Ionic liquids as synergistic stabilizers in biopharmaceuticals: controlling protein aggregation in formulation and...

Ionic liquids (ILs) have emerged as a versatile class of tunable additives with growing relevance in the stabilization and processing of monoclonal antibodies (mAbs) and other therapeutic proteins. This review critically examines the application of ILs, with particular emphasis on imidazolium and choline-based systems, as synergistic additives and co-excipients for mitigating protein aggregation and enhancing stability across biopharmaceutical manufacturing workflows. Unlike previous broad reviews of ionic liquids in pharmaceutical applications, this review specifically focuses on their role as stabilizing co-excipients for therapeutic proteins and critically examines their translational relevance through comparative, regulatory, and safety-oriented perspectives across the biopharmaceutical manufacturing continuum. Rather than positioning ILs as replacements for conventional excipients, this manuscript highlights their integration into the existing formulation buffers, downstream purification steps, and alternative separation platforms to improve product robustness, recovery, and shelf life. Application-driven case studies have been discussed to illustrate the stabilizing and process-enabling roles of ILs, including the use of 2-methyl imidazolium dihydrogen phosphate in antibody formulation and protein A chromatography, choline-based ILs in high-concentration antibody stabilization, and IL-assisted aqueous biphasic and micellar systems for antibody isolation and purification. Mechanistic insights into ion-protein interactions, hydration-shell modulation, and concentration-dependent effects have been discussed alongside structure-toxicity relationships to contextualize performance within biological and regulatory constraints. In addition, the review addresses critical considerations related to biocompatibility, cytotoxicity, scalability, and regulatory acceptance, emphasizing the importance of rational IL design and application-specific safety assessment. Collectively, this work provides an integrated framework correlating stabilization mechanisms, comparative formulation performance, translational safety considerations, and regulatory perspectives of ILs, positioning them as multifunctional co-excipients that may strengthen existing biopharmaceutical formulation and processing strategies while guiding future research toward safe and effective industrial translation.