A swellographic approach to monitoring continuous-flow solid-phase peptide synthesis.

A new type of practical low pressure continuous-flow reaction system has been developed, allowing continuous "dead volume free" handling of polystyrene-based peptide-resins (PR) under conventional Boc/Bzl solid-phase peptide synthesis (SPPS). The reaction system offers a unique opportunity for direct recording of bed volume changes accompanying chemical and physical manipulations with PRs. A new monitoring principle, called "swellography," based on a straightforward interpretation of PR bed volume dynamics, is described. It seems to provide a basis for a novel, automated, non-invasive feedback control system. This novel technique does not complicate SPPS practice; and, moreover, it provides useful information about the swelling behavior of PRs in the real time of SPPS. Although the approach is not directly applicable for quantitation of deprotection and coupling reactions, it does give a good opportunity for real-time optimization of solvent and re-agent usage during the washing and neutralization steps of SPPS. A number of 8- to 16-membered peptides were synthesized manually with complete swellographic monitoring. The practical merits of the new approach are discussed in some detail.