Most microreactor-based chemical syntheses have been applied to chemistries with relatively small reaction times – reactions that vary from a few milliseconds up to 30-40 minutes residence time in the microreactor. Long reaction time chemistries have been a challenge for the microreactor community. Increasing residence time by making longer channels is one solution, but it presents increased pressure drop. The problem of high pressure drop is even more significant in reactions involving packed bed microreactors.

We have developed a microchemical system that recirculates flow to increase the residence time, permitting slower reactions to be studied in microreactors without much increase in flow pressure drop. Flow recirculation was performed by pumping the microdevice outlet stream back in the inlet of the microdevice, thus increasing the residence time. The inline pumping technique used gas pressure from a high pressure gas source and involved no moving parts. The flow recirculation system involved three enclosures – E1, E2 and E3 connected in cyclic fashion to form the recirculation loop, with the microdevice between E1 and E2, which were kept at constant pressures, P1 and P2, respectively, in order to maintain constant pressure drop, hence a constant flowrate across the microdevice. Pressure in E3 was varied periodically as in a square-wave profile with the higher pressure as P3 and lower as P0, such that P3>P1>P2>P0, to enable the flow recirculation. We demonstrated the recirculation at two scales of enclosures – 40 microliter and 10 milliliter to achieve flowrates up from 1 µl/min to several ml/min.

Solid phase peptide synthesis on polymeric matrix using the Merrifield technique was demonstrated using the recirculation system. The chemistry involved successive steps of deprotection of amino acid on the matrix, activation and addition of new amino acid, and washing to grow the peptide chain, followed by cleavage of the final peptide from the resin. The typical coupling times (30-50 minutes) were more than what most microdevices provide, hence the recirculation system was used to increase the residence time.

Most current microdevices offer substantial pressure drop when used as packed-bed reactors. The challenges are even more when the packed bed increases in volume during operation, as is the case with the peptide synthesis supports that swell in size during synthesis. New silicon-based microchips were fabricated that permit volume change of the packed solid phase and were used for the peptide synthesis using flow recirculation.

We will discuss details of the packed-bed microchip, recirculation system and its demonstration involving packed-bed microreactors for peptide synthesis.