{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:07:43Z","timestamp":1788782863637,"version":"build-2803163510"},"reference-count":38,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/na","name":"State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory","doi-asserted-by":"publisher","award":["2025XAKJ0101004"],"award-info":[{"award-number":["2025XAKJ0101004"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Central Funds Guiding Local Science and Technology Development","doi-asserted-by":"publisher","award":["2025ZY01093"],"award-info":[{"award-number":["2025ZY01093"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Zhejiang Provincial Science and Technology Project for Marine Industry","doi-asserted-by":"publisher","award":["2026HYC10005"],"award-info":[{"award-number":["2026HYC10005"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China","doi-asserted-by":"publisher","award":["LHDMZ24H300003"],"award-info":[{"award-number":["LHDMZ24H300003"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Central Funds Guiding Local Science and Technology Development","doi-asserted-by":"publisher","award":["SZYZ2025-01"],"award-info":[{"award-number":["SZYZ2025-01"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Driven by the evolving demands of modern pharmaceutical industry, high-concentration monoclonal antibody formulations (HCMFs) have emerged as a central research hotspot in biopharmaceutical development, attributable to their merits such as low administration volume and reduced medical expenditure. For lyophilized HCMFs, reconstitution performance serves as a critical quality attribute of equivalent importance to long-term storage stability. As components in direct contact with lyophilized drug products, primary packaging containers are indispensable critical excipients for pharmaceutical preparation. This work systematically investigated the effects of inner surface characteristics of glass vials on the long-term stability and reconstitution behaviors of lyophilized HCMFs. The results demonstrated that the surface hydrophilicity\/hydrophobicity of vial walls exerted no remarkable influence on the physicochemical stability of mAb-X during prolonged storage. Nevertheless, in the reconstitution process, the intrinsically high viscosity of concentrated mAb solutions, combined with the ultralow surface free energy, intense hydrophobicity and weakened contact line pinning effect of such vials, triggered massive visible-bubbles to adhere beneath the liquid\u2013solid interface. These trapped bubbles failed to ascend and dissipate along the inner walls and bottom of vials. Collectively, this study verifies that hydrophobic primary packaging materials, when adopted as storage containers for lyophilized HCMFs, will induce severe reconstitution defects, which may further lead to inaccurate dosing and compromised clinical operability.<\/jats:p>","DOI":"10.1021\/acs.molpharmaceut.6c00599","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:32:53Z","timestamp":1785144773000},"page":"4729-4742","source":"Crossref","is-referenced-by-count":0,"title":["Primary\nPackaging Hydrophilicity\/Hydrophobicity: A\nCritical Factor Governing Visible-Bubbles during Reconstitution Process\nof Lyophilized High-Concentration Monoclonal Antibody Formulations"],"prefix":"10.1021","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0132-2813","authenticated-orcid":true,"given":"Han","family":"Gao","sequence":"first","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Taizhou Institute of Zhejiang University , ,","place":["Taizhou, China, 317000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Lin","family":"Ding","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Taizhou Institute of Zhejiang University , ,","place":["Taizhou, China, 317000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Zhejiang Institute for Food and Drug Control , , ,","place":["Hangzhou, Zhejiang, China, 310004"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3375-7360","authenticated-orcid":true,"given":"Wei-Jie","family":"Fang","sequence":"additional","affiliation":[{"name":"Zhejiang University , , ,","place":["Hangzhou, China, 310058"]},{"name":"Taizhou Institute of Zhejiang University , ,","place":["Taizhou, China, 317000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"issue":"1","key":"2026090707080913100_cit1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2024.2443538","article-title":"Antibodies to watch\nin 2025","volume":"17","author":"Crescioli","year":"2025","journal-title":"MAbs"},{"issue":"1","key":"2026090707080913100_cit2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2026.2614669","article-title":"Antibodies\nto watch in 2026","volume":"18","author":"Crescioli","year":"2026","journal-title":"MAbs"},{"issue":"2","key":"2026090707080913100_cit3","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1038\/s43018-023-00516-z","article-title":"Advances in\nantibody-based therapy in oncology","volume":"4","author":"Zinn","year":"2023","journal-title":"Nat. Cancer"},{"issue":"8","key":"2026090707080913100_cit4","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/j.amjmed.2023.05.001","article-title":"An update on monoclonal antibody\ntherapy to treat moderate-to-severe asthma: benefits, choices, and\nlimitations","volume":"136","author":"Elliott","year":"2023","journal-title":"Am. J. Med."},{"issue":"17","key":"2026090707080913100_cit5","doi-asserted-by":"publisher","first-page":"2159","DOI":"10.3390\/cells12172159","article-title":"Cancer vaccine\ntherapeutics: limitations and effectiveness-A literature review","volume":"12","author":"Kaczmarek","year":"2023","journal-title":"Cells"},{"issue":"1","key":"2026090707080913100_cit6","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2023.2285277","article-title":"Monoclonal\nantibody and protein therapeutic formulations for subcutaneous delivery:\nhigh-concentration, low-volume vs. low-concentration, high-volume","volume":"15","author":"Desai","year":"2023","journal-title":"MAbs"},{"key":"2026090707080913100_cit7","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.ejpb.2021.04.023","article-title":"Preparation of high concentration protein powder suspensions\nby milling of lyophilizates","volume":"166","author":"Marschall","year":"2021","journal-title":"Eur. J. 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Controlled Release"},{"issue":"11","key":"2026090707080913100_cit11","doi-asserted-by":"publisher","first-page":"5842","DOI":"10.1021\/acs.molpharmaceut.3c00694","article-title":"Predicting colloidal\nstability of high-concentration monoclonal antibody formulations in\ncommon pharmaceutical buffers using improved polyethylene glycol induced\nprotein precipitation assay","volume":"20","author":"Meza","year":"2023","journal-title":"Mol. Pharmaceutics"},{"issue":"9","key":"2026090707080913100_cit12","doi-asserted-by":"publisher","first-page":"4553","DOI":"10.1021\/acs.molpharmaceut.4c00460","article-title":"Flow activation energy of high-concentration monoclonal antibody\nsolutions and protein-protein interactions influenced by NaCl and\nsucrose","volume":"21","author":"Yuan","year":"2024","journal-title":"Mol. 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Technol."},{"issue":"11","key":"2026090707080913100_cit15","doi-asserted-by":"publisher","first-page":"4025","DOI":"10.1002\/jps.23293","article-title":"Heat transfer characteristics\nof current primary packaging\nsystems for pharmaceutical freeze-drying","volume":"101","author":"Hibler","year":"2012","journal-title":"J.\nPharm. Sci."},{"issue":"4","key":"2026090707080913100_cit16","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.xphs.2022.01.011","article-title":"Stress factors in primary packaging,\ntransportation and handling of protein drug products and their impact\non product quality","volume":"111","author":"Narhi","year":"2022","journal-title":"J. Pharm. 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Pharm."},{"key":"2026090707080913100_cit25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2024.125152","article-title":"The effect of glass\ncontainer surface silanol density on monoclonal\nantibody formulation stability after application of mechanical shock","volume":"670","author":"Wang","year":"2025","journal-title":"Int. J. Pharm."},{"key":"2026090707080913100_cit26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2024.114502","article-title":"Utilizing a hydrophobic primary container\nsurface to reduce the formation of subvisible particles in monoclonal\nantibody solution caused by fluid shear","volume":"204","author":"Wang","year":"2024","journal-title":"Eur.\nJ. Pharm. Biopharm"},{"issue":"4","key":"2026090707080913100_cit27","doi-asserted-by":"publisher","first-page":"1691","DOI":"10.1021\/acs.molpharmaceut.3c00991","article-title":"Effect of annealing on visible-bubble formation and\nstability profiles of freeze-dried high concentration omalizumab formulations","volume":"21","author":"Gao","year":"2024","journal-title":"Mol. Pharmaceutics"},{"issue":"12","key":"2026090707080913100_cit28","doi-asserted-by":"publisher","first-page":"7664","DOI":"10.1021\/acs.molpharmaceut.5c01347","article-title":"Contradictory effects\nof different freezing rates on visible bubbles and reconstitution\ntime during the reconstitution of freeze-dried high-concentration\nmonoclonal antibody formulations","volume":"22","author":"Gao","year":"2025","journal-title":"Mol. Pharmaceutics"},{"issue":"1","key":"2026090707080913100_cit29","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1208\/s12248-024-01009-2","article-title":"Formulation\nfactors affecting the formation of visible-bubbles during the reconstitution\nprocess of freeze-dried etanercept formulations: protein concentration,\nstabilizers, and surfactants","volume":"27","author":"Gao","year":"2025","journal-title":"AAPS J."},{"key":"2026090707080913100_cit30","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.ejpb.2021.05.005","article-title":"Key factors governing\nthe reconstitution time of high\nconcentration lyophilized protein formulations","volume":"165","author":"Kulkarni","year":"2021","journal-title":"Eur. J. Pharm. Biopharm"},{"issue":"5","key":"2026090707080913100_cit31","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1016\/j.xphs.2020.02.006","article-title":"Reconstitution\nof highly concentrated lyophilized proteins: Part 1 amorphous formulations","volume":"109","author":"Sane","year":"2020","journal-title":"J. Pharm. Sci."},{"key":"2026090707080913100_cit32","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ejpb.2018.07.022","article-title":"Mechanisms\nby which crystalline mannitol improves the reconstitution time of\nhigh concentration lyophilized protein formulations","volume":"131","author":"Kulkarni","year":"2018","journal-title":"Eur. J. Pharm. Biopharm"},{"issue":"7","key":"2026090707080913100_cit33","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1016\/j.xphs.2017.03.014","article-title":"Lyophilized drug product cake appearance: What is acceptable?","volume":"106","author":"Patel","year":"2017","journal-title":"J. Pharm. Sci."},{"key":"2026090707080913100_cit34","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.ejpb.2021.10.011","article-title":"Adjustment of specific residual moisture\nlevels in completely freeze-dried protein formulations by controlled\nspiking of small water volumes","volume":"169","author":"Lo Presti","year":"2021","journal-title":"Eur. J. Pharm.\nBiopharm"},{"issue":"4","key":"2026090707080913100_cit35","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3390\/pharmaceutics12040303","article-title":"The Influence of Moisture Content and Temperature on\nthe Long-Term Storage Stability of Freeze-Dried High Concentration\nImmunoglobulin G (IgG)","volume":"12","author":"Duralliu","year":"2020","journal-title":"Pharmaceutics"},{"issue":"11","key":"2026090707080913100_cit36","doi-asserted-by":"publisher","first-page":"4912","DOI":"10.1021\/la0502894","article-title":"Influence of surfactant\non gas bubble stability","volume":"21","author":"Hanwright","year":"2005","journal-title":"Langmuir"},{"key":"2026090707080913100_cit37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cis.2026.103838","article-title":"Recent advances in atomic force microscopy\nfor micro- and nanobubble research","volume":"352","author":"Zhang","year":"2026","journal-title":"Adv. Colloid\nInterface Sci."},{"key":"2026090707080913100_cit38","first-page":"101","volume-title":"Nucleation and\nstabilization of microbubbles in liquids","author":"Crum","year":"1982"}],"container-title":["Molecular Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.molpharmaceut.6c00599","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/23\/9\/4729\/66279178\/acs.molpharmaceut.6c00599.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/23\/9\/4729\/66279178\/acs.molpharmaceut.6c00599.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T11:10:21Z","timestamp":1788779421000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article\/23\/9\/4729\/5233895\/Primary-Packaging-Hydrophilicity-Hydrophobicity-A"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,7,27]]},"published-print":{"date-parts":[[2026,9,7]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.molpharmaceut.6c00599","relation":{},"ISSN":["1543-8384","1543-8392"],"issn-type":[{"value":"1543-8384","type":"print"},{"value":"1543-8392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]}}}