Green-By-Design Pharmaceuticals: from Human Admet to Environmental Safety in AI-Enabled Sustainable Drug Discovery
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Objectives to analyze how the concept of pharmaceutical sustainability could be taken further into the upstream processes of candidate selection to combine human ADMET, synthetic efficiency, environmental fate, ecotoxicity, biodegradability and AI without affecting therapeutic performance. This is a critical narrative review, which gave priority to peer-reviewed literature published 2021 to 30 August 2026 (with preference to 2024-2026) and the older foundational studies were retained. Official EMA, EUR-Lex, European Commission SSbD, OECD and PREMIER sources were added to PubMed search and targeted publisher searches. The study design, relevance of the endpoints, validation, transparency and relevance to an actionable R&D decision were evaluated, and no PRISMA flow or meta-analysis will be asserted. Prevention by design is supported, with an uneven maturity. Process metrics, solvent selection, catalysis, biocatalysis and continuous processing are relatively developed; prediction of PBT-related endpoints, bioaccumulation and ecotoxicity are being developed, but biodegradability prediction is less certain. The multi-objective prioritization can be assisted by AI when the domains of applicability, uncertainty, and experimental validation are clear. Out of the sources found, no prospective program could support the entire therapeutic-process-environmental framework in its entirety; instead, a stage-gated structure of evidence is suggested. The green reaction or environment score alone does not characterize a Green-by-Design pharmaceutical. It is a medically plausible therapy whose molecular characteristics, manufacturing burden and post consumption ecological conduct are taken into account as long as judgments are changeable. AI must not replace transparent evidence, regulatory assessment or validation but reveal trade-offs and focus on experiments.
[1] J. L. Wilkinson, A. B. A. Boxall, D. W. Kolpin, K. M. Y. Leung, R. W. S. Lai, C. Galbán-Malagón, et al., “Pharmaceutical pollution of the world's rivers,” Proc. Natl. Acad. Sci. U.S.A., vol. 119, no. 8, Art. no. e2113947119, 2022, doi: 10.1073/pnas.2113947119.
[2] A. Bouzas-Monroy, J. L. Wilkinson, M. Melling, and A. B. A. Boxall, “Assessment of the potential ecotoxicological effects of pharmaceuticals in the world's rivers,” Environ. Toxicol. Chem., vol. 41, no. 8, pp. 2008–2020, 2022, doi: 10.1002/etc.5355.
[3] T. Brodin, M. G. Bertram, K. E. Arnold, A. B. A. Boxall, B. W. Brooks, D. Cerveny, et al., “The urgent need for designing greener drugs,” Nat. Sustain., vol. 7, pp. 949–951, 2024, doi: 10.1038/s41893-024-01374-y.
[4] R. Vidaurre, I. Bramke, N. Puhlmann, S. F. Owen, D. Angst, C. Moermond, et al., “Design of greener drugs: Aligning parameters in pharmaceutical R&D and drivers for environmental impact,” Drug Discov. Today, vol. 29, no. 7, Art. no. 104022, 2024, doi: 10.1016/j.drudis.2024.104022.
[5] N. Puhlmann, R. Vidaurre, and K. Kümmerer, “Designing greener active pharmaceutical ingredients: Insights from pharmaceutical industry into drug discovery and development,” Eur. J. Pharm. Sci., vol. 192, Art. no. 106614, 2024, doi: 10.1016/j.ejps.2023.106614.
[6] N. Puhlmann, E. Abbate, K. Kümmerer, A. G. Oomen, A. M. J. Ragas, and C. Moermond, “Applicability of the European Commission's framework on safe and sustainable by design to the pharmaceutical sector,” Sustain. Chem. Pharm., vol. 42, Art. no. 101845, 2024, doi: 10.1016/j.scp.2024.101845.
[7] L. Van Wilder, L. Boone, A. Ragas, C. Moermond, L. Pieters, A. Rechlin, et al., “A holistic framework for integrated sustainability assessment of pharmaceuticals,” J. Clean. Prod., vol. 467, Art. no. 142978, 2024, doi: 10.1016/j.jclepro.2024.142978.
[8] N. Puhlmann, R. Mols, O. Olsson, J. C. Slootweg, and K. Kümmerer, “Towards the design of active pharmaceutical ingredients mineralizing readily in the environment,” Green Chem., vol. 23, pp. 5006–5023, 2021, doi: 10.1039/D1GC01048D.
[9] M. G. Bertram, B. B. M. Wong, K. Kümmerer, and M. Jörg, “Development of environmentally biodegradable drugs: What are the key challenges?” Expert Opin. Drug Discov., vol. 20, no. 1, pp. 1–4, 2025, doi: 10.1080/17460441.2024.2442746.
[10] N. Puhlmann, O. Olsson, and K. Kümmerer, “How data on transformation products can support the redesign of sulfonamides towards better biodegradability in the environment,” Sci. Total Environ., vol. 921, Art. no. 171027, 2024, doi: 10.1016/j.scitotenv.2024.171027.
[11] D. Evangelista, E. Nelson, R. Skyner, B. Tehan, M. Bernetti, M. Roberti, et al., “Application of deep learning to predict the persistence, bioaccumulation, and toxicity of pharmaceuticals,” J. Chem. Inf. Model., vol. 65, no. 7, pp. 3248–3261, 2025, doi: 10.1021/acs.jcim.4c02293.
[12] E. Tsoukas, M. Papadourakis, E. Chontzopoulou, S. Vythoulkas, C. Didachos, D. Cavouras, et al., “G.AI.A: An integrated machine-learning platform for predicting bioaccumulation and ecotoxicity of pharmaceuticals,” J. Chem. Inf. Model., vol. 66, no. 3, pp. 1414–1428, 2026, doi: 10.1021/acs.jcim.5c02286.
[13] H. Boucetta, P. Russell, D. Rudd, and M. Jörg, “From lab to environment: Forecasting pharmaceutical impact using in silico and analytical tools,” RSC Med. Chem., vol. 17, no. 2, pp. 768–783, 2026, doi: 10.1039/D5MD01000D.
[14] S. Groth, K. Kümmerer, and O. Olsson, “Predicting the biodegradability of active pharmaceutical ingredients using freely available in silico models: New application area or impossible?” Sustain. Chem. Pharm., vol. 51, Art. no. 102387, 2026, doi: 10.1016/j.scp.2026.102387.
[15] European Medicines Agency, Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use—Revision 1, EMEA/CHMP/SWP/4447/00 Rev. 1-Corr., effective Sep. 1, 2024.
[16] European Parliament and Council, “Directive (EU) 2024/3019 of 27 November 2024 concerning urban wastewater treatment (recast),” Official Journal of the European Union, 2024.
[17] E. D. van Vliet, N. M. Kannegieter, C. T. A. Moermond, and T. L. Alves, “Keystones in the implementation of greener pharmaceuticals: A scoping review,” Sustain. Chem. Pharm., vol. 44, Art. no. 101938, 2025, doi: 10.1016/j.scp.2025.101938.
[18] E. López-López, P. I. Hernández-Estrada, A. N. Toto-Vazquez, D. V. Ávila-Martínez, O. Spjuth, and J. L. Medina-Franco, “Benign-by-design chemistry: Reinventing ligand-based drug design at the edge of AI,” Drug Discov. Today, vol. 31, no. 4, Art. no. 104691, 2026, doi: 10.1016/j.drudis.2026.104691.
[19] European Commission, “Commission Recommendation (EU) 2026/510 of 6 March 2026 on revising the European assessment framework for safe and sustainable by design chemicals and materials,” Official Journal of the European Union, vol. L 2026/510, 2026.
[20] PREMIER Consortium, PREMIER Digital Assessment System, database version 0.10.1, Jun. 5, 2026. [Online]. Available: https://premier.marionegri.it/
[21] Organisation for Economic Co-operation and Development (OECD), Test No. 301: Ready Biodegradability, OECD Guidelines for the Testing of Chemicals, Section 3. Paris, France: OECD Publishing, 1992, doi: 10.1787/9789264070349-en.
[22] Organisation for Economic Co-operation and Development (OECD), Test No. 305: Bioaccumulation in Fish: Aqueous and Dietary Exposure, OECD Guidelines for the Testing of Chemicals, Section 3. Paris, France: OECD Publishing, 2012, doi: 10.1787/9789264185296-en.
[23] Organisation for Economic Co-operation and Development (OECD), Test No. 201: Freshwater Alga and Cyanobacteria, Growth Inhibition Test, OECD Guidelines for the Testing of Chemicals, Section 2. Paris, France: OECD Publishing, 2026, doi: 10.1787/9789264069923-en.
[24] Organisation for Economic Co-operation and Development (OECD), Test No. 202: Daphnia sp. Acute Immobilisation Test, OECD Guidelines for the Testing of Chemicals, Section 2. Paris, France: OECD Publishing, 2004, doi: 10.1787/9789264069947-en.
[25] Organisation for Economic Co-operation and Development (OECD), Test No. 203: Fish, Acute Toxicity Test, OECD Guidelines for the Testing of Chemicals, Section 2. Paris, France: OECD Publishing, 2025, doi: 10.1787/9789264069961-en.
[26] P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice. Oxford, U.K.: Oxford University Press, 1998.
[27] S. Kar, H. Sanderson, K. Roy, E. Benfenati, and J. Leszczynski, “Green chemistry in the synthesis of pharmaceuticals,” Chem. Rev., vol. 122, no. 3, pp. 3637–3710, 2022, doi: 10.1021/acs.chemrev.1c00631.
[28] S. Ahmad, R. Jaiswal, R. Yadav, and S. Verma, “Recent advances in green chemistry approaches for pharmaceutical synthesis,” Sustainable Chemistry One World, vol. 4, Art. no. 100029, 2024, doi: 10.1016/j.scowo.2024.100029.
[29] J. Colberg, J. L. Tucker, I. Martínez, J. D. Bailey, C. Briddell, S. G. Koenig, et al., “Environmental sustainability strategy of active pharmaceutical ingredient manufacturing: A perspective from the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable,” ACS Sustain. Chem. Eng., vol. 13, no. 27, pp. 10268–10284, 2025, doi: 10.1021/acssuschemeng.5c01094.
[30] Z. Chen, J. Z. Lian, H. Zhu, J. Zhang, Y. Zhang, X. Xiang, et al., “Application of life cycle assessment in the pharmaceutical industry: A critical review,” J. Clean. Prod., vol. 459, Art. no. 142550, 2024, doi: 10.1016/j.jclepro.2024.142550.
[31] E. Lucas, A. J. Martín, S. Mitchell, A. Nabera, L. F. Santos, J. Pérez-Ramírez, and G. Guillén-Gosálbez, “The need to integrate mass- and energy-based metrics with life cycle impacts for sustainable chemicals manufacture,” Green Chem., vol. 26, pp. 9300–9309, 2024, doi: 10.1039/D4GC00394B.
[32] P. Richardson, M. C. Bryan, L. Diorazio, F. Gallou, S. Keily, I. Martinez, et al., “Solvent sustainability in drug discovery: Where are we now, and how can we improve?” J. Med. Chem., vol. 68, no. 24, pp. 25625–25664, 2025, doi: 10.1021/acs.jmedchem.5c01220.
[33] L. J. Nolan, S. J. King, S. Wharry, T. S. Moody, and M. Smyth, “A pharma perspective on sustainability advantages through adoption of continuous flow,” Curr. Opin. Green Sustain. Chem., vol. 46, Art. no. 100886, 2024, doi: 10.1016/j.cogsc.2024.100886.
[34] F. Falcioni, L. Humphreys, R. C. Lloyd, H. Wu, I. Martinez, J. Jones, et al., “The evolving landscape of industrial biocatalysis in perspective from the ACS Green Chemistry Institute Pharmaceutical Roundtable,” ACS Catal., vol. 15, no. 12, pp. 10780–10794, 2025, doi: 10.1021/acscatal.5c01646.
[35] S. S. Panda, “Advancements in ecotoxicological assessment of anticancer agents: Bridging sustainability and innovation in chemical testing,” Green Anal. Chem., vol. 11, Art. no. 100162, 2024, doi: 10.1016/j.greeac.2024.100162.
[36] A. S. Gaikwad, “Green organic synthesis in drug discovery: Emerging roles of artificial intelligence and quantum chemical approaches,” Discover Chemistry, vol. 3, Art. no. 330, 2026, doi: 10.1007/s44371-026-00784-5.
[37] A. Gangwal and A. Lavecchia, “AI-driven synthesis in medicinal chemistry: Integrating large language models, robotic automation, and sustainability metrics to accelerate drug discovery,” Med. Res. Rev., 2026, doi: 10.1002/med.70074.
[38] J. Xu, T. Ren, S. Chen, F. Li, N. Zhang, L. Zhao, et al., “Life cycle thinking in early drug discovery: Reducing environmental impact and animal testing via interpretable machine learning- and chemometrics-based oral acute toxicity screening,” ACS Sustain. Chem. Eng., vol. 14, no. 23, pp. 10819–10838, 2026, doi: 10.1021/acssuschemeng.6c03787.
[39] M. Wang, Z. Jia, H. Peng, W. Peng, J. Ran, J. Zhu, et al., “Green chemistry-oriented multiobjective optimization with semiautomated process monitoring for apixaban intermediate synthesis,” ACS Sustain. Chem. Eng., vol. 13, no. 30, pp. 12134–12145, 2025, doi: 10.1021/acssuschemeng.5c03852.
[40] L. Marotta, F. M. P. R. Giammarino, B. B. Senenou Tambou, V. Tudino, S. Butini, L. Broccardo, et al., “Oxyprenyl-chalcones as antibacterial hits: Design of experiments-optimized synthesis, antibacterial evaluation, early drug-like profiling and biodegradability prediction,” RSC Med. Chem., vol. 17, no. 3, pp. 1573–1585, 2026, doi: 10.1039/D5MD00839E.
[41] I. Egaña, V. Akhrimenko, M. Ayerbe, E. Abasolo, U. Lertxundi, and G. Orive, “Promoting sustainable pharmacy for tackling environmental pharmaceutical pollution,” Drug Discov. Today, vol. 31, no. 1, Art. no. 104559, 2026, doi: 10.1016/j.drudis.2025.104559.
[42] A. Shalin, M. L. Diamond, and Z. Wang, “Breaking lock-ins to enable a green pharmacy,” Environ. Sci. Technol., vol. 60, no. 8, pp. 5960–5969, 2026, doi: 10.1021/acs.est.5c12437.
[43] B. Martinengo, E. Diamanti, E. Uliassi, and M. L. Bolognesi, “Medicinal chemistry: A key driver in achieving the global Sustainable Development Goals,” J. Med. Chem., vol. 68, no. 7, pp. 6916–6931, 2025, doi: 10.1021/acs.jmedchem.4c03016.
[44] B. Martinengo, E. Diamanti, E. Uliassi, and M. L. Bolognesi, “The many facets of sustainability in medicinal chemistry: Our personal experience,” RSC Med. Chem., vol. 17, pp. 738–742, 2026, doi: 10.1039/D5MD00882D.
[45] A. Singh, R. Debnath, V. Chawla, and P. A. Chawla, “Green drug discovery: Leveraging biodiversity for sustainable pharmaceutical solutions,” Chem. Biodivers., vol. 23, no. 1, Art. no. e00733, 2026, doi: 10.1002/cbdv.202500733.
[46] F. D. Spilsbury, P. A. Inostroza, P. Svedberg, C. Cannata, A. M. J. Ragas, and T. Backhaus, “Defining the data gap: What do we know about environmental exposure, hazards and risks of pharmaceuticals in the European aquatic environment?” Water Res., vol. 251, Art. no. 121002, 2024, doi: 10.1016/j.watres.2023.121002.
