{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T03:58:10Z","timestamp":1792900690023,"version":"4.5.0"},"reference-count":70,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2022-NR070862"],"award-info":[{"award-number":["RS-2022-NR070862"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2022-NR070862"],"award-info":[{"award-number":["RS-2022-NR070862"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003662","name":"Korea Evaluation Institute of Industrial Technology","doi-asserted-by":"publisher","award":["RS-2024-00441601"],"award-info":[{"award-number":["RS-2024-00441601"]}],"id":[{"id":"10.13039\/501100003662","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003662","name":"Korea Evaluation Institute of Industrial Technology","doi-asserted-by":"publisher","award":["RS-2025-11902968"],"award-info":[{"award-number":["RS-2025-11902968"]}],"id":[{"id":"10.13039\/501100003662","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2024-00441601"],"award-info":[{"award-number":["RS-2024-00441601"]}],"id":[{"id":"https:\/\/ror.org\/03z9cwa38","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS-2025-11902968"],"award-info":[{"award-number":["RS-2025-11902968"]}],"id":[{"id":"https:\/\/ror.org\/03z9cwa38","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Arginine and related amino acids are widely used to suppress protein aggregation, thereby affecting stability, manufacturability, and therapeutic performance. However, their effectiveness remains limited, necessitating the exploration of alternative strategies. Previous studies have shown that N-acetyl-L-arginine (NA-Arg) can improve protein stability; however, the potential of other N-acetylated amino acids has not been fully explored. Methods: This study aimed to investigate the effects of multiple N-acetylated amino acids as alternative excipients on aggregation, colloidal stability, and viscosity in intravenous immunoglobulin (IVIG) formulations. Dynamic light scattering (DLS) was used to evaluate diffusion behavior and aggregation tendencies, while complementary analyses were performed using size-exclusion chromatography (SEC) and flow-imaging microscopy (FI). Results: Overall, N-acetylation of amino acids improved colloidal stability, shifting the kD values from \u22125.87 to 6.83 mL\/g for arginine and from \u22128.17 to 16.22 mL\/g for histidine, and increased the aggregation onset temperature (Tagg) to above 60 \u00b0C. Among the tested compounds, N-acetyl-L-histidine (NA-His) showed the most favorable results, increasing the monomer proportion by approximately 4%, reducing high-molecular-weight species to below 2%, and producing a greater than 10-fold decrease in subvisible particles relative to histidine hydrochloride after 5 days of agitation. At 50 mM, both NA-His and NA-Arg reduced the viscosity of highly concentrated 200 mg\/mL IVIG formulations, with NA-His exhibiting the lowest viscosity (7.24 \u00b1 0.12 mPa\u00b7s). Protein\u2013protein interaction and surface charge analyses indicated improved colloidal stability relative to parent amino acids, attributable to the presence of the acetyl group. Conclusions: These findings support the potential of N-acetylation as a strategy to modulate interaction-driven instability and suggest NA-His as a promising candidate excipient for stabilizing highly concentrated therapeutic proteins at acidic pH.<\/jats:p>","DOI":"10.3390\/pharmaceutics18050544","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:46:11Z","timestamp":1777455971000},"page":"544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Modulation of Intravenous Immunoglobulin Aggregation, Subvisible Particle Formation, and Viscosity by Acetylated Amino Acids"],"prefix":"10.3390","volume":"18","author":[{"given":"Arun","family":"Mainali","sequence":"first","affiliation":[{"name":"College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea"},{"name":"Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan 58554, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binod","family":"Lamichhane","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea"},{"name":"Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan 58554, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea"},{"name":"Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan 58554, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Hoon","family":"Jeong","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1970-6877","authenticated-orcid":false,"given":"Nam Ah","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Mokpo National University, Muan 58554, Republic of Korea"},{"name":"Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Muan 58554, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1007\/s13205-024-03958-z","article-title":"Therapeutic proteins: Developments, progress, challenges, and future perspectives","volume":"14","author":"Kumar","year":"2024","journal-title":"3 Biotech"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1038\/s41467-023-38039-x","article-title":"Engineering protein-based therapeutics through structural and chemical design","volume":"14","author":"Ebrahimi","year":"2023","journal-title":"Nat. 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