Toward Quantitative End-Group Fidelity in the Synthesis of High Molecular Weight Polysarcosine

Polymers applied in pharmaceutical applications need to meet stringent quality standards to ensure reproducibility of product properties, such as efficacy and safety of therapeutics. End-group fidelity is a crucial quality feature that ensures functional integrity, reproducible synthesis, and robust therapeutic performance. The contemporary production of poly(ethylene glycol) (PEG) exemplifies this requirement, which has consolidated its position as a gold standard in pharmaceutical applications. However, modest to severe immune responses toward PEG in patients generate the need for alternative polymers in the development of pharmaceuticals or cosmetics. Among such alternatives, polysarcosine (pSar) displays PEG-like stealth properties in vivo while displaying improved immunogenicity and toxicity profiles, generating the need for heterotelechelic pSar polymers of the highest end-group integrity. Here, we compared current synthetic methods for the controlled synthesis of pSar over a broad molecular weight range and assessed the end-group fidelity by ion exchange chromatography. Subsequent isolation allowed the identification of impurities via mass spectrometry, thus yielding mechanistic insights into the <i>N</i>-substituted <i>N</i>-carboxyanhydride ring-opening polymerization (ROP). Our results reveal a nuanced role of organocatalysts in the ROP, highlighting opportunities for better catalysts. Finally, this work showcases a scalable purification method to obtain high molecular weight pSar with quantitative end-group fidelity.