Abstract
Aqueous Two-Phase Systems (ATPSs) have been extensively studied for their ability to simultaneously separate and purify active pharmaceutical ingredients (APIs) and key intermediates with high yields and high purity. Depending on the ATPS composition, it can be adapted for the separation and purification of cells, nucleic acids, proteins, antibodies, and small molecules. This method has been shown to be scalable, allowing it to be used in the milliliter scale for early drug development to thousands of liters in manufacture for commercial supply. The benefits of ATPS in pharmaceutical separations is increasingly being recognized and investigated by larger pharmaceutical companies. ATPSs use identical instrumentation and similar methodology, therefore a change from traditional methods has a theoretical low barrier of adoption. The cost of typical components used to form an ATPS at large scale, particularly that of polymer-polymer systems, is the primary challenge to widespread use across industry. However, there are a few polymer-salt examples where the increase in yield at commercial scale justifies the cost of using ATPSs for macromolecule purification. More recently, Ionic Liquids (ILs) have been used for ATPS separations that is more sustainable as a solvent, and more economical than polymers often used in ATPSs for small molecule applications. Such IL-ATPSs still retain much of the attractive characteristics such as customizable chemical and physical properties, stability, safety, and most importantly, can provide higher yield separations of organic compounds, and efficient solvent recycling to lower financial and environmental costs of large scale manufacturing.
Highlights
The adoption of methods from the scientific literature into industrial applications often follows a period of dormancy
While Aqueous Two-Phase Systems (ATPSs) have experienced a recent prolific rise in applications in microfluidics, cellular engineering, bioprinting, and biopatterning since the 2000s (Teixeira et al, 2017), the industrial applications of ATPSs are typically separations and purification, first described in the 1950s (Albertsson, 1956, 1958). Such ATPSs popularized by Albertsson are polymer-polymer or polymer-salt emulsions that have been well-studied for viral (Norrby and Albertsson, 1960; Liu et al, 1998; Effio et al, 2015), cellular (Walter et al, 1976; Sharp et al, 1986; Kumar et al, 2001), nucleic acid (Ribeiro et al, 2002; Gomes et al, 2009; Nazer et al, 2017), ionic liquids (ILs)-ATPSs: A Pharmaceutical Perspective protein (Schmidt et al, 1994; Balasubramaniam et al, 2003), and antibody (Desbuquois and Aurbach, 1971; Selber et al, 2004; Rosa et al, 2007b; Azevedo et al, 2009a) separations
While polymer ATPSs are limited to partitioning of macromolecules due to size of the polymers used, the isolation and separation of small molecules (
Summary
The adoption of methods from the scientific literature into industrial applications often follows a period of dormancy. The process of ATPS separations and purification occurs in three major steps: molecular partitioning, physical separation, and isolation of phase of interest (Figure 1). Aside from changes in molecular weight, the properties of PEG with respect to partitioning are limited To overcome this challenge, multiple groups have functionalized PEG in PEG/salt and PEG/dextran ATPSs with glutaric acid to improve extraction yields of immunoglobins from 28 to 93% (Rosa et al, 2007a), and 23 to 97% (Azevedo et al, 2009b) as well as increasing extraction efficiencies of penicillin up to 96% using imidazole-terminal PEG (Jiang et al, 2009). The use of ATPSs present an opportunity to simplify the manufacturing process of plasmid DNA by allowing for the lysis, recovery, purification and extraction in a single high yield step (Frerix et al, 2005). Tall vessels result in long centrifugal distances and longer sedimentation times to achieve complete separation
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