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Machine learning is becoming useful in formulation research because it can connect scattered formulation data to excipient selection, property prediction, and experimental decision-making. In particular, machine learning models can help extract useful patterns from fragmented formulation data, prioritize candidate excipients, and guide formulation decisions before extensive experimental screening. This review summarizes recent advances in machine-learning-driven optimization of functional excipients and their biointeractions in drug formulations. We first discuss the methodological foundations of this field, including data acquisition, feature engineering, model architecture selection, optimization, and evaluation strategies. Representative application scenarios are then reviewed, including the identification of functional excipients related to drug efflux inhibition, formulation stability enhancement, biological barrier penetration, and metabolic clearance reduction. This review also discusses practical barriers that still limit this field related to data quality, representation design, experimental feedback, computational cost, and deployability. These issues need to be addressed before artificial intelligence (AI)-assisted formulation systems can become reliable tools for routine pharmaceutical development.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00322","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T14:42:31Z","timestamp":1784212951000},"page":"2137-2150","source":"Crossref","is-referenced-by-count":1,"title":["Machine-Learning-Driven\nOptimization of Functional\nExcipients and Their Biointeractions in Drug Formulations"],"prefix":"10.1021","volume":"9","author":[{"given":"Xiaoyue","family":"Liu","sequence":"first","affiliation":[{"name":"National University of Singapore , , ,","place":["Singapore, Singapore, 117583"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liulu","family":"Xie","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]},{"name":"Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3611-2760","authenticated-orcid":true,"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]},{"name":"Huazhong University of Science and Technology , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"issue":"5","key":"2026081411080182100_cit1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics12050393","article-title":"The role of\nfunctional excipients in solid oral dosage forms to overcome poor\ndrug dissolution and bioavailability","volume":"12","author":"van der Merwe","year":"2020","journal-title":"Pharmaceutics"},{"issue":"5","key":"2026081411080182100_cit2","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics17050598","article-title":"Biofunctional excipients: their emerging role in overcoming\nthe inherent poor biopharmaceutical characteristics of drugs","volume":"17","author":"Qelliny","year":"2025","journal-title":"Pharmaceutics"},{"issue":"21","key":"2026081411080182100_cit3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21218224","article-title":"Pharmaceutical\nexcipients and drug\nmetabolism: A mini-review","volume":"21","author":"Patel","year":"2020","journal-title":"Int. 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Sci."},{"issue":"4","key":"2026081411080182100_cit6","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics10040165","article-title":"An evaluation of\nthe potential of NMR spectroscopy and computational modelling methods\nto inform biopharmaceutical formulations","volume":"10","author":"Pandya","year":"2018","journal-title":"Pharmaceutics"},{"issue":"5","key":"2026081411080182100_cit7","doi-asserted-by":"publisher","DOI":"10.1208\/s12249-023-02573-0","article-title":"Drug-excipient\ncompatibility study through a novel\nvial-in-vial experimental setup: A benchmark study","volume":"24","author":"Jain","year":"2023","journal-title":"AAPS PharmSciTech"},{"key":"2026081411080182100_cit8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2025.125625","article-title":"Quality by digital design to accelerate\nsustainable\nmedicines development","volume":"681","author":"Mustoe","year":"2025","journal-title":"Int. J. 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