{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T04:29:16Z","timestamp":1786768156178,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"crossref","award":["ZR2023QH171"],"award-info":[{"award-number":["ZR2023QH171"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy, and LY-11h is a novel acylhydrazide-based histone deacetylase inhibitor with promising therapeutic potential for AML. However, its poor aqueous solubility, limited intestinal dissolution, and narrow therapeutic window hinder oral formulation development and motivate the development of dosage forms with flexible dose-design capabilities. Herein, an integrated hot-melt extrusion (HME)\u2013fused deposition modeling (FDM) strategy was developed to convert LY-11h into printable amorphous solid dispersion (ASD) dosage forms. Methods: HPMC-AS was used as a pH-responsive carrier to enhance intestinal release while restricting premature gastric release, and HPC-EF was incorporated to improve filament processability. Single-factor and DoE studies identified critical formulation and process variables and established formulation\u2013process\u2013property relationships, while machine learning further modeled nonlinear interactions and guided optimization. In-line near-infrared spectroscopy combined with polarized light microscopy enabled real-time monitoring of LY-11h amorphization and melt homogenization during HME. Results: ExtraTrees and Bagging models showed promising predictive performance for key filament properties, and PAT-stage validation confirmed strong agreement with experimental values. The 15 DoE-designed ASD filaments were successfully fabricated into FDM-printed tablets with reproducible geometry. Equilibrium-solubility and in vitro dissolution studies demonstrated enhanced intestinal-pH solubility and reproducible pH-responsive release. Conclusions: Collectively, these findings establish a technological proof of concept for the manufacture of LY-11h dosage forms with adjustable formulation and geometric attributes. Further in vivo pharmacokinetic studies are required to determine whether these manufacturing capabilities translate into predictable dose\u2013exposure relationships and individualized dose control.<\/jats:p>","DOI":"10.3390\/pharmaceutics18081002","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T17:01:35Z","timestamp":1786640495000},"page":"1002","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Precision Drug Delivery of LY-11h for Acute Myeloid Leukemia Treatment Using Machine Learning-Assisted Hot Melt Extrusion and 3D-Printed Technologies"],"prefix":"10.3390","volume":"18","author":[{"given":"Lianghao","family":"Huang","sequence":"first","affiliation":[{"name":"Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danhui","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4467-5885","authenticated-orcid":false,"given":"Weiwei","family":"Yang","sequence":"additional","affiliation":[{"name":"Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao 266101, China"},{"name":"Shandong Energy Institute, Qingdao 266101, China"},{"name":"Qingdao New Energy Shandong Laboratory, Qingdao 266101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minqing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Material Characterization, Thermo Fisher Scientific, Shanghai 201203, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9167-0840","authenticated-orcid":false,"given":"Xia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China"},{"name":"Pharmaceutical Products Research and Development Center, Marine Biomedical Research Institute of Qingdao, Qingdao 266137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/s11912-024-01503-y","article-title":"Novel Therapeutic Targets in Acute Myeloid Leukemia (AML)","volume":"26","author":"Wysota","year":"2024","journal-title":"Curr. Oncol. Rep."},{"key":"ref_2","first-page":"46","article-title":"Acute Myeloid Leukemia Management and Research in 2025","volume":"75","author":"Kantarjian","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100870","DOI":"10.1016\/j.blre.2021.100870","article-title":"The Association between Excess Body Weight at Diagnosis and Pediatric Leukemia Prognosis: A Systematic Review and Meta-Analysis","volume":"51","author":"Galati","year":"2022","journal-title":"Blood Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1002\/pbc.24464","article-title":"Epidemiology of Childhood Acute Myeloid Leukemia","volume":"60","author":"Puumala","year":"2013","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1001\/jamaoncol.2024.2662","article-title":"Contemporary Management of Acute Myeloid Leukemia","volume":"10","author":"Venugopal","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev-publhealth-040617-014158","article-title":"Precision Medicine from a Public Health Perspective","volume":"39","author":"Ramaswami","year":"2018","journal-title":"Annu. Rev. Public Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1021\/acs.jmedchem.1c01472","article-title":"Potent Hydrazide-Based HDAC Inhibitors with a Superior Pharmacokinetic Profile for Efficient Treatment of Acute Myeloid Leukemia In Vivo","volume":"65","author":"Jiang","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1208\/s12248-022-00760-8","article-title":"Challenges and Strategies for Solubility Measurements and Dissolution Method Development for Amorphous Solid Dispersion Formulations","volume":"25","author":"Hermans","year":"2022","journal-title":"AAPS J."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Budiman, A., Handini, A.L., Muslimah, M.N., Nurani, N.V., Laelasari, E., Kurniawansyah, I.S., and Aulifa, D.L. (2023). Amorphous Solid Dispersion as Drug Delivery Vehicles in Cancer. Polymers, 15.","DOI":"10.3390\/polym15163380"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1007\/s13346-015-0256-9","article-title":"Amorphous Solid Dispersion Technique for Improved Drug Delivery: Basics to Clinical Applications","volume":"5","author":"Mishra","year":"2015","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1002\/jps.21172","article-title":"Site-Specific Drug Delivery to the Middle Region of the Small Intestine by Application of Enteric Coating with Hypromellose Acetate Succinate (HPMCAS)","volume":"97","author":"Tanno","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1002\/jps.2600820713","article-title":"Use of Hydroxypropyl Methylcellulose Acetate Succinate in an Enteric Polymer Matrix to Design Controlled-Release Tablets of Amoxicillin Trihydrate","volume":"82","author":"Hilton","year":"1993","journal-title":"J. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Fu, M., Blechar, J.A., Sauer, A., Al-Gousous, J., and Langguth, P. (2020). In Vitro Evaluation of Enteric-Coated HPMC Capsules\u2014Effect of Formulation Factors on Product Performance. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12080696"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"115828","DOI":"10.1016\/j.carbpol.2020.115828","article-title":"Hypromellose Acetate Succinate Based Amorphous Solid Dispersions via Hot Melt Extrusion: Effect of Drug Physicochemical Properties","volume":"233","author":"Sarabu","year":"2020","journal-title":"Carbohydr. Polym."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1136\/gut.29.8.1035","article-title":"Measurement of Gastrointestinal PH Profiles in Normal Ambulant Human Subjects","volume":"29","author":"Evans","year":"1988","journal-title":"Gut"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1016\/j.xphs.2020.04.014","article-title":"Impact of Hypromellose Acetate Succinate Grade on Drug Amorphous Solubility and In Vitro Membrane Transport","volume":"109","author":"Ueda","year":"2020","journal-title":"J. Pharm. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ahmed, Y., Mahmoud, A.A.K., Ludasi, K., and Sov\u00e1ny, T. (2024). Advances in Loading Techniques and Quality by Design for Fused Deposition Modeling in Pharmaceutical Production: A Systematic Review. Pharmaceuticals, 17.","DOI":"10.3390\/ph17111496"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Iqbal, H., Fernandes, Q., Idoudi, S., Basineni, R., and Billa, N. (2024). Status of Polymer Fused Deposition Modeling (FDM)-Based Three-Dimensional Printing (3DP) in the Pharmaceutical Industry. Polymers, 16.","DOI":"10.3390\/polym16030386"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1208\/s12249-021-02114-7","article-title":"Preformulation Studies to Guide the Production of Medicines by Fused Deposition Modeling 3D Printing","volume":"22","author":"Pinho","year":"2021","journal-title":"AAPS PharmSciTech"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"121972","DOI":"10.1016\/j.ijpharm.2022.121972","article-title":"Fabrication of Bilayer Tablets Using Hot Melt Extrusion-Based Dual-Nozzle Fused Deposition Modeling 3D Printing","volume":"624","author":"Zhang","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Huang, L., Guo, J., Li, Y., Yang, W., Ni, W., Jia, Y., Yu, M., and Zhang, J. (2024). Improve Solubility and Develop Personalized Itraconazole Dosages via Forming Amorphous Solid Dispersions with Hydrophilic Polymers Utilizing HME and 3D Printing Technologies. Polymers, 16.","DOI":"10.3390\/polym16233302"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Huang, L., Zhang, X., Huang, Q., Zhu, M., Yang, T., and Zhang, J. (2025). Three-Dimensional Printing of Personalized Carbamazepine Tablets Using Hydrophilic Polymers: An Investigation of Correlation Between Dissolution Kinetics and Printing Parameters. Polymers, 17.","DOI":"10.3390\/polym17152126"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tan, D.K., Maniruzzaman, M., and Nokhodchi, A. (2018). Advanced Pharmaceutical Applications of Hot-Melt Extrusion Coupled with Fused Deposition Modelling (FDM) 3D Printing for Personalised Drug Delivery. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10040203"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"123905","DOI":"10.1016\/j.ijpharm.2024.123905","article-title":"Development of Multiple Structured Extended Release Tablets via Hot Melt Extrusion and Dual-Nozzle Fused Deposition Modeling 3D Printing","volume":"653","author":"Zhang","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103660","DOI":"10.1016\/j.jddst.2022.103660","article-title":"Mucoadhesive Buccal Films for Treatment of Xerostomia Prepared by Coupling HME and 3D Printing Technologies","volume":"75","author":"Elkanayati","year":"2022","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113806","DOI":"10.1016\/j.addr.2021.05.016","article-title":"Machine Learning Directed Drug Formulation Development","volume":"175","author":"Bannigan","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"443","DOI":"10.2478\/acph-2020-0038","article-title":"Process Analytical Technology Tools for Process Control of Roller Compaction in Solid Pharmaceuticals Manufacturing","volume":"70","author":"Vovko","year":"2020","journal-title":"Acta Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1080\/03639045.2017.1291672","article-title":"Design of Experiments (DoE) in Pharmaceutical Development","volume":"43","author":"Politis","year":"2017","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00216-010-3781-x","article-title":"Process Analytical Technology (PAT) for Biopharmaceutical Products","volume":"398","author":"Rathore","year":"2010","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.ijpharm.2015.07.025","article-title":"A Novel Transflectance near Infrared Spectroscopy Technique for Monitoring Hot Melt Extrusion","volume":"496","author":"Kelly","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1208\/s12249-020-01747-4","article-title":"Digital Pharmaceutical Sciences","volume":"21","author":"Damiati","year":"2020","journal-title":"AAPS PharmSciTech"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"101034","DOI":"10.1016\/j.coche.2024.101034","article-title":"Bayesian Data-Driven Models for Pharmaceutical Process Development","volume":"45","author":"Chang","year":"2024","journal-title":"Curr. Opin. Chem. Eng."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Djuris, J., Vasiljevic, D., and Ibric, S. (2024). Experimental Design Application and Interpretation in Pharmaceutical Technology. Computer-Aided Applications in Pharmaceutical Technology, Elsevier.","DOI":"10.1016\/B978-0-443-18655-4.00002-9"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"106562","DOI":"10.1016\/j.ejps.2023.106562","article-title":"Advancing Algorithmic Drug Product Development: Recommendations for Machine Learning Approaches in Drug Formulation","volume":"191","author":"Murray","year":"2023","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_35","first-page":"100576","article-title":"Supervised Machine Learning in Drug Discovery and Development: Algorithms, Applications, Challenges, and Prospects","volume":"17","author":"Obaido","year":"2024","journal-title":"Mach. Learn. Appl."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"115108","DOI":"10.1016\/j.addr.2023.115108","article-title":"Revolutionizing Drug Formulation Development: The Increasing Impact of Machine Learning","volume":"202","author":"Bao","year":"2023","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Huang, L., Ni, W., Jia, Y., Zhu, M., Yang, T., Yu, M., and Zhang, J. (2025). Process Development for the Continuous Manufacturing of Carbamazepine-Nicotinamide Co-Crystals Utilizing Hot-Melt Extrusion Technology. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17050568"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1080\/03639045.2016.1178769","article-title":"Optimization of Hot Melt Extrusion Parameters for Sphericity and Hardness of Polymeric Face-Cut Pellets","volume":"42","author":"Alshetaili","year":"2016","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/adv.21652","article-title":"Understanding the Processing Window of Hypromellose Acetate Succinate for Hot-Melt Extrusion, Part I: Polymer Characterization and Hot-Melt Extrusion","volume":"37","author":"Lu","year":"2018","journal-title":"Adv. Polym. Technol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1208\/s12249-008-9138-5","article-title":"Hydroxypropyl Methylcellulose Acetate Succinate: Potential Drug\u2013Excipient Incompatibility","volume":"9","author":"Dong","year":"2008","journal-title":"AAPS PharmSciTech"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.carbpol.2013.09.017","article-title":"Stability Assessment of Hypromellose Acetate Succinate (HPMCAS) NF for Application in Hot Melt Extrusion (HME)","volume":"101","author":"Sarode","year":"2014","journal-title":"Carbohydr. Polym."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"120755","DOI":"10.1016\/j.ijpharm.2021.120755","article-title":"Investigation on Hot Melt Extrusion and Prediction on 3D Printability of Pharmaceutical Grade Polymers","volume":"604","author":"Tabriz","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"113723","DOI":"10.1016\/j.jconrel.2025.113723","article-title":"Tailoring the Release of Highly Loaded Amorphous Solid Dispersions via Additive Manufacturing","volume":"382","author":"Alva","year":"2025","journal-title":"J. Control. Release"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"9854","DOI":"10.1021\/ma101704k","article-title":"Macromolecular Orientation in Glassy Starch Materials That Exhibit Shape Memory Behavior","volume":"43","author":"Chaunier","year":"2010","journal-title":"Macromolecules"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1002\/pol.1977.180150914","article-title":"Stress Birefringence in Amorphous Polymers under Nonisothermal Conditions","volume":"15","author":"Matsumoto","year":"1977","journal-title":"J. Polym. Sci. Polym. Phys. Ed."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.ijpharm.2015.10.039","article-title":"Fabrication of Controlled-Release Budesonide Tablets via Desktop (FDM) 3D Printing","volume":"496","author":"Goyanes","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1007\/s13346-021-01078-2","article-title":"Optimization of FDM 3D Printing Process Parameters to Produce Haemodialysis Curcumin-Loaded Vascular Grafts","volume":"13","author":"Basile","year":"2023","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_48","unstructured":"United States Pharmacopeia (2017). Simulated Gastric Fluid TS. USP\u2013NF, United States Pharmacopeial Convention."},{"key":"ref_49","unstructured":"United States Pharmacopeia (2017). Simulated Intestinal Fluid TS. USP\u2013NF, United States Pharmacopeial Convention."},{"key":"ref_50","unstructured":"United States Pharmacopeia (2023). General Chapter <711> Dissolution. USP\u2013NF, United States Pharmacopeial Convention."},{"key":"ref_51","unstructured":"United States Pharmacopeia (2020). General Chapter <1092> The Dissolution Procedure: Development and Validation. USP\u2013NF, United States Pharmacopeial Convention."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"106655","DOI":"10.1016\/j.ejps.2023.106655","article-title":"Overcoming Drug Impurity Challenges in Amorphous Solid Dispersion with Rational Development of a Biorelevant Dissolution\u2013Permeation Method","volume":"192","author":"Huzjak","year":"2024","journal-title":"Eur. J. Pharm. Sci."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/1002\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T04:14:15Z","timestamp":1786767255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/1002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":52,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["pharmaceutics18081002"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18081002","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]}}}