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A QbD strategy leverages the acidic wound pH (4.5–6.0) by combining mucoadhesive, cationic chitosan with pH-sensitive graphene oxide to form a nanocomposite hydrogel for sustained levofloxacin delivery, reducing dosing frequency and resistance pressure. Box-Behnken design and RSM optimize four critical process parameters to tune critical quality attributes, achieving high entrapment and pH-triggered release, supported by antimicrobial and in vivo efficacy.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/box-behnken-design-optimization-of-ph-responsive-chitosan-graphene-oxide-nanocomposite-hydrogel-for-sustained-levofloxacin-delivery-research-study/156109/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/box-behnken-design-optimization-of-ph-responsive-chitosan-graphene-oxide-nanocomposite-hydrogel-for-sustained-levofloxacin-delivery-research-study/156109.png","ImageObject",300,407,{"name":92,"@type":93},"Noah","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-08","2026-08-28",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does the formulation achieve pH-responsive sustained levofloxacin release?","Question",{"text":112,"@type":113},"The system uses chitosan as a mucoadhesive polymer and graphene oxide as a pH-sensitive component. Levofloxacin release is tuned to be higher under infected-wound pH conditions, supporting sustained delivery at the wound site.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which factors were optimized using Box-Behnken design and RSM?",{"text":117,"@type":113},"Risk assessment identified four critical process parameters: Cs:GO ratio, glutaraldehyde concentration, stirring speed, and sonication time. These parameters were optimized to improve critical quality attributes such as entrapment efficiency and particle uniformity.",{"name":119,"@type":110,"acceptedAnswer":120},"What antimicrobial and in vivo outcomes are reported for the optimized hydrogel system?",{"text":121,"@type":113},"In vitro testing shows effective MRSA inhibition and bacterial killing linked to oxidative damage from GO-based materials. In vivo evaluation in a rat MRSA wound model reports a 90% bacterial reduction and complete re-epithelialization by day 21 with lower pro-inflammatory cytokines versus controls.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},156109,1787953694,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":129,"read_time":31},8796095462418,"https://ap-avatar.wpscdn.com/avatar/80000253c1241d02b47?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778826106357471780","Journal of Pharmaceutical Innovation (2026) 21:108 [https://doi.org/10.1007/s12247-025-10319-7](https://doi.org/10.1007/s12247-025-10319-7)  \nRESEARCH  \nBox-Behnken Design Optimization of pH-Responsive ChitosanGraphene Oxide Nanocomposite Hydrogel for Sustained Levofloxacin Delivery in Antimicrobial Wound Therapeutics  \nPriyanka Rathore1 · Prem Prakash Singh1 · Peeyush Bhardwaj1 · Anshu Awasthi1 · Brajesh Lodhi2 · Prakash Chandra Yadav3 · Ankita Kishore4 · Prashant Pandey5,6 · Alok Kumar Mahor1  \nReceived: 7 November 2025 / Accepted: 15 December 2025 / Published online: 9 January 2026  \n© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2026  \nAbstract  \nChronic wounds colonized by methicillin-resistant Staphylococcus aureus (MRSA) prolong hospitalization, heighten amputation risk and accelerate antimicrobial resistance (AMR) . To counter this, we exploited the acidic pH (4.5-6.0) of infected tissue and employed ICH Q8/Q9 Quality-by-Design (QbD) to fuse mucoadhesive, cationic chitosan (Cs) with high-surface-area, pH-sensitive graphene oxide (GO), creating a nanocomposite that sustainably releases levofloxacin (LVX) at the wound site, thereby reducing dosing frequency and selection pressure for resistance. This QbD-driven study developed Cs-GO nanocomposite hydrogel for pH-responsive LVX release, optimized via Box-Behnken design (BBD) and response surface methodology (RSM) in Design-Expert® v13 .0. Risk assessment (ICH Q9) identified four critical process parameters (CPPs); Cs: GO ratio (X₁), glutaraldehyde concentration (X₂), stirring speed (X₃), and sonication time (X₄) to refine critical quality attributes (CQAs) like entrapment efficiency and particle uniformity, yielding nanoparticles with 82.31% entrapment, 180 nm size, -29.86 mV zeta potential, and polydispersity index of 0.293 (R² >0.85) . These LVX-loaded Cs-GO nanoparticles were subsequently dispersed in an HPMC/Eudragit hydrogel matrix (TGLN4) to produce the final nanocomposite hydrogel dressing. The formulation exhibited pH-dependent release kinetics (85% LVX over 20 h at pH 5.5, mimicking infected wounds), driven by ionic gelation, hydrogen bonding, and glutaraldehyde crosslinking, with anomalous diffusion (Peppas n = 0.65) . In vitro assessments demonstrated enhanced mechanical properties (viscosity ≈ 3.4 × 10³ cP) and an effective MRSA inhibition (MIC 0.5 µg/mL). The LVX/GO combination produced rapid bacterial killing consistent with oxidative damage reported for GO-based materials. In vivo studies in a rat MRSA wound model confirmed 90% bacterial reduction and complete re-epithelialization by day 21, with fivefold lower pro-inflammatory cytokines versus controls. ICH stability studies affirmed shelf-life viability (minimal degradation over 6 months) . This scalable QbD platform advances manufacturable bionanocomposites for topical antimicrobial therapeutics, reducing dosing frequency and AMR risks while enabling a scalable platform with potential for further manufacturing development.  \nKeywords Chitosan-Graphene oxide nanocomposite · Box-Behnken design · pH-responsive hydrogel · Levofloxacin delivery · Quality-By-Design · Wound therapeutics  \n􀀍 Alok Kumar Mahor[alokmahor522@bujhansi.ac.in](alokmahor522@bujhansi.ac.in)  \n1 Institute of Pharmacy, Bundelkhand University, Jhānsi, India  \n2 Department of Mechanical Engineering, Institute of Engineering & Technology, Bundelkhand University, Jhānsi, India  \n3 Department of Chemistry, Bundelkhand University, Jhānsi, Uttar Pradesh 284128, India  \n4 Amity University Madhya Pradesh, Gwalior 474005, India  \n5 Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh India, India  \n6 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton T6G 2E1, Canada  \nIntroduction  \nWound healing represents a dynamic cascade essential for restoring tissue integrity [1, 2] . However, chronic wounds exacerbated by un","cbCainsC68KbAXMK","https://ap.wps.com/l/cbCainsC68KbAXMK","pdf",3069547,"English","# Abstract\n## Keywords\n# Introduction\n## Problem background and limitations of current antibiotics\n## Rationale for QbD and sustained-release strategies\n## Role of chitosan and graphene oxide in topical delivery\n## Identified research gap and study objective","[{\"question\":\"How does the formulation achieve pH-responsive sustained levofloxacin release?\",\"answer\":\"The system uses chitosan as a mucoadhesive polymer and graphene oxide as a pH-sensitive component. Levofloxacin release is tuned to be higher under infected-wound pH conditions, supporting sustained delivery at the wound site.\"},{\"question\":\"Which factors were optimized using Box-Behnken design and RSM?\",\"answer\":\"Risk assessment identified four critical process parameters: Cs:GO ratio, glutaraldehyde concentration, stirring speed, and sonication time. These parameters were optimized to improve critical quality attributes such as entrapment efficiency and particle uniformity.\"},{\"question\":\"What antimicrobial and in vivo outcomes are reported for the optimized hydrogel system?\",\"answer\":\"In vitro testing shows effective MRSA inhibition and bacterial killing linked to oxidative damage from GO-based materials. In vivo evaluation in a rat MRSA wound model reports a 90% bacterial reduction and complete re-epithelialization by day 21 with lower pro-inflammatory cytokines versus controls.\"}]","Box-Behnken Design Optimization of pH-Responsive Chitosan-Graphene Oxide Nanocomposite Hydrogel for Sustained Levofloxacin Delivery - Research Study | PDF"]