As of 2021, there were 15 oligonucleotide drugs and over 100 peptide drugs on the market in the U.S., Europe, and Japan. Chemically, these therapeutics are classified as defined sequence polymers (DSPs), with DSPs characterised by having a fully defined length and an exactly defined monomer sequence. The current industrial manufacture of pharmaceutical DSPs is through solid phase synthesis (SPS). However, SPS is expensive, difficult to scale, and often requires extensive purification by chromatography.
In this work, a new DSP manufacturing platform was developed. This new technology was based on liquid phase reactions, which are fast, scalable, and have the potential to achieve high product purities. These reactions were coupled to organic solvent-based membrane purifications to achieve efficient, high purity, high yield separations of the DSP from the reaction debris. This formed the basis for the new platform technology: membrane enabled liquid phase DSP synthesis. The success of this new platform technology required the design of a new range of organic solvent stable membranes. These membranes were manufactured using a previously untested high molecular weight polybenzimidazole (PBI) polymer (60,000 Da), which produced membranes with improved long-term stability in organic solvents, compared to the standard grade of PBI (27,000 Da), which has been used for almost all other PBI organic solvent nanofiltration (OSN) membranes in literature. These membranes were crosslinked with dibromoxylene (DBX) and shown to be mechanically, thermally, and chemically stable at DSP manufacturing conditions, specifically in polar aprotic solvents, acids, and bases. Post crosslinking, the PBI membrane was graft modified with long polyether amines. By controlling the extent of graft modification, the rejection profile of the PBI membranes was customisable. Additionally, the graft modification imparted significant anti-fouling properties to the membranes, creating the first organic solvent stable membranes specifically targeting fouling resistance...