(605c) Process Bottleneck of Packed Bed Oligonucleotide Reactors Arising from Critical Flux Due to Solid Phase Compressibility
AIChE Annual Meeting
Thursday, November 17, 2022 - 8:48am to 9:12am
In this work, we have studied the pressure drop across a packed bed of polystyrene resin for oligonucleotide synthesis and quantified critical flux as a function of bed height, solvent, and length of oligo. We have found that the relationship between pressure drop and flux is nonlinear and the pressure drop increases exponentially as the flux reaches a certain critical value. We have also found that the packed bed is compressible under flow â bed height decreases as flux increases. Factors impacting the critical flux include the solvent, the bed height, the bed diameter and the length of oligonucleotide on resin. The more the solvent swells the resin, the lower the critical flux is in that solvent. The taller the bed, the lower the critical flux. The critical flux decreases as the bed diameter increases until it reaches around 2.5 cm. The longer the oligonucleotide on resin, the higher the critical flux (smaller specific cake resistance). We developed a mathematical model by considering bed compression under pressure drop and corresponding change in local porosity. This model can quantitatively describe our experimental data. We also developed a novel synthesis condition that allows detritylation reaction to be conducted in acetonitrile instead of toluene. There are already commercially available ACN-rich oxidation and sulfurization reagents. Performing detritylation in acetonitrile, together with those ACN-rich oxidation and sulfurization reagents, and with less concentrated capping reagents, over-pressurization problem can be made less severe, bed height can be higher, more solid phase can be packed in reactor, and therefore process throughput can be greatly increased.