Entropy–Enthalpy Switching and Protonation-Gated Fluorescence in Olanzapine–Cyclodextrin Inclusion Complexes

Entropy–Enthalpy Switching and Protonation-Gated Fluorescence in Olanzapine–Cyclodextrin Inclusion Complexes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Entropy–Enthalpy Switching and Protonation-Gated Fluorescence in Olanzapine–Cyclodextrin Inclusion Complexes Raed Ghanem, Khaldoun Al-Sou'od, Fakhri Yousef, Sarmad Fathi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8495712/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Olanzapine (OLP), a poorly water-soluble antipsychotic, forms host–guest inclusion complexes with cyclodextrins (CDs) that can improve aqueous solubility and photostability. Here, we quantify OLP binding to α-, β-, γ-, and hydroxypropyl-β-cyclodextrin (HP-β-CD) using pH-resolved UV–visible and steady-state fluorescence spectroscopy, supported by density-functional theory (DFT). Benesi–Hildebrand (1:1) analysis yields association constants (K 11 ) of 6–110 M⁻¹ at 25°C with pronounced pH dependence. Temperature-dependent measurements (25–45°C) enable extraction of standard thermodynamic parameters, showing that inclusion is spontaneous (ΔG° = −RT lnK 0) compensated by favorable entropy gains (ΔS° > 0). Accordingly, the standard free energies fall within the expected range ( ≈ − 5 to − 12 kJ·mol⁻¹ at 298 K). DFT calculations predict stabilizing electronic interaction energies that mirror the experimental affinity trends (e.g., ΔE stab = − 31.8 kJ·mol⁻¹ for β-CD and − 27.4 kJ·mol⁻¹ for HP-β-CD). Ground- and excited-state acidity constants (pK a ≈ 8.8; pK a * ≈ 7.7) indicate protonation-gated inclusion that modulates fluorescence intensity and spectral shifts. Overall, the study establishes a quantitative, pH-resolved connection between photophysics and thermodynamics in OLP–CD complexes and provides mechanistic guidance for the rational design of CD-based delivery systems for aromatic psychotropics. Olanzapine cyclodextrin inclusion fluorescence spectroscopy pH-dependent binding Thermodynamics (ΔG° ΔH° ΔS°) DFT Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8495712","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":569580766,"identity":"85b508c6-e783-496a-a600-b5a705aae0eb","order_by":0,"name":"Raed Ghanem","email":"","orcid":"","institution":"Al al-Bayt University","correspondingAuthor":false,"prefix":"","firstName":"Raed","middleName":"","lastName":"Ghanem","suffix":""},{"id":569580774,"identity":"a610af23-8cc2-4f2f-ad31-bb1a3f4122c0","order_by":1,"name":"Khaldoun 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Complexes","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Olanzapine, cyclodextrin inclusion, fluorescence spectroscopy, pH-dependent binding, Thermodynamics (ΔG°, ΔH°, ΔS°), DFT","lastPublishedDoi":"10.21203/rs.3.rs-8495712/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8495712/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOlanzapine (OLP), a poorly water-soluble antipsychotic, forms host\u0026ndash;guest inclusion complexes with cyclodextrins (CDs) that can improve aqueous solubility and photostability. Here, we quantify OLP binding to α-, β-, γ-, and hydroxypropyl-β-cyclodextrin (HP-β-CD) using pH-resolved UV\u0026ndash;visible and steady-state fluorescence spectroscopy, supported by density-functional theory (DFT). Benesi\u0026ndash;Hildebrand (1:1) analysis yields association constants (K\u003csub\u003e11\u003c/sub\u003e) of 6\u0026ndash;110 M⁻\u0026sup1; at 25\u0026deg;C with pronounced pH dependence. Temperature-dependent measurements (25\u0026ndash;45\u0026deg;C) enable extraction of standard thermodynamic parameters, showing that inclusion is spontaneous (ΔG\u0026deg; = \u0026minus;RT lnK\u0026thinsp;\u0026lt;\u0026thinsp;0) over the studied range, with small-to-large positive enthalpy changes (ΔH\u0026deg; \u0026gt; 0) compensated by favorable entropy gains (ΔS\u0026deg; \u0026gt; 0). Accordingly, the standard free energies fall within the expected range (\u0026thinsp;\u0026asymp;\u0026thinsp;\u0026minus;\u0026thinsp;5 to \u0026minus;\u0026thinsp;12 kJ\u0026middot;mol⁻\u0026sup1; at 298 K). DFT calculations predict stabilizing electronic interaction energies that mirror the experimental affinity trends (e.g., ΔE\u003csub\u003estab\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;31.8 kJ\u0026middot;mol⁻\u0026sup1; for β-CD and \u0026minus;\u0026thinsp;27.4 kJ\u0026middot;mol⁻\u0026sup1; for HP-β-CD). Ground- and excited-state acidity constants (pK\u003csub\u003ea\u003c/sub\u003e \u0026asymp; 8.8; pK\u003csub\u003ea\u003c/sub\u003e* \u0026asymp; 7.7) indicate protonation-gated inclusion that modulates fluorescence intensity and spectral shifts. Overall, the study establishes a quantitative, pH-resolved connection between photophysics and thermodynamics in OLP\u0026ndash;CD complexes and provides mechanistic guidance for the rational design of CD-based delivery systems for aromatic psychotropics.\u003c/p\u003e","manuscriptTitle":"Entropy–Enthalpy Switching and Protonation-Gated Fluorescence in Olanzapine–Cyclodextrin Inclusion Complexes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-06 12:10:01","doi":"10.21203/rs.3.rs-8495712/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"abd7788f-b4e4-4c88-85c1-a4d974ede665","owner":[],"postedDate":"January 6th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-10T03:53:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-06 12:10:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8495712","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8495712","identity":"rs-8495712","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}