Development of hesperidin solid dispersion for improved solubility and dissolution using mannitol and PVP K30 as carriers
DOI:
https://doi.org/10.69857/joapr.v12i6.723Keywords:
Hesperidin, Solid dispersion, Solubility enhancement, Dissolution rate, Kneading method, Solvent evaporation methodAbstract
Background: Despite its six-hour half-life, Hesperidin, a bioflavonoid with therapeutic benefits, has low water solubility and bioavailability. This limits treatment. This study improved hesperidin solubility and dissolution by making solid dispersions using appropriate carriers. Methodology: Solid dispersions of hesperidin were prepared using two methods: kneading and solvent evaporation. The carriers utilized in the study were polyvinylpyrrolidone K30 (PVP K30) and mannitol. The formulations were evaluated based on various parameters, including yield, solubility, dissolution rate, drug content, and structural analysis using techniques such as X-ray diffraction (XRD), differential scanning calorimetry (DSC), and infrared (IR) spectroscopy. Results: Solid dispersions yielded 81.2% to 97.5% by weight and included 93.7% to 98.4% drug content. Hesperidin's solubility increased 3.72- to 24.05-fold, with a maximum drug release of 64.06% within 30 minutes. Comparatively, formulations with mannitol as the carrier demonstrated higher solubility (24.05 times) and dissolution (54.06%) than those containing PVP K30 (20.16 times and 34.36%). Discussion: Different carriers alter hesperidin solubility and dissolution. Mannitol improved drug release more than PVP K30. XRD and DSC experiments showed hesperidin's crystalline character changed in solid dispersions, possibly explaining its improved dissolving. IR spectroscopy showed physical dispersion because medication and carriers did not interact chemically. Conclusion: The study showed that solid dispersing hesperidin improves its solubility and dissolution. Drug release was greater with mannitol than with PVP K30. Solid dispersion formulations may improve the bioavailability of poorly soluble medicines like hesperidin.
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Khan MK and Zill-E-Huma DO. A comprehensive review on flavonones, the major citrus polyphenols. J. Food Comp. Anal., 33, 85-104 (2014) https://doi.org/10.1016/j.jfca.2013.11.004.
Homayouni F, Haidari F, Hedayati M, Zakerkish M, Ahmadi K. Blood pressure lowering and anti-inflammatory effects of hesperidin in type 2 diabetes; a randomized double-blind controlled clinical trial. Phytother. Res., 32, 1073-1079 (2018) https://doi.org/10.1002/ptr.6046.
Aalikhani M, Safdari Y, Jahanshahi M, Alikhani M, Khalili M. Comparison between hesperidin, coumarin, and deferoxamine iron chelation and antioxidant activity against excessive iron in the iron overloaded mice. Front. Neurosci., 15, 811080, (2021) https://doi.org/10.3389/fnins.2021.811080.
Dias MC, Pinto DCG, Silva AMS. Plant flavonoids: Chemical characteristics and biological activity. Molecules, 26, 5377, (2021) https://doi.org/10.3390/molecules26175377.
Xiao S, Liu W, Bi J, Lu S, Zhao H, Gong N, Xing D, Gao H, Gong M. Anti-inflammatory effect of hesperidin enhances chondrogenesis of human mesenchymal stem cells for cartilage tissue repair. J. Inflamm., 15, 14 (2018) https://doi.org/10.1186/s12950-018-0190-y.
Famureva AC, Renu K, Eladl MA, Chakraborty R, Myakala H, El-Sherbiny M, Elsherbiny DMA, Vellingiri B, Madhyastha H, Wanjari UR, Mukherjee AG, Gopalkrishnan AB. Hesperidin and hesperetin against heavy metal toxicity: Insight on the molecular mechanism of mitigation. Biomed Pharmaco., 149, 112914 (2022) https://doi.org/10.1016/j.biopha.2022.112914.
Pyrzynska K. Hesperidin: A Review on Extraction Methods, Stability and Biological Activities. Nutrients., 14, 2387 (2022) https://doi.org/10.3390/nu14122387.
Xiong H, Wang J, Ran Q, Lou G, Peng C, Gan Q, Hu J, Sun J, Yao R, Huang Q. Hesperidin: A therapeutic agent for obesity. Drug Des. Devel. Ther., 13, 3855-3866 (2019) https://doi.org/10.2147/DDDT.S227499.
Ávila-Gálvez MA, Giménez-Bastida JA, González-Sarrías A, Espín JC. New insights into the metabolism of the flavanones eriocitrin and hesperidin: A comparative human pharmacokinetic study. Antioxidants., 10, 435, (2021) https://doi.org/10.3390/antiox10030435.
Wan W, Xia N, Zhu S, Liu Q, Gao Y. A novel and high-effective biosynthesis pathway of hesperetin-7-O-glucoside based on the construction of immobilized rhamnosidase reaction platform. Front. Bioeng. Biotechnol., 8, 608, (2020) https://doi.org/10.3389/fbioe.2020.00608.
Kuntic V, Boboric J, Holchajtner-Anatunovic I, Uskokovic-Markovic S. Evaluating the bioactive effects of flavonoid hesperidin-A new literature data survey. Vojn. Pregl., 7, 60-65 (2014) https://doi.org/10.2298/vsp1401060k.
Li YM, Li XM, Li GM, Du WC, Zhang J, Li WX, Xu J, Hu M, Zhu Z. In vivo pharmacokinetics of hesperidin are affected by treatment with glucosidase-like BglA protein isolated from yeast. J. Agric. Food Chem., 56, 5550-5557 (2008) https://doi.org/10.1021/jf800105c.
Cao R, Zhao Y, Zhou Z, Zhao X. Enhancement of the water solubility and antioxidant activity of hesperidin by chitooligosaccharide. J. Sci. Food Agric., 98, 2422-2427 (2018) https://doi.org/10.1002/jsfa.8734.
Lucas-Abellán C, Pérez-Abril M, Castillo J, Serrano A, Mercader MT, Fortea MI, Gabaldón JA, Núñez-Delicado E. Effect of temperature, pH, β- and HP-β-cds on the solubility and stability of flavanones: Naringenin and hesperetin. LWT, 108, 233-239 (2019) https://doi.org/10.1016/j.lwt.2019.03.059.
Corciova A, Ciobanu C, Poiata A, Mircea C, Nicolescu A, Drobota M, Varganici CD, Pinteala T, Marangoci N. Antibacterial and antioxidant properties of hesperidin:β-cyclodextrin complexes obtained by different techniques. J. Incl. Phenom. Macrocycl. Chem., 81, 71-84 (2015) https://doi.org/10.1007/s10847-014-0434-2.
Kapoor, Mahendra P. Structural investigation of hesperetin-7-O-glucoside inclusion complex with β-cyclodextrin: a spectroscopic assessment. Molecules, 27, 5395 (2022) https://doi.org/10.3390/molecules27175395.
Majumdar S, Srirangam R. Solubility, Stability, Physicochemical Characteristics and In Vitro Ocular Tissue Permeability of Hesperidin: A Natural Bioflavonoid. Pharm. Res., 26, 1217-1225 (2009) https://doi.org/10.1007/s11095-008-9729-6.
Saad S, Ahmad I, Kawish SM, Khan UA, Ahmad FJ, Ali A, Jain GK. Improved cardioprotective effects of hesperidin solid lipid nanoparticles prepared by supercritical antisolvent technology. Colloids Surf. B Biointerfaces, 187, 110628 (2020) https://doi.org/10.1016/j.colsurfb.2019.110628.
Ali SH, Sulaiman GM, Al-Halbosiy MMF, Jabir MS, Hameed AH. Fabrication of hesperidin nanoparticles loaded by poly lactic co-Glycolic acid for improved therapeutic efficiency and cytotoxicity. Artif. Cells Nanomed. Biotechnol., 47, 378-394 (2019) https://doi.org/10.1080/21691401.2018.1559175.
Ersoz M, Erdemir A, Duranoglu D, Uzunoglu D, Arasoglu T, Derman S, Mansuroglu B. Comparative evaluation of hesperetin loaded nanoparticles for anticancer activity against C6 glioma cancer cells. Artif. Cells Nanomed. Biotechnol., 47, 319-329 (2019) https://doi.org/10.1080/21691401.2018.1556213.
Gurushankar K, Gohulkumar M, Prasad NR, Krishnakumar N. Synthesis, characterization and in vitro anti-cancer evaluation of hesperetin-loaded nanoparticles in human oral carcinoma (KB) cells. Adv. Nat. Sci. Nanosci. Nanotechnol., 5, 015006 (2013) https://doi.org/10.1088/2043-6262/5/1/015006.
Wei Q, Keck CM, Müller RH. Oral hesperidin-Amorphization and improved dissolution properties by controlled loading onto porous silica. Int. J. Pharm., 518, 253-263 (2017) https://doi.org/10.1016/j.ijpharm.2016.11.005.
Stahr PL, Grewal R, Eckert GP, Keck CM. Investigating hesperetin nanocrystals with tailor-made sizes for the prevention and treatment of Alzheimer’s disease. Drug Deliv. Transl. Res., 11, 659-674 (2021) https://doi.org/10.1007/s13346-020-00888-0.
Wei Q, Keck CM, Müller RH. Solidification of hesperidin nanosuspension by spray drying optimized by design of experiment (DoE). Drug Dev. Ind. Pharm., 44, 1-12 (2018) https://doi.org/10.1080/03639045.2017.1285309.
Alherz, F. A., El-Masry, T. A., Oriquat, G. A., Elekhnawy, E., Al-Shaalan, N. H., Gaballa, M. M. S., El Zahaby, E. I., & El-Nagar, M. M. F. Hesperidin Nanoformulation: A Potential Strategy for Reducing Doxorubicin-Induced Renal Damage via the Sirt-1/HIF1-α/VEGF/NF-κB Signaling Cascade. Pharmaceuticals, 17, 1144 (2024). https://doi.org/10.3390/ph17091144.
Chadha K, Karan M, Chadha R, Bhalla Y, Vasisht K. Is failure of cocrystallization actually a failure? Eutectic formation in cocrystal screening of hesperetin. J. Pharm. Sci., 106, (2017) https://doi.org/10.1016/j.xphs.2017.04.038.
Fanda AK, Jadhav A, Naruka PS, Rana D, Benival D. Apremilast amorphous solid dispersions: Formulation optimization using QbD and comprehensive in vitro in silico assessment. Drug Delivery Lett., (2024) https://doi.org/10.2174/0122103031309026240905115815.
Chen T, Li Q, Ai G, Huang Z, Liu J, Zeng L, Su Z, Dou Y. Enhancing hepatoprotective action: oxyberberine amorphous solid dispersion system targeting TLR4. Scientific Reports., 14, 14924 (2024) https://doi.org/10.1038/s41598-024-65190-2.
Kim T-K, Fina F, Rossignolo F, Kim S-H, Lee H, Jeong K, Xu X, Pignaffo C, Yang C, Koo J, Lee M, Baek M-J, Kim D, Kim D-D. Evaluation of spray dried amorphous solid dispersion formulation of ID11916, a new molecular entity with dual inhibition mechanisms targeting the androgen receptor and phosphodiesterase type-5. J. Pharm. Inves., 54, 317-327 (2024) https://doi.org/10.1007/s40005-023-00652-9
Budhwar V, Kaushik D. An Overview on Recent Patents and Technologies on Solid Dispersion. Recent Pat. Drug Deliv. Formul., 14, 63-74 (2020) https://doi.org/10.2174/1872211314666200117094406.
Cid AG, Simonazzi A, Palma SD, Bermúdez JM. Solid dispersion technology as a strategy to improve the bioavailability of poorly soluble drugs. Ther. Deliv., 10, 363-382 (2019) https://doi.org/10.4155/tde-2019-0007.
Mishra DK, Dhote V, Bhargava A, Jain DK, Mishra PK. Amorphous solid dispersion technique for improved drug delivery: Basics to clinical applications. Drug Deliv. Transl. Re., 5, 3380 (2015) https://doi.org/10.3390/polym15163380.
Srilatha D, Nasare M, Nagasandhya B, Prasad V, Diwan P. Method for Simultaneous Estimation of Hesperidin and Diosmin in the Pharmaceutical Dosage Form. ISRN Spectroscopy., 534830, (2013) http://dx.doi.org/10.1155/2013/534830.
Bennani, Ismail, Madiha Alami Chentoufi, Ibrahim Sbai El Otmani, Amine Cheikh, Nouriddin Bamou, Miloud El Karbane, and Mustapha Bouatia. Development and validation of two spectrophotometric methods for simultaneous determination of diosmine and hesperidin in mixture and their applications. Journal of Applied Pharmaceutical Science, 10, 100-107 (2020). http://dx.doi.org/10.7324/JAPS.2020.10713.
Adeli E, Mortazavi SA. Design, formulation and evaluation of Azithromycin binary solid dispersions using Kolliphor series for the solubility and in vitro dissolution rate enhancement. J. Pharmaceu Inves., 44, 119-131 (2013) http://dx.doi.org/10.1007/s40005-013-0108-x.
Shukla S, Upadhyay S, Gupta RK. Formulation and evaluation of griseofulvin solid dispersion incorporated gel for topical application. Res. J. Pharm. Tech., 15, 4389-94 (2022) http://dx.doi.org/10.52711/0974-360X.2022.00736.
Vora, Chintan, Riddhish Patadia, Karan Mittal, and Rajashree Mashru. Formulation development, process optimization, and in vitro characterization of spray-dried lansoprazole enteric microparticles. Scientia Pharmaceutica, 84, 393-408 (2015) https://doi.org/10.3797/scipharm.1501-08.
Tarawneh, Ola A., Atif M. Madi, Rania Hamed, Rania Qirem, Walid Qerem, Ala Alhusban, Suhair Sunoqrot, Nouf Mahmoud, Samah Ata, and Iyad Alsheikh. In vitro characterization and evaluation of commercialized paracetamol products in Jordan. Dissolut. Technol, 26, (2019) https://doi.org/10.14227/DT260119P36.
Sharma, A, Jain CP, Tanwar YS. Preparation and characterization of solid dispersions of carvedilol with poloxamer 188. Journal of the Chilean Chemical Society, 58, 1553-1557 (2013) http://dx.doi.org/10.4067/S0717-97072013000100012.
Tran P, Pyo Y-C, Kim D-H, Lee S-E, Kim J-K, Park J-S. Overview of the Manufacturing Methods of Solid Dispersion Technology for Improving the Solubility of Poorly Water-Soluble Drugs and Application to Anticancer Drugs. Pharmaceutics., 11, 132 (2019) http://dx.doi.org/10.3390/pharmaceutics11030132.
Alshehri S, Imam SS, Altamimi MA, Hussain A, Shakeel F, Elzayat E, Mohsin K, Ibrahim M, Alanazi F. Enhanced Dissolution of Luteolin by Solid Dispersion Prepared by Different Methods: Physicochemical Characterization and Antioxidant Activity. ACS Omega., 5, 6461-6471 (2020) https://doi.org/10.1021/acsomega.9b04075.
Bhatia M, Devi S. Development, Characterisation and Evaluation of PVP K-30/PEG Solid Dispersion Containing Ketoprofen. Acta Pharmaceu Scie., 58, 83-99 (2020) http://dx.doi.org/10.23893/1307-2080.APS.05806.
Swarup P, Agrawal GP. Formulating Amorphous Azithromycin Solid Dispersion using Mannitol and Povidone K30 for Improving Aqueous Solubility and Dissolution Rate (in vitro). Afri J. Bio Sci., 6, 1761-1775 (2024) https://doi.org/10.33472/AFJBS.6.6.2024.1761-1775.
Yadav PS, Kumar V, Singh UP, Bhat HR, Mazumder B. Physicochemical characterization and in vitro dissolution studies of solid dispersions of ketoprofen with PVP K30 and D-mannitol. Saudi Pharmaceu J., 21, 77-84 (2023) http://dx.doi.org/10.1016/j.jsps.2011.12.007.
Rosiak N, Wdowiak K, Tykarska E, Cielecka-Piontek J, Amorphous Solid Dispersion of Hesperidin with Polymer Excipients for Enhanced Apparent Solubility as a More Effective Approach to the Treatment of Civilization Diseases. Inter J Mol Sci., 23, 15198 (2022) https://doi.org/10.3390/ijms232315198.
Hancock BC, Zografi G. The relationship between glass transition temperature and the water content of amorphous pharmaceutical solids. Pharmaceu Res., 11, 471-47 (1994) https://doi.org/10.1023/A:1018941810744.
Joshi S, Dhingra AK, Chopra B, Dass R, Guarve K, Sapra S. Formulation and Evaluation of Solid Dispersions of Poorly Water-Soluble Drug- Hesperidin. Letter App NanoBioSci., 12, 50 (2023) https://doi.org/10.33263/LIANBS122.050.
Agrawal GP, Maheshwari RK, Mishra P. Solubility enhancement of cefixime trihydrate by solid dispersions using hydrotropic solubilization technique and their characterization. Brazilian J Pharmaceu Sci., 58, (2022) https://doi.org/10.1590/s2175-97902020000118553.
Zajc N, Obreza A, Bele M, Srčič S. Physical Properties and Dissolution Behaviour of Nifedipine/Mannitol Solid Dispersions Prepared by Hot Melt Method. Inter J Pharma., 291, 51-58 (2005) https://doi.org/10.1016/j.ijpharm.2004.07.042.
Madgulkar A, Bandivadekar M, Shid T, Rao S. Sugars as Solid Dispersion Carrier to Improve Solubility and Dissolution of the BCS Class II Drug: Clotrimazole. Drug Develop Indus Pharm., 42, 28-38 (2016) https://doi.org/10.3109/03639045.2015.1024683.
Poka MS, Milne M, Wessels A, Aucamp M. Sugars and Polyols of Natural Origin as Carriers for Solubility and Dissolution Enhancement. Pharmaceutics., 15, 2557 (2023) https://doi.org/10.3390/pharmaceutics15112557.
Schittny A, Huwyler J, Puchkov M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Delivery., 27, 110-127 (2020) https://doi.org/10.1080/10717544.2019.1704940.
Rahman, Z., Zidan, A.S. and Khan, M.A. Risperidone solid dispersion for orally disintegrating tablet: Its formulation design and non-destructive methods of evaluation. International Journal of Pharmaceutics, 400, 49-58 (2010) https://doi.org/10.1016/j.ijpharm.2010.08.025.
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