis on the reaction or bond-forming phase, with less attention given to the work-up and product isolation stages. However, work-up and isolation techniques in the pharmaceutical industry are critical steps in drug development and production, ensuring the purity and quality of pharmaceutical products. These processes involve separating and purifying active pharmaceutical ingredients (APIs) from reaction mixtures, impurities, and other components. Paradoxically, it's quite common that more resources, such as solvents, process water, manufacturing plant time, and energy, are consumed during work-up than in the actual reaction (Peterson et al., 2014). Achieving sustainability necessitates a reduction in the burden imposed by downstream processing stages. This section explores various methodologies and techniques aimed at improving work-up and product isolation processes after the synthesis of the targeted API. 

Distillation

Distillation exploits differences in boiling points to separate components in a mixture. It is particularly useful for purifying volatile solvents and removing impurities from liquid reaction products. The efficiency of separations by distillation depends on the boiling point of the components, which must be sufficiently different, as well as the column packing, which affects resolution and purity, and the reflux ratio, which influences the efficiency of separation in fractional distillation.

APIs are not typically volatile enough to be purified by distillation, although it might be appropriate as a way to recover solvents. In API manufacturing the quality of the (recycled) solvent must be monitored for water content and other impurities that could effect the next batch of API. Although it is possible to recycle solvents within a pharmaceutical manufacturing process (Aboagye et al, 2021), in practice it is not cost-effective and safer to send the waste solvent for disposal by incineration (Constable et al., 2007).

Filtration and centrifugation

Filtration and centrifugation are physical separation techniques used to remove particulate matter or separate phases based on density differences. Filtration can be applied in various forms, such as microfiltration, ultrafiltration, and nanofiltration, depending on the size of the particles or molecules to be separated. Centrifugation, on the other hand, utilises centrifugal force to separate components of different densities and is relevant to the formulation of medicinal products (Koehler et al., 2023).

Crystallisation

Crystallisation is a widely used technique for purifying solid compounds. It involves the formation of solid crystals from a homogeneous solution. This method is particularly effective for APIs with high purity requirements. The technique relies on the differential solubility of compounds in various solvents or solvent mixtures at different temperatures. Controlled cooling or solvent evaporation are common methods to induce crystallisation. This process can be optimised through anti-solvent addition, seeding, or by adjusting the pH and ionic strength of the solution. The crystallisation of APIs is important for consistent formulation and performance (Chen et al., 2011).

Chromatography

Chromatography is a powerful separation technique used for the analysis and purification of APIs, offering high resolution and selectivity. Techniques such as High-Performance Liquid Chromatography (HPLC), Gas Chromatography (GC), and Supercritical Fluid Chromatography (SFC) are commonly used in pharmaceutical applications. Chromatography works on the principle of differential partitioning between a mobile phase and a stationary phase, allowing for the separation of compounds based on their chemical or physical properties (Dixon et al., 2006).  Phase selection affects separation efficiency, gradient elution improves separation through gradual changes in mobile phase composition, and temperature control influences analyte behavior and the stationary phase.

Preparatory chromatography is ideally avoided because it is time consuming and produces a lot of waste from the solvent (mobile phase) and silica (stationary phase). The aforementioned techniques can sometimes be used instead, particularly recrystallisation.

Purification avoidance

To reiterate the 12 principles of Green Chemistry and the Waste Hierarchy, it is better to avoid waste than to dispose of it. It is not acceptable to just skip the purification of pharmaceutical ingredients, but some strategies can help avoid the need for it. These strategies have been summarised by Peterson et al. (2014). These include telescoping reactions (combining reaction steps removes the need to purify intermediate products), and asymmetric synthesis to avoid the separation of enantiomers. There is also interest in new reaction methodologies that reduce contamination from residual toxic metal catalysts to below regulatory limits (Strappaveccia et al., 2014).