Solubilization of Azelnidipine in TPGS Micelles: Structural Insights, Micellar Stability, and Sustained Drug Release Behavior

Solubilization of Azelnidipine in TPGS Micelles: Structural Insights, Micellar Stability, and Sustained Drug Release Behavior | 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 Solubilization of Azelnidipine in TPGS Micelles: Structural Insights, Micellar Stability, and Sustained Drug Release Behavior Srushti Shah, Vandana Patel This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7144838/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Polyethoxylated (PEO)-based nonionic surfactants, such as D-α-Tocopheryl polyethylene glycol succinate (TPGS), offer significant advantages in drug delivery due to their low toxicity, mild interaction with biological membranes, and ability to form stable micellar systems. This study investigates the solubilization and delivery of the poorly water-soluble drug AZP using TPGS micelles. TPGS exhibited a low critical micelle concentration (0.002% w/v), forming stable, spherical, and monodisperse micelles (9.99–13.51 nm) with high drug-loading efficiency (86%). Fluorescence quenching studies confirmed the encapsulation of AZP in the hydrophobic micellar core, protecting it from aqueous degradation. In vitro release profiles showed sustained drug release from TPGS micelles, with less than 20% drug release in 6 hours compared to 90% from free AZP. Dilution studies showed micelle stability up to 30-fold dilution, with disassembly observed at higher dilutions. These findings underscore the potential of TPGS micelles as effective nanocarriers to improve the solubility, stability, and bioavailability of hydrophobic drugs, while enabling controlled release for better therapeutic performance. Azelnidipine TPGS Micelles Critical Micelle Concentration Drug Delivery Solubility Enhancement Controlled release Entrapment Efficiency Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Highlights Low CMC (0.002 % w/v) of TPGS displayed monodisperse spherical morphology confirmed via DLS and TEM. High drug entrapment efficiency (86 %) was achieved for the poorly soluble drug AZP. Fluorescence studies confirmed AZP localization in the micelle core, ensuring protection from aqueous environments. Nanocarriers are used to enhance solubility, stability, and systemic delivery. 1. Introduction Nonionic surfactants that have been polyethoxylated (PEO) typically produce higher surface or interfacial tension than ionic surfactants at certain concentrations at which they form aggregates, making the nonionic less irritating, toxic, and less damaging to cell membranes. Nonionic surfactants associate with one another at much lower concentrations to lower the surface free energy since they are typically larger, less polar, and less preferentially adsorbed at the surface [ 1 , 2 ]. Cremophor EL, Poloxamer, polysorbates, Pluronics, Brij, and α-tocopherol polyethylene glycol succinate (TPGS) are some of the PEO-based surfactants that have been widely used [ 3 , 4 ]. PEO-based surfactants have a lipophilic portion comprising an alkyl or aryl-alkyl group and oxyethylene as a hydrophilic part. D-α-Tocopheryl polyethylene glycol succinate (TPGS) is a water-soluble derivative of vitamin E with polyethylene glycol (PEG) chain, making it highly attractive for various applications [ 5 ]. Similar to poloxamers, TPGS can form polymeric micelles and possesses a hydrophilic segment. However, it demonstrates superior inhibition of P-glycoprotein (P-gp) transporters, which are a major barrier to the permeability of numerous anticancer drugs [ 6 ]. Among its variants, TPGS-1000 composed of a hydrophilic block with 23 ethylene oxide (EO) units—has been the most extensively studied [ 7 , 8 ]. It undergoes self-aggregation at a critical concentration of 0.02%, leading to the formation of stable, spherical core-shell micelles with an aggregation number of approximately 100, maintaining structural integrity across temperature variations. Azelnidipine (AZP), a dihydropyridine calcium channel blocker, is BCS Class II drug for the management of hypertension. The limited solubility presents a major challenge for its oral bioavailability. Various approaches were used to solubilize hydrophobic drugs and improve their permeability through TPGS alone or as mixed micelles with other amphiphiles [ 9 – 11 ]. Yan et al. [ 12 ] enhanced camptothecin solubility and stability using a TPGS-P105 mixed micellar system, which increased its cytotoxicity against MCF-7 cell lines. Solubility of naproxen increased to 350 mg/l in 1% total concentration of TPGS-T1107 mixed micelles from 28 mg/ml in water. The prepared mixed micelles significantly increase drug transmembrane diffusion in a gel form [ 13 ].Yang et al. developed solid dispersion with TPGS and Poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA) to improve the dissolution and bioavailability of aprimilast reports 8-folds greater absorption in physical mixture than free drug. This study focused on improving the solubility and encapsulation of the hydrophobic drug AZP by incorporating it into micelles formed by TPGS. The micellar formulations were systematically analyzed using DLS, TEM, and fluorescence spectroscopy to examine the drug’s spatial distribution within the micelles. The results indicated strong interactions between AZP and the micellar core, with the drug preferentially partitioning into the hydrophobic region. This suggests that TPGS micelles effectively enhance drug solubilization while offering a protective environment that supports stability in aqueous conditions. 2. Materials and Methods 2.1 Materials Azelnidipine (99% pure) and D-α-Tocopheryl polyethylene glycol succinate (TPGS, ≥ 98%, MW 1513 Da) were generously provided by Pure Chem Pvt. Ltd., India. Pyrene was purchased from Sigma-Aldrich, USA. All reagents were of analytical grade. Deuterated water was procured from Tokyo Chemical Industries, Japan. Buffers were prepared according to the Indian Pharmacopoeia. 2.2 Determination of Critical Micelle Concentration (CMC) and Cloud Point (CP) The CMC of TPGS was determined at 30°C using both surface tension and pyrene fluorescence techniques. Surface tension measurements were performed using a tensiometer (Krüss, Germany), and the data were plotted against log concentration. For fluorescence, pyrene (5 × 10⁻⁷ M) was added to a series of TPGS concentrations (0.0001 to 0.1 mM), incubated in the dark for 24 h, and analyzed with a Shimadzu RF5301PC spectrofluorometer. The I₁/I₃ intensity ratio was plotted to determine the CMC. Cloud point was determined by heating TPGS solutions (1–5%) and noting the temperature at which turbidity appeared. 2.3 Drug Loading and Entrapment Efficiency Excess AZP was added to TPGS micelle solutions and stirred at 37°C for 48 h. Unsolubilized drug was removed via 0.22 µm filtration. Drug content in the filtrate was determined spectrophotometrically at 254 nm. Entrapment efficiency (EE %) was calculated as: EE % = (Amount of drug solubilized / Initial drug added) × 100 2.4 In Vitro Drug Release AZP-loaded micelles were placed in a dialysis bag (MWCO 12–14 kDa) and immersed in phosphate buffer (pH 6.8) at 37°C. At predetermined intervals, samples were withdrawn and replaced with fresh buffer. Drug concentration was measured spectrophotometrically. 2.5 Preparation and Characterization of Micelles Micelles were prepared by dissolving the required amount of TPGS in de-ionized water. It was then equilibrated at 25°C for 24 h. Dynamic light scattering (DLS) was used to determine micelle size and polydispersity index (PDI) of undiluted samples (Nano ZS, Malvern Instruments, UK). Acquisitions were carried out with a He–Ne laser at 130° scattering angle and data were analyzed by normalized intensity distribution using CONTIN method for cumulants,size distribution, and PDI. 2.6 Solubilization and Localization of AZP into TPGS Micelles Excess AZP was equilibrated with a fixed volume of micelle dispersion under orbital stirring (37°C; 48 h). The samples were filtered (0.20 µm pore size) to remove unsolubilized AZP. The concentration of AZP in filtrate was quantified by UV-vis spectrophotometry (Shimadzu 3092, Japan). In order to assess the physical stability of AZP-loaded micelles, the formulation was incubated in a shaker maintained at 37°C. At predetermined time intervals, the sample was filtered (0.22 µm) and analyzed to record the amount of AZP precipitated with time. Photoluminescence quenching of pyrene (5 × 10 − 7 M) was exploited to locate AZP solubilized into the micelles. Intensity ratio of first-to-third vibronic peaks (I1/I3) in pyrene emission spectrum senses the polarity of medium (19). Micelles, labeled with pyrene, were titrated against increasing concentration of Azelnidipine. 3. Results and discussion The critical micelle concentration (CMC) of TPGS was determined using pyrene fluorescence spectroscopy, by evaluating the intensity ratio (I₁/I₃) of its emission peaks. As shown in the plot (Figure 1), the I₁/I₃ ratio exhibited a sharp decrease with increasing TPGS concentration until reaching a plateau, indicating micelle formation. The inflection points in the curve, marked by a significant change in slope, corresponds to the CMC. The CMC value for TPGS was identified to be approximately in the range of 0.002 % w/v (2×10⁻³ %), consistent with literature reports on the low CMC of TPGS due to its hydrophobic vitamin E moiety and hydrophilic polyethylene glycol chain [14, 15]. This low CMC is advantageous for drug delivery applications, ensuring micelle stability even under high dilution in systemic circulation. Moreover, the sigmoidal nature of the plot confirms the cooperative nature of micelle formation, characteristic of amphiphilic block copolymers such as TPGS. A notable characteristic of TPGS is its high cloud point, reported at approximately 74 °C [16].The high cloud point of TPGS is advantageous in drug delivery, particularly in maintaining micellar stability under physiological and elevated temperatures encountered during sterilization or formulation processing. This thermal stability ensures sustained solubilization of hydrophobic drugs, preventing premature precipitation and enhancing bioavailability [17]. Micelles formed at various concentrations of TPGS (2 %) were systematically characterized using DLS and TEM to evaluate their size distribution and morphology. The hydrodynamic diameter of the micelles ranged from 9.99 nm to 13.51 nm depending on the concentration and the medium (sterile water). All micelle samples exhibited PDI values below 0.3, indicative of a narrow and monodisperse size distribution, which is desirable for consistent in vivo performance [18]. The DLS size distribution Fig. 1(A) shows that unloaded TPGS micelles exhibited a sharp intensity peak with a D h around 11 nm, confirming a homogeneous nano micellar population. Upon incorporation of AZP (a hydrophobic compound), the micelle size increased slightly, shifting the peak to approximately 20 nm, consistent with drug encapsulation increasing the hydrodynamic radius. This increase in size and broadening of the distribution curve for TPGS-AZP micelles suggests successful drug loading while maintaining acceptable uniformity [19]. Transmission electron microscopy Fig. 2(B) further confirmed the formation of well-defined micelles. The micelles appeared spherical and were uniformly dispersed without signs of aggregation. The average diameter observed under TEM was consistent with DLS measurements, confirming the nanoscale size and morphological integrity of the micelles. The high contrast and uniform shape observed in the TEM micrograph support the effective self-assembly of TPGS into core–shell nanostructures, which is a characteristic of amphiphilic surfactants [15]. The small size, spherical morphology, and low PDI values are particularly advantageous for biomedical applications such as drug delivery. These characteristics enhance systemic circulation stability and promote passive tumor targeting through the enhanced permeability and retention (EPR) effect [20]. The entrapment efficiency (EE) and drug loading (DL) of AZP in TPGS micelles were quantitatively assessed to evaluate the micellar system’s drug-carrying capacity. As illustrated in Fig.3 , the TPGS-AZP micellar formulation exhibited a high entrapment efficiency of approximately 86 %, while the drug loading was relatively lower, near 9 %. The high EE value is indicative of effective solubilization and encapsulation of the hydrophobic drug within the micellar core. This is consistent with literature demonstrating that TPGS, owing to its amphiphilic structure, forms micelles with a hydrophobic core that efficiently accommodates poorly water-soluble compounds like AZP [21, 22]. Entrapment efficiency was found to be optimal at a TPGS concentration of 3 %. At concentrations beyond this threshold, a decline in EE was observed, likely due to the saturation of the micellar core, limiting additional drug incorporation. This saturation effect is commonly reported in micellar systems, where the solubilization capacity reaches a plateau with increasing surfactant concentration [23]. Moreover, excessive surfactant may contribute to micelle restructuring or aggregation, potentially reducing drug entrapment. To further validate the localization of AZP within the micellar structure, pyrene fluorescence quenching studies were performed. A significant shift in the I₁/I₃ fluorescence intensity ratio confirmed that AZP resided predominantly in the hydrophobic core of the TPGS micelles. The decreased I₁/I₃ ratio reflects a more nonpolar environment, typical of micellar cores, supporting effective incorporation of the drug within the lipophilic domain [24]. These findings underline the suitability of TPGS micelles as efficient nanocarriers for hydrophobic drugs like AZP, balancing high entrapment with favorable localization in the core, which is essential for stability and controlled release profiles. The in vitro release behavior of AZP from TPGS micelles (TPGS-AZP) was evaluated over 24 hours to assess the formulation's ability to provide sustained drug delivery. As shown in Fig.4 , the free AZP exhibited a rapid release, with over 90 % of the drug released within 6 hours, reaching a plateau shortly thereafter. In contrast, the TPGS-AZP micellar system demonstrated a significantly slower and sustained release profile, with less than 20 % cumulative release over the same period. This marked difference in release kinetics highlights the role of micellar encapsulation in modulating drug release. The sustained release from the TPGS micelles can be attributed to the drug being embedded within the hydrophobic core of the micellar structure, which acts as a barrier to immediate diffusion into the aqueous medium. This encapsulation not only enhances drug solubility but also protects the active compound from rapid dissolution and degradation, leading to a controlled and extended release [25]. The release profile of TPGS-AZP follows a diffusion-controlled mechanism, as is typical for micellar and nanoparticulate systems where drug molecules gradually migrate from the hydrophobic core into the surrounding medium [26]. Such controlled release behavior is advantageous for poorly water-soluble drugs like Azelnidipine, as it may improve therapeutic efficacy, reduce dosing frequency, and minimize peak-related side effects [27]. Furthermore, the slower release rate observed with TPGS-AZP indicates the stability of the micellar structure under physiological conditions, reinforcing its potential as a nanocarrier for sustained drug delivery applications. The findings align with previous reports where TPGS-based micelles were shown to prolong the release and circulation time of encapsulated therapeutics due to their steric stabilization and hydrophobic interactions [14]. The colloidal stability of TPGS micelles under dilution was assessed using dynamic light scattering (DLS), as illustrated in Fig. 5 . The aqueous dispersion of micelles was serially diluted from the original concentration up to 1000-fold, and their hydrodynamic size distributions were recorded to evaluate the retention of micellar structure. DLS data show that at lower dilutions (e.g., up to 30-fold), TPGS micelles retained a relatively narrow and unimodal distribution, with hydrodynamic diameters consistent with intact micelles. However, at higher dilution levels (100-fold and above), the emergence of additional peaks and the broadening of the size distribution became apparent, indicating partial disassembly of micelles and formation of smaller aggregates or free unimers. These results suggest that TPGS micelles exhibit limited colloidal stability under extensive dilution, likely due to their reliance on non-covalent interactions for micelle formation. When the concentration falls below the CMC, micellar integrity is compromised, leading to dissociation. This behaviour is consistent with previous findings that non-crosslinked surfactant micelles tend to disassemble at low concentrations due to the dynamic equilibrium between monomers and micellar aggregates [28]. The dilution-induced instability of TPGS micelles underscores the importance of maintaining an appropriate concentration during formulation and delivery to ensure structural integrity and effective drug encapsulation. 4. Conclusion This study systematically investigated the solubilization and delivery of the poorly water-soluble drug AZP using TPGS micelles, demonstrating their effectiveness as a nanocarrier system. The research revealed that TPGS forms stable micelles at an exceptionally CMC of 0.002 % w/v, attributed to its amphiphilic structure combining a hydrophobic vitamin E core and hydrophilic PEG shell. Comprehensive characterization using DLS and TEM confirmed the formation of monodisperse, spherical micelles with a narrow size distribution (9.99-13.51 nm), ideal for systemic circulation and passive targeting. The micellar system exhibited remarkable drug-loading capabilities, achieving 86 % entrapment efficiency for AZP, with optimal performance at 3 % TPGS concentration. Fluorescence quenching studies using pyrene confirmed the preferential localization of AZP within the hydrophobic core, ensuring protection from aqueous degradation. Importantly, in vitro release studies demonstrated sustained drug release kinetics, with less than 20 % of AZP released within 6 hours compared to 90 % for free drug, highlighting the system's ability to modulate drug release. These findings collectively establish TPGS micelles as a promising platform for enhancing the solubility, stability, and bioavailability of hydrophobic drugs like AZP, while offering controlled release properties that could improve therapeutic outcomes and reduce dosing frequency. The study provides valuable insights for developing TPGS-based nanocarriers for poorly soluble pharmaceuticals. Declarations Credit authorship contribution statement Srushti Shah: Investigation, Formal analysis, Writing – original draft. Formal analysis. Vandana Patel : Conceptualization, Writing – review & editing, Project administration. Funding The author had not received any funding for carrying this work. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Acknowledgments Thanks Central Instrumentation Facility of Parul University for Dynamic light scattering and spectroscopy experiments. Data Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request. Ethics declaration: Not applicable. References Azum, N., et al., Micellar and interfacial properties of amphiphilic drug–non-ionic surfactants mixed systems: Surface tension, fluorescence and UV–vis studies. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2017. 522 : p. 183-192. Luz, A.M., et al., Tween-80 on water/oil interface: structure and interfacial tension by molecular dynamics simulations. Langmuir, 2023. 39 (9): p. 3255-3265. 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Thomas, Environmental effects on vibronic band intensities in pyrene monomer fluorescence and their application in studies of micellar systems. 1977. 99 (7): p. 2039-2044. Zhang, Z., S. Tan, and S.-S.J.B. Feng, Vitamin E TPGS as a molecular biomaterial for drug delivery. 2012. 33 (19): p. 4889-4906. Torchilin, V.P.J.N.r.D.d., Recent advances with liposomes as pharmaceutical carriers. 2005. 4 (2): p. 145-160. Rytting, E., et al., Biodegradable polymeric nanocarriers for pulmonary drug delivery. 2008. 5 (6): p. 629-639. Kedar, U., et al., Advances in polymeric micelles for drug delivery and tumor targeting. 2010. 6 (6): p. 714-729. Additional Declarations No competing interests reported. Supplementary Files GraphicalAbstract.jpg Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 06 Sep, 2025 Reviews received at journal 01 Aug, 2025 Reviews received at journal 30 Jul, 2025 Reviewers agreed at journal 24 Jul, 2025 Reviewers agreed at journal 23 Jul, 2025 Reviewers invited by journal 23 Jul, 2025 Editor assigned by journal 18 Jul, 2025 Submission checks completed at journal 18 Jul, 2025 First submitted to journal 17 Jul, 2025 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-7144838","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":490199148,"identity":"1347e8ea-f306-46a7-80cb-49eed52a1777","order_by":0,"name":"Srushti Shah","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIie3RP0vDQBgG8CsHcXndAye5TyC85SA6SPstnC8IzXIVXYqDSKZO+QCFCH6FlILgdqHgFOtacNE9QyBLR+8yN6lugvdMx/H+eO4PIS4ufzSUEJ8gAaLru/vA7ujPg0S2ZFAsylfREnmYEEvo+nhOo8Ru9RGelaK53Z2Pz47etCFe/HS5/jIto+A02U9wo0K2kH70kl7L4nFzMl1+TNCQKxHqDgIQUpC+RK1QVzNvusykJTp67iA8BdEYMsb3CjV4NB5mcd1LSAnIDBnkW4UFzKnkTPW3YOnNGEz8KN9WaB95mDN1oyV234WndNXAxYM5mBK1+UrOs3hlFqOgi+zpbSfxp+Ntb/KbaRcXF5f/kG/9HWNqECzwTAAAAABJRU5ErkJggg==","orcid":"","institution":"Parul Institute of Pharmaceutical Education and Research, Parul University","correspondingAuthor":true,"prefix":"","firstName":"Srushti","middleName":"","lastName":"Shah","suffix":""},{"id":490199149,"identity":"549cd7da-e8ed-4e4c-ad6d-2b4ebe75cf6f","order_by":1,"name":"Vandana Patel","email":"","orcid":"","institution":"Smt. S. M. Shah Pharmacy College, Gujarat Technological University","correspondingAuthor":false,"prefix":"","firstName":"Vandana","middleName":"","lastName":"Patel","suffix":""}],"badges":[],"createdAt":"2025-07-17 04:38:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7144838/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7144838/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87588101,"identity":"9f9fa8b2-225e-4f89-b3a5-c4ff454b9137","added_by":"auto","created_at":"2025-07-25 14:12:21","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":27967,"visible":true,"origin":"","legend":"\u003cp\u003eCritical micellization concentration of TPGS.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7144838/v1/a1ccc5bee5444228a9b16d7a.jpg"},{"id":87588102,"identity":"1a8bb327-2b2e-43b1-a739-2248d4e97413","added_by":"auto","created_at":"2025-07-25 14:12:21","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":87935,"visible":true,"origin":"","legend":"\u003cp\u003eHydrodynamic diameter of AZP loaded (blue) and neat TPGS (pink). TEM image of TPGS-AZP micelles.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7144838/v1/8d6a283b6e755e3b22c8e89e.jpg"},{"id":87588103,"identity":"09e965cb-70f3-4dbd-942e-cd84f256c5b8","added_by":"auto","created_at":"2025-07-25 14:12:21","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":22436,"visible":true,"origin":"","legend":"\u003cp\u003eEntrapment efficiency of Azelnidipine(AZP) in pure and glucose-mixed TPGS micelles\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7144838/v1/21e9528e04c1dcbcef312e87.jpg"},{"id":87588106,"identity":"6fee4c8d-6c20-4794-aa54-fd5a6517d753","added_by":"auto","created_at":"2025-07-25 14:12:21","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":51886,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eIn vitro\u003c/em\u003e release behavior of AZP from TPGS micelles (TPGS-AZP) and pure water.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7144838/v1/3e54f83ec4e6b38dfee001b8.jpg"},{"id":87588114,"identity":"57c41031-89d0-4809-9fd7-e14458f3bbbe","added_by":"auto","created_at":"2025-07-25 14:12:21","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":55413,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eDilution profile of AZP trapped TPGS micelles.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7144838/v1/e49eed248c8997421759e40c.jpg"},{"id":87589770,"identity":"ae27176c-02e6-4050-89f7-1db020cc523c","added_by":"auto","created_at":"2025-07-25 14:36:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":863929,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7144838/v1/9fbd9d3e-2923-43d3-b67a-ccd544d85809.pdf"},{"id":87588105,"identity":"e730d58e-2722-493e-ad91-550a8c77639c","added_by":"auto","created_at":"2025-07-25 14:12:21","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":80438,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7144838/v1/daee41506e78da44427b54cd.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Solubilization of Azelnidipine in TPGS Micelles: Structural Insights, Micellar Stability, and Sustained Drug Release Behavior","fulltext":[{"header":"Highlights","content":"\u003cul\u003e\n \u003cli\u003eLow CMC (0.002 % w/v) of TPGS displayed monodisperse spherical morphology confirmed via DLS and TEM.\u003c/li\u003e\n \u003cli\u003eHigh drug entrapment efficiency (86 %) was achieved for the poorly soluble drug AZP.\u003c/li\u003e\n \u003cli\u003eFluorescence studies confirmed AZP localization in the micelle core, ensuring protection from aqueous environments.\u003c/li\u003e\n \u003cli\u003eNanocarriers are used to enhance solubility, stability, and systemic delivery.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eNonionic surfactants that have been polyethoxylated (PEO) typically produce higher surface or interfacial tension than ionic surfactants at certain concentrations at which they form aggregates, making the nonionic less irritating, toxic, and less damaging to cell membranes. Nonionic surfactants associate with one another at much lower concentrations to lower the surface free energy since they are typically larger, less polar, and less preferentially adsorbed at the surface [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Cremophor EL, Poloxamer, polysorbates, Pluronics, Brij, and α-tocopherol polyethylene glycol succinate (TPGS) are some of the PEO-based surfactants that have been widely used [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. PEO-based surfactants have a lipophilic portion comprising an alkyl or aryl-alkyl group and oxyethylene as a hydrophilic part.\u003c/p\u003e\u003cp\u003eD-α-Tocopheryl polyethylene glycol succinate (TPGS) is a water-soluble derivative of vitamin E with polyethylene glycol (PEG) chain, making it highly attractive for various applications [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Similar to poloxamers, TPGS can form polymeric micelles and possesses a hydrophilic segment. However, it demonstrates superior inhibition of P-glycoprotein (P-gp) transporters, which are a major barrier to the permeability of numerous anticancer drugs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Among its variants, TPGS-1000 composed of a hydrophilic block with 23 ethylene oxide (EO) units\u0026mdash;has been the most extensively studied [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It undergoes self-aggregation at a critical concentration of 0.02%, leading to the formation of stable, spherical core-shell micelles with an aggregation number of approximately 100, maintaining structural integrity across temperature variations.\u003c/p\u003e\u003cp\u003eAzelnidipine (AZP), a dihydropyridine calcium channel blocker, is BCS Class II drug for the management of hypertension. The limited solubility presents a major challenge for its oral bioavailability. Various approaches were used to solubilize hydrophobic drugs and improve their permeability through TPGS alone or as mixed micelles with other amphiphiles [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Yan et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] enhanced camptothecin solubility and stability using a TPGS-P105 mixed micellar system, which increased its cytotoxicity against MCF-7 cell lines. Solubility of naproxen increased to 350 mg/l in 1% total concentration of TPGS-T1107 mixed micelles from 28 mg/ml in water. The prepared mixed micelles significantly increase drug transmembrane diffusion in a gel form [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].Yang et al. developed solid dispersion with TPGS and Poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA) to improve the dissolution and bioavailability of aprimilast reports 8-folds greater absorption in physical mixture than free drug.\u003c/p\u003e\u003cp\u003eThis study focused on improving the solubility and encapsulation of the hydrophobic drug AZP by incorporating it into micelles formed by TPGS. The micellar formulations were systematically analyzed using DLS, TEM, and fluorescence spectroscopy to examine the drug\u0026rsquo;s spatial distribution within the micelles. The results indicated strong interactions between AZP and the micellar core, with the drug preferentially partitioning into the hydrophobic region. This suggests that TPGS micelles effectively enhance drug solubilization while offering a protective environment that supports stability in aqueous conditions.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Materials\u003c/h2\u003e\u003cp\u003eAzelnidipine (99% pure) and D-α-Tocopheryl polyethylene glycol succinate (TPGS, \u0026ge; 98%, MW 1513 Da) were generously provided by Pure Chem Pvt. Ltd., India. Pyrene was purchased from Sigma-Aldrich, USA. All reagents were of analytical grade. Deuterated water was procured from Tokyo Chemical Industries, Japan. Buffers were prepared according to the Indian Pharmacopoeia.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Determination of Critical Micelle Concentration (CMC) and Cloud Point (CP)\u003c/h2\u003e\u003cp\u003eThe CMC of TPGS was determined at 30\u0026deg;C using both surface tension and pyrene fluorescence techniques. Surface tension measurements were performed using a tensiometer (Kr\u0026uuml;ss, Germany), and the data were plotted against log concentration. For fluorescence, pyrene (5 \u0026times; 10⁻⁷ M) was added to a series of TPGS concentrations (0.0001 to 0.1 mM), incubated in the dark for 24 h, and analyzed with a Shimadzu RF5301PC spectrofluorometer. The I₁/I₃ intensity ratio was plotted to determine the CMC. Cloud point was determined by heating TPGS solutions (1\u0026ndash;5%) and noting the temperature at which turbidity appeared.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Drug Loading and Entrapment Efficiency\u003c/h2\u003e\u003cp\u003eExcess AZP was added to TPGS micelle solutions and stirred at 37\u0026deg;C for 48 h. Unsolubilized drug was removed via 0.22 \u0026micro;m filtration. Drug content in the filtrate was determined spectrophotometrically at 254 nm.\u003c/p\u003e\u003cp\u003eEntrapment efficiency (EE %) was calculated as:\u003c/p\u003e\u003cp\u003e\u003cb\u003eEE % = (Amount of drug solubilized / Initial drug added) \u0026times; 100\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 In \u003cem\u003eVitro\u003c/em\u003e Drug Release\u003c/h2\u003e\u003cp\u003eAZP-loaded micelles were placed in a dialysis bag (MWCO 12\u0026ndash;14 kDa) and immersed in phosphate buffer (pH 6.8) at 37\u0026deg;C. At predetermined intervals, samples were withdrawn and replaced with fresh buffer. Drug concentration was measured spectrophotometrically.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Preparation and Characterization of Micelles\u003c/h2\u003e\u003cp\u003eMicelles were prepared by dissolving the required amount of TPGS in de-ionized water. It was then equilibrated at 25\u0026deg;C for 24 h. Dynamic light scattering (DLS) was used to determine micelle size and polydispersity index (PDI) of undiluted samples (Nano ZS, Malvern Instruments, UK). Acquisitions were carried out with a He\u0026ndash;Ne laser at 130\u0026deg; scattering angle and data were analyzed by normalized intensity distribution using CONTIN method for cumulants,size distribution, and PDI.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e\u003cb\u003e2.6 Solubilization and Localization of AZP into TPGS Micelles\u003c/b\u003e\u003c/h2\u003e\u003cp\u003eExcess AZP was equilibrated with a fixed volume of micelle dispersion under orbital stirring (37\u0026deg;C; 48 h). The samples were filtered (0.20 \u0026micro;m pore size) to remove unsolubilized AZP. The concentration of AZP in filtrate was quantified by UV-vis spectrophotometry (Shimadzu 3092,\u003c/p\u003e\u003cp\u003eJapan). In order to assess the physical stability of AZP-loaded micelles, the formulation was incubated in a shaker maintained at 37\u0026deg;C. At predetermined time intervals, the sample was filtered (0.22 \u0026micro;m) and analyzed to record the amount of AZP precipitated with time.\u003c/p\u003e\u003cp\u003ePhotoluminescence quenching of pyrene (5 \u0026times; 10\u0026thinsp;\u0026minus;\u0026thinsp;7 M) was exploited to locate AZP solubilized into the micelles. Intensity ratio of first-to-third vibronic peaks (I1/I3) in pyrene emission spectrum senses the polarity of medium (19). Micelles, labeled with pyrene, were titrated against increasing concentration of Azelnidipine.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results and discussion","content":"\u003cp\u003eThe critical micelle concentration (CMC) of TPGS was determined using pyrene fluorescence spectroscopy, by evaluating the intensity ratio (I₁/I₃) of its emission peaks. As shown in the plot (Figure 1), the I₁/I₃ ratio exhibited a sharp decrease with increasing TPGS concentration until reaching a plateau, indicating micelle formation. The inflection points in the curve, marked by a significant change in slope, corresponds to the CMC. The CMC value for TPGS was identified to be approximately in the range of 0.002 % w/v (2\u0026times;10⁻\u0026sup3; %), consistent with literature reports on the low CMC of TPGS due to its hydrophobic vitamin E moiety and hydrophilic polyethylene glycol chain [14, 15]. This low CMC is advantageous for drug delivery applications, ensuring micelle stability even under high dilution in systemic circulation. Moreover, the sigmoidal nature of the plot confirms the cooperative nature of micelle formation, characteristic of amphiphilic block copolymers such as TPGS. A notable characteristic of TPGS is its high cloud point, reported at approximately 74 \u0026deg;C [16].The high cloud point of TPGS is advantageous in drug delivery, particularly in maintaining micellar stability under physiological and elevated temperatures encountered during sterilization or formulation processing. This thermal stability ensures sustained solubilization of hydrophobic drugs, preventing premature precipitation and enhancing bioavailability [17].\u003c/p\u003e\n\u003cp\u003eMicelles formed at various concentrations of TPGS (2 %) were systematically characterized using DLS and TEM to evaluate their size distribution and morphology. The hydrodynamic diameter of the micelles ranged from 9.99 nm to 13.51 nm depending on the concentration and the medium (sterile water). All micelle samples exhibited PDI values below 0.3, indicative of a narrow and monodisperse size distribution, which is desirable for consistent in vivo performance [18]. The DLS size distribution \u003cstrong\u003eFig. 1(A)\u003c/strong\u003e shows that unloaded TPGS micelles exhibited a sharp intensity peak with a D\u003csub\u003eh\u003c/sub\u003e around 11 nm, confirming a homogeneous nano micellar population. Upon incorporation of AZP (a hydrophobic compound), the micelle size increased slightly, shifting the peak to approximately 20 nm, consistent with drug encapsulation increasing the hydrodynamic radius. This increase in size and broadening of the distribution curve for TPGS-AZP micelles suggests successful drug loading while maintaining acceptable uniformity [19]. Transmission electron microscopy \u003cstrong\u003eFig. 2(B)\u003c/strong\u003e further confirmed the formation of well-defined micelles. The micelles appeared spherical and were uniformly dispersed without signs of aggregation. \u003c/p\u003e\n\u003cp\u003eThe average diameter observed under TEM was consistent with DLS measurements, confirming the nanoscale size and morphological integrity of the micelles. The high contrast and uniform shape observed in the TEM micrograph support the effective self-assembly of TPGS into core\u0026ndash;shell nanostructures, which is a characteristic of amphiphilic surfactants [15]. The small size, spherical morphology, and low PDI values are particularly advantageous for biomedical applications such as drug delivery. These characteristics enhance systemic circulation stability and promote passive tumor targeting through the enhanced permeability and retention (EPR) effect [20].\u003c/p\u003e\n\u003cp\u003eThe entrapment efficiency (EE) and drug loading (DL) of AZP in TPGS micelles were quantitatively assessed to evaluate the micellar system\u0026rsquo;s drug-carrying capacity. As illustrated in \u003cstrong\u003eFig.3\u003c/strong\u003e, the TPGS-AZP micellar formulation exhibited a high entrapment efficiency of approximately 86 %, while the drug loading was relatively lower, near 9 %. The high EE value is indicative of effective solubilization and encapsulation of the hydrophobic drug within the micellar core. This is consistent with literature demonstrating that TPGS, owing to its amphiphilic structure, forms micelles with a hydrophobic core that efficiently accommodates poorly water-soluble compounds like AZP [21, 22]. Entrapment efficiency was found to be optimal at a TPGS concentration of 3 %. At concentrations beyond this threshold, a decline in EE was observed, likely due to the saturation of the micellar core, limiting additional drug incorporation. This saturation effect is commonly reported in micellar systems, where the solubilization capacity reaches a plateau with increasing surfactant concentration [23]. Moreover, excessive surfactant may contribute to micelle restructuring or aggregation, potentially reducing drug entrapment. To further validate the localization of AZP within the micellar structure, pyrene fluorescence quenching studies were performed. A significant shift in the I₁/I₃ fluorescence intensity ratio confirmed that AZP resided predominantly in the hydrophobic core of the TPGS micelles. The decreased I₁/I₃ ratio reflects a more nonpolar environment, typical of micellar cores, supporting effective incorporation of the drug within the lipophilic domain [24]. These findings underline the suitability of TPGS micelles as efficient nanocarriers for hydrophobic drugs like AZP, balancing high entrapment with favorable localization in the core, which is essential for stability and controlled release profiles.\u003c/p\u003e\n\u003cp\u003eThe in \u003cem\u003evitro \u003c/em\u003erelease behavior of AZP from TPGS micelles (TPGS-AZP) was evaluated over 24 hours to assess the formulation\u0026apos;s ability to provide sustained drug delivery. As shown in \u003cstrong\u003eFig.4\u003c/strong\u003e, the free AZP exhibited a rapid release, with over 90 % of the drug released within 6 hours, reaching a plateau shortly thereafter. In contrast, the TPGS-AZP micellar system demonstrated a significantly slower and sustained release profile, with less than 20 % cumulative release over the same period. This marked difference in release kinetics highlights the role of micellar encapsulation in modulating drug release. The sustained release from the TPGS micelles can be attributed to the drug being embedded within the hydrophobic core of the micellar structure, which acts as a barrier to immediate diffusion into the aqueous medium. This encapsulation not only enhances drug solubility but also protects the active compound from rapid dissolution and degradation, leading to a controlled and extended release [25]. The release profile of TPGS-AZP follows a diffusion-controlled mechanism, as is typical for micellar and nanoparticulate systems where drug molecules gradually migrate from the hydrophobic core into the surrounding medium [26]. Such controlled release behavior is advantageous for poorly water-soluble drugs like Azelnidipine, as it may improve therapeutic efficacy, reduce dosing frequency, and minimize peak-related side effects [27]. Furthermore, the slower release rate observed with TPGS-AZP indicates the stability of the micellar structure under physiological conditions, reinforcing its potential as a nanocarrier for sustained drug delivery applications. The findings align with previous reports where TPGS-based micelles were shown to prolong the release and circulation time of encapsulated therapeutics due to their steric stabilization and hydrophobic interactions [14].\u003c/p\u003e\n\u003cp\u003eThe colloidal stability of TPGS micelles under dilution was assessed using dynamic light scattering (DLS), as illustrated in \u003cstrong\u003eFig. 5\u003c/strong\u003e. The aqueous dispersion of micelles was serially diluted from the original concentration up to 1000-fold, and their hydrodynamic size distributions were recorded to evaluate the retention of micellar structure. DLS data show that at lower dilutions (e.g., up to 30-fold), TPGS micelles retained a relatively narrow and unimodal distribution, with hydrodynamic diameters consistent with intact micelles. However, at higher dilution levels (100-fold and above), the emergence of additional peaks and the broadening of the size distribution became apparent, indicating partial disassembly of micelles and formation of smaller aggregates or free unimers. These results suggest that TPGS micelles exhibit limited colloidal stability under extensive dilution, likely due to their reliance on non-covalent interactions for micelle formation. When the concentration falls below the CMC, micellar integrity is compromised, leading to dissociation. This behaviour is consistent with previous findings that non-crosslinked surfactant micelles tend to disassemble at low concentrations due to the dynamic equilibrium between monomers and micellar aggregates [28]. The dilution-induced instability of TPGS micelles underscores the importance of maintaining an appropriate concentration during formulation and delivery to ensure structural integrity and effective drug encapsulation.\u003c/p\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eThis study systematically investigated the solubilization and delivery of the poorly water-soluble drug AZP using TPGS micelles, demonstrating their effectiveness as a nanocarrier system. The research revealed that TPGS forms stable micelles at an exceptionally CMC of 0.002 % w/v, attributed to its amphiphilic structure combining a hydrophobic vitamin E core and hydrophilic PEG shell. Comprehensive characterization using DLS and TEM confirmed the formation of monodisperse, spherical micelles with a narrow size distribution (9.99-13.51 nm), ideal for systemic circulation and passive targeting. The micellar system exhibited remarkable drug-loading capabilities, achieving 86 % entrapment efficiency for AZP, with optimal performance at 3 % TPGS concentration. Fluorescence quenching studies using pyrene confirmed the preferential localization of AZP within the hydrophobic core, ensuring protection from aqueous degradation. Importantly, in \u003cem\u003evitro\u003c/em\u003e release studies demonstrated sustained drug release kinetics, with less than 20 % of AZP released within 6 hours compared to 90 % for free drug, highlighting the system\u0026apos;s ability to modulate drug release. These findings collectively establish TPGS micelles as a promising platform for enhancing the solubility, stability, and bioavailability of hydrophobic drugs like AZP, while offering controlled release properties that could improve therapeutic outcomes and reduce dosing frequency. The study provides valuable insights for developing TPGS-based nanocarriers for poorly soluble pharmaceuticals.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCredit authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSrushti Shah:\u0026nbsp;\u003c/strong\u003eInvestigation, Formal analysis, Writing – original draft. Formal analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVandana Patel\u003c/strong\u003e: Conceptualization, Writing – review \u0026amp; editing, Project administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author had not received any funding for carrying this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThanks Central Instrumentation Facility of Parul University for Dynamic light scattering and spectroscopy experiments.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e The data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declaration:\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAzum, N., et al., \u003cem\u003eMicellar and interfacial properties of amphiphilic drug\u0026ndash;non-ionic \u003c/em\u003e\u003cem\u003esurfactants mixed systems: Surface tension, fluorescence and UV\u0026ndash;vis studies.\u003c/em\u003e Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2017. \u003cstrong\u003e522\u003c/strong\u003e: p. 183-192.\u003c/li\u003e\n\u003cli\u003eLuz, A.M., et al., \u003cem\u003eTween-80 on water/oil interface: structure and interfacial tension by molecular dynamics simulations.\u003c/em\u003e Langmuir, 2023. \u003cstrong\u003e39\u003c/strong\u003e(9): p. 3255-3265.\u003c/li\u003e\n\u003cli\u003eAleid, G.M., et al., \u003cem\u003ePolymeric surfactants: recent advancement in their synthesis, properties, and industrial applications.\u003c/em\u003e Macromolecular Chemistry and Physics, 2023. \u003cstrong\u003e224\u003c/strong\u003e(17): p. 2300107.\u003c/li\u003e\n\u003cli\u003eLi, S., et al., \u003cem\u003eWhat is the role of PEO chains in the assembly of core-corona supraparticles in aqueous dispersions?\u003c/em\u003e Journal of Colloid and Interface Science, 2023. \u003cstrong\u003e646\u003c/strong\u003e: p. 461-471.\u003c/li\u003e\n\u003cli\u003ePuig-Rigall, J., et al., \u003cem\u003eMorphology, gelation and cytotoxicity evaluation of D-\u0026alpha;-Tocopheryl polyethylene glycol succinate (TPGS)\u0026ndash;Tetronic mixed micelles.\u003c/em\u003e Journal of colloid and interface science, 2021. \u003cstrong\u003e582\u003c/strong\u003e: p. 353-363.\u003c/li\u003e\n\u003cli\u003eRathod, S., et al., \u003cem\u003eNon-ionic surfactants as a P-glycoprotein (P-gp) efflux inhibitor for optimal drug delivery\u0026mdash;a concise outlook.\u003c/em\u003e Aaps Pharmscitech, 2022. \u003cstrong\u003e23\u003c/strong\u003e(1): p. 55.\u003c/li\u003e\n\u003cli\u003eCerqueira, R., et al., \u003cem\u003eDevelopment and Characterization of Curcumin-Loaded TPGS/F127/P123 Polymeric Micelles as a Potential Therapy for Colorectal Cancer.\u003c/em\u003e International Journal of Molecular Sciences, 2024. \u003cstrong\u003e25\u003c/strong\u003e(14): p. 7577.\u003c/li\u003e\n\u003cli\u003eMehata, A.K., et al., \u003cem\u003eVitamin E TPGS-based nanomedicine, nanotheranostics, and targeted drug delivery: past, present, and future.\u003c/em\u003e Pharmaceutics, 2023. \u003cstrong\u003e15\u003c/strong\u003e(3): p. 722.\u003c/li\u003e\n\u003cli\u003eBernabeu, E., et al., \u003cem\u003eNovel Soluplus\u0026reg;\u0026mdash;TPGS mixed micelles for encapsulation of paclitaxel with enhanced in \u003c/em\u003evitro \u003cem\u003ecytotoxicity on breast and ovarian cancer cell lines.\u003c/em\u003e Colloids and Surfaces B: Biointerfaces, 2016. \u003cstrong\u003e140\u003c/strong\u003e: p. 403-411.\u003c/li\u003e\n\u003cli\u003eGrimaudo, M.A., et al., \u003cem\u003ePoloxamer 407/TPGS mixed micelles as promising carriers for cyclosporine ocular delivery.\u003c/em\u003e Molecular pharmaceutics, 2018. \u003cstrong\u003e15\u003c/strong\u003e(2): p. 571-584.\u003c/li\u003e\n\u003cli\u003eMi, Y., J. 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Feng, \u003cem\u003eVitamin E TPGS as a molecular biomaterial for drug delivery.\u003c/em\u003e 2012. \u003cstrong\u003e33\u003c/strong\u003e(19): p. 4889-4906.\u003c/li\u003e\n\u003cli\u003eTorchilin, V.P.J.N.r.D.d., \u003cem\u003eRecent advances with liposomes as pharmaceutical carriers.\u003c/em\u003e 2005. \u003cstrong\u003e4\u003c/strong\u003e(2): p. 145-160.\u003c/li\u003e\n\u003cli\u003eRytting, E., et al., \u003cem\u003eBiodegradable polymeric nanocarriers for pulmonary drug delivery.\u003c/em\u003e 2008. \u003cstrong\u003e5\u003c/strong\u003e(6): p. 629-639.\u003c/li\u003e\n\u003cli\u003eKedar, U., et al., \u003cem\u003eAdvances in polymeric micelles for drug delivery and tumor targeting.\u003c/em\u003e 2010. \u003cstrong\u003e6\u003c/strong\u003e(6): p. 714-729.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"biomedical-materials-and-devices","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Biomedical Materials \u0026 Devices](https://link.springer.com/journal/44174)","snPcode":"44174","submissionUrl":"https://submission.springernature.com/new-submission/44174/3","title":"Biomedical Materials \u0026 Devices","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Azelnidipine, TPGS Micelles, Critical Micelle Concentration, Drug Delivery, Solubility Enhancement, Controlled release, Entrapment Efficiency","lastPublishedDoi":"10.21203/rs.3.rs-7144838/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7144838/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePolyethoxylated (PEO)-based nonionic surfactants, such as D-α-Tocopheryl polyethylene glycol succinate (TPGS), offer significant advantages in drug delivery due to their low toxicity, mild interaction with biological membranes, and ability to form stable micellar systems. This study investigates the solubilization and delivery of the poorly water-soluble drug AZP using TPGS micelles. TPGS exhibited a low critical micelle concentration (0.002% w/v), forming stable, spherical, and monodisperse micelles (9.99–13.51 nm) with high drug-loading efficiency (86%). Fluorescence quenching studies confirmed the encapsulation of AZP in the hydrophobic micellar core, protecting it from aqueous degradation. In vitro release profiles showed sustained drug release from TPGS micelles, with less than 20% drug release in 6 hours compared to 90% from free AZP. Dilution studies showed micelle stability up to 30-fold dilution, with disassembly observed at higher dilutions. These findings underscore the potential of TPGS micelles as effective nanocarriers to improve the solubility, stability, and bioavailability of hydrophobic drugs, while enabling controlled release for better therapeutic performance.\u003c/p\u003e","manuscriptTitle":"Solubilization of Azelnidipine in TPGS Micelles: Structural Insights, Micellar Stability, and Sustained Drug Release Behavior","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-25 14:12:16","doi":"10.21203/rs.3.rs-7144838/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-06T11:25:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-01T13:34:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-30T04:43:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286106588029546461552776259359332290722","date":"2025-07-25T02:41:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"74118993502046564827962248978153378595","date":"2025-07-23T17:43:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-23T13:05:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-18T14:36:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-18T14:33:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Biomedical Materials \u0026 Devices","date":"2025-07-17T04:35:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"biomedical-materials-and-devices","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Biomedical Materials \u0026 Devices](https://link.springer.com/journal/44174)","snPcode":"44174","submissionUrl":"https://submission.springernature.com/new-submission/44174/3","title":"Biomedical Materials \u0026 Devices","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"adb9424f-f12c-4636-bd1e-57ee11b0e1fe","owner":[],"postedDate":"July 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-16T18:53:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-25 14:12:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7144838","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7144838","identity":"rs-7144838","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}