[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-detail-43264-en":3,"doc-seo-43264-105":30,"detail-sidebar-cat-0-en-105":91},{"code":4,"msg":5,"data":6},0,"success",{"doc_id":7,"user_id":8,"nickname":9,"user_avatar":10,"doc_module":4,"category_id":11,"category_name":12,"doc_title":13,"doc_description":14,"doc_content":15,"file_id":16,"file_url":17,"file_type":18,"file_size":19,"view_count":20,"is_deleted":4,"is_public":21,"is_downloadable":21,"audit_status":21,"page_count":22,"language":23,"language_code":24,"site_id":25,"html_lang":24,"table_of_contents":26,"faqs":27,"seo_title":13,"seo_description":14,"update_tm":28,"read_time":29},43264,1374391975076,"Riley","https://ap-avatar.wpscdn.com/avatar/14000253ca4ec9f6853?x-image-process=image/resize,m_fixed,w_180,h_180&k=1783305029341752051",8,"Research & Report","Quantitative Analysis of Physical Stability Mechanisms of Amorphous Solid Dispersions by Molecular Dynamic Simulation","Amorphous solid dispersions (ASDs) offer a powerful route to improve the solubility of poorly soluble drugs, yet their physical stability mechanisms are not fully clarified. This study uses molecular dynamics simulations to determine quantitative thresholds for the maximum stable drug loading. Using PVP and PVPVA64 as polymer carriers and naproxen and acetaminophen as model drugs, 18 ASD formulations are analyzed and compared with experiments. Molecular mobility of APIs governs stability, with a critical polymer concentration C* marking drug-rich region formation that promotes aggregation, rearrangement, and recrystallization. Interaction energy and diffusion coefficient exhibit sharp fluctuations at the maximum stable loading, supported by pre-crystalline site search and integrated kinetic, thermodynamic, and pre-crystalline analyses to guide future formulation development.","The AAPS Journal (2024) 27:9  \n[https://doi.org/10.1208/s12248-024-01001-w](https://doi.org/10.1208/s12248-024-01001-w)  \nQuantitative Analysis of Physical Stability Mechanisms of Amorphous Solid Dispersions by Molecular Dynamic Simulation  \nHao Zhong1 · Tianshu Lu1,3 · Ruifeng Wang1 · Defang Ouyang1,2  \nReceived: 25 September 2024 / Accepted: 22 November 2024 / Published online: 5 December 2024  \n© The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists 2024, corrected publication 2025  \nAbstract  \nAmorphous solid dispersions (ASDs) represent a promising strategy for enhancing the solubility of poorly soluble drugs. However, the mechanisms underlying the physical stability of ASDs remain insufficiently understood. This study aims to investigate these mechanisms and propose quantitative thresholds to predict the maximum stable drug loading using molecular dynamics simulations. Poly(vinylpyrrolidone) (PVP) and poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA64) are selected as polymeric carriers, while naproxen and acetaminophen serve as model drugs, resulting in the formulation of 18 distinct ASDs across four types for comparison with experimental results. Our findings indicate that the molecular mobility of active pharmaceutical ingredients (APIs) is the primary determinant of solid dispersion stability. High polymer concentrations limit drug molecular mobility through spatial structural constraints and ASD viscosity. As drug loading increases, the polymer concentration reaches a critical threshold (C*), beyond which drug-rich regions form, leading to potential aggregation, rearrangement, and recrystallization of drug molecules into more energetically stable forms. Notably, both the interaction energy and diffusion coefficient show sharp fluctuations at the maximum stable drug loading, which can serve as predictive indicators for ASD stability. Additionally, a search strategy is used to identify potential pre-crystalline sites. By integrating kinetic, thermodynamic, and pre-crystalline analyses through molecular dynamics simulations, this study provides a foundation for more accurate predictions of ASD stability, significantly aiding future formulation development.  \nKeywords amorphous solid dispersion · stability · molecular dynamics · kinetic · thermodynamic  \nIntroduction  \nAmorphous solid dispersion (ASD) is a uniform mixture in which amorphous drugs are molecularly dispersed within a polymeric matrix, attracting considerable interest for its potential to enhance the solubility of active pharmaceutical ingredients (APIs) (1–3) . The energy level difference between the amorphous and crystalline forms of APIs leads to significantly higher water solubility in the amorphous state (4–6). However, the inherent thermodynamic instability  \n* Defang Ouyang [defangouyang@um.edu.mo](defangouyang@um.edu.mo)  \n1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, 999078 Macau, China  \n2 Faculty of Health Sciences, University of Macau,  \n999078 Macau, China  \n3 Institute of Applied Physics and Materials Engineering, University of Macau, 999078 Macau, China  \nof the amorphous form renders it highly susceptible to recrystallization over time during processing and storage (7) . Therefore, understanding the mechanisms that govern the physical stability of ASDs is essential for the successful development of these formulations. Consequently, the assessment and maintenance of long-term physical stability pose significant challenges in advancing ASD technology (8) .  \nIt is widely recognized that the physical stability of a specific ASD is intricately linked to several key factors, including the solubility of the APIs in the polymer, the degree of mixing between drug molecules and polymers, and the glass transition temperature (Tg) of the ASD (9) . Briefly, the role of polymers in solid dispersions significantly influences the solid-state c","cbCaieWKMOeJSxmz","https://ap.wps.com/l/cbCaieWKMOeJSxmz","pdf",4106652,3,1,13,"English","en",105,"# Abstract\n# Introduction\n## Physical stability drivers of ASDs\n## Existing methods and modeling approaches","[{\"question\":\"What is the main goal of the study on amorphous solid dispersion stability?\",\"answer\":\"The study investigates mechanisms of ASD physical stability and proposes quantitative thresholds to predict the maximum stable drug loading using molecular dynamics simulations.\"},{\"question\":\"Which factor is identified as the primary determinant of ASD solid dispersion stability?\",\"answer\":\"The molecular mobility of the active pharmaceutical ingredients (APIs) is identified as the primary determinant of solid dispersion stability.\"},{\"question\":\"What happens when drug loading increases beyond the critical polymer concentration C*?\",\"answer\":\"Beyond C*, drug-rich regions form, which can lead to aggregation, molecular rearrangement, and recrystallization into more energetically stable forms.\"}]",1783379392,33,{"code":4,"msg":31,"data":32},"ok",{"site_id":25,"language":24,"slug":33,"title":13,"keywords":34,"description":14,"schema_data":35,"social_meta":86,"head_meta":88,"extra_data":90,"updated_unix":28},"quantitative-analysis-of-physical-stability-mechanisms-of-amorphous-solid-dispersions-by-molecular-dynamic-simulation","",{"@graph":36,"@context":85},[37,53,68],{"@type":38,"itemListElement":39},"BreadcrumbList",[40,44,48,50],{"item":41,"name":42,"@type":43,"position":21},"https://docshare.wps.com","Home","ListItem",{"item":45,"name":46,"@type":43,"position":47},"https://docshare.wps.com/document/","Document",2,{"item":49,"name":12,"@type":43,"position":20},"https://docshare.wps.com/document/research-report/",{"item":51,"name":13,"@type":43,"position":52},"https://docshare.wps.com/document/quantitative-analysis-of-physical-stability-mechanisms-of-amorphous-solid-dispersions-by-molecular-dynamic-simulation/43264/",4,{"url":51,"name":13,"@type":54,"author":55,"headline":13,"publisher":57,"fileFormat":60,"inLanguage":24,"description":14,"dateModified":61,"datePublished":62,"encodingFormat":60,"isAccessibleForFree":63,"interactionStatistic":64},"DigitalDocument",{"name":9,"@type":56},"Person",{"url":41,"name":58,"@type":59},"DocShare","Organization","application/pdf","2026-07-16","2026-07-06",true,{"@type":65,"interactionType":66,"userInteractionCount":20},"InteractionCounter",{"@type":67},"ViewAction",{"@type":69,"mainEntity":70},"FAQPage",[71,77,81],{"name":72,"@type":73,"acceptedAnswer":74},"What is the main goal of the study on amorphous solid dispersion stability?","Question",{"text":75,"@type":76},"The study investigates mechanisms of ASD physical stability and proposes quantitative thresholds to predict the maximum stable drug loading using molecular dynamics simulations.","Answer",{"name":78,"@type":73,"acceptedAnswer":79},"Which factor is identified as the primary determinant of ASD solid dispersion stability?",{"text":80,"@type":76},"The molecular mobility of the active pharmaceutical ingredients (APIs) is identified as the primary determinant of solid dispersion stability.",{"name":82,"@type":73,"acceptedAnswer":83},"What happens when drug loading increases beyond the critical polymer concentration C*?",{"text":84,"@type":76},"Beyond C*, drug-rich regions form, which can lead to aggregation, molecular rearrangement, and recrystallization into more energetically stable 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