(421b) Organic Solvent Nanofiltration in Pharmaceutical Manufacturing – Membrane-Based Peptide Synthesizer
AIChE Annual Meeting
Tuesday, November 17, 2020 - 8:00am to 8:15am
To fill in the gap, we have developed a membrane-based peptide synthesiser to synthesise peptides in liquid phase and utilise OSN for intermediate isolation. This retains all liquid-phase advantages, while benefiting from facile separations to facilitate solid-phase-like rapid synthesis. The following synthesis cycle was devised for the synthesiser: coupling of amino acid (AA) to the growing peptide intermediates, inactivation and deprotection of excess AA, and diafiltration to remove all reaction debris. At the end of the cycle, growing peptide intermediates are retained by the OSN membrane and ready for next coupling.
To deliver rapid synthesis, repeated syntheses and intermediate isolations need to take place continuously inside the synthesiser without any liquid transfers in between. Under this condition, OSN membrane being the key element of the synthesiser must withstand harsh chemical environments and possess superior long-term stability. Crosslinked Polybenzimidazole (PBI) membrane was chosen for its high chemical stability and mechanical strength. To increase the selectivity between peptide intermediates and reaction debris, the membrane surface was modified with polymer brushes to alter the surface hydrophilicity-hydrophobicity balance. This classs of PBI membrane was proven to have excellent performances which remained constant after many synthesis cycles. To enhance the diafiltration efficiency, the membrane-based peptide synthesiser was configured into a 2-stage cascade system. Continuous synthesis cycles took place in the 1st stage, with 2nd stage purposed to recycle partial flow back to the 1st stage.
Our progress to date has validated the membrane-based peptide synthesiser through the synthesis of model peptides (5 and 10 AA) with crude purities that are higher than, or at least comparable to, peptides synthesised via solid-phase. Currently, we are working on the development of full process automation and the synthesis of drug candidates eg. Octreotide (8 AA). We envisage that this membrane-based synthesiser will become a new standard for pharmaceuticals manufacturing.