Cover Image

Increase of solubility and transmembrane permeability of niclosamide from its mechanochemically synthesized solid dispersions

Elizaveta S. Meteleva, Elizaveta A. Roenko, Nikolay E. Polyakov


More than 4.5 billion people worldwide are affected by parasitic diseases, with helminth infections accounting for 99% of the total number. Niclosamide (NS) is a weakly acidic active pharmaceutical ingredient (API) used to treat helminth infections. However, the pharmaceutical use of pure niclosamide is limited by its low bioavailability due to its poor aqueous solubility. The aim of this work is a mechanochemical preparation of niclosamide solid dispersions with increased solubility. Due to the pH dependence of NS water solubility and possible complexes formation, NS solid dispersions (SD) with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and alkalizing agents, such as calcium carbonate (CaCO3) and N-methyl-D-glucamine (MG) are mechanochemically prepared in this study. The physical properties of NS SD in solid state are characterized by differential scanning calorimetry, X-ray diffraction, FT-IR spectroscopy, and scanning electron microscopy studies. The characteristics of the water solutions formed from the obtained SDs are analyzed by HPLC. It is shown that the solubility increases for all studied compositions. These phenomena are obliged by complexation with HP-β-CD, which was shown by 1H-NMR methods, and enhanced ionization in the cases of using calcium carbonate and MG. Results of the parallel artificial membrane permeability assay (PAMPA) have shown that mechanochemically obtained NS/MG SD (1/1 mass ratio, 8 h milling) significantly enhances permeation of NS across an artificial membrane. Thus, the obtained compositions are a promising basis for the development of NS-based preparations for oral administration, with reduced dose and high pharmacological effect.


niclosamide; solubility enhancement; solid dispersions; mechanochemical synthesis; hydroxypropyl-β-cyclodextrin; calcium carbonate; N-methyl-D-glucamine

Full Text:



Krivopustov SP, Shcherbinskaya EN, Loginova IA, Chernij EF, Pavlik EV, Gerasimenko AV. Helminthiasis in clinical pediatrics: issues of diagnosis, therapy, and prevention. Child Health. 2011;4(31):71–75.

Loukas A, Hotez PJ. Chemotherapy of helminth infections. Goodman and Gilman’s the pharmacological basis of therapeutics, 11th ed. New York: McGraw-Hill. 2006: P. 1073–1093.

Arkhipov IA, Sadov KM, Limova YV, Sadova AK, Varlamova AI, Khalikov SS, Dushkin AV, Chistyachenko YS. The efficacy of the supramolecular complexes of niclosamide obtained by mechanochemical technology and targeted delivery against cestode infection of animals. Vet Parasitol. 2017;246:25–9. doi:10.1016/j.canlet.2014.04.003

Varlamova AI, Arhipov IA, Dushkin AV, Chistyachenko YUS., Limova YV, Sadov KM, Khalikov SS. Activity of supramolecular complex of anrhelmintics against Hymenolepisnana. Theory Practice Parasitic Disease Cont. 2017;(18):87–89.

Limova YV, Sadov KM, Kanatbaev SG, Arkhipov I.A. Anthelmintic efficacy of Phenasalum based on supramolecular drug delivery systems (DDS) at monieziasis in cattle. Russ J Parasitol. 2016;36:223–227. doi:10.12737/20066

Limova YV, Sadov KM, Korogodina EV, Arkhipov IA, Khalikov SS. Anthelmintic efficiency of new Phenasal formulations based on supramolecular, nanoscale drug delivery systems for anoplocephalidosis in horses. Rus J Parasitol. 2017;40:188–191.

Li Y, Li PK, Roberts MJ, Arend RC, SamantRS,Buchsbaum DJ. Multi-targeted therapy of cancer by niclosamide: A new application for an old drug. Cancer Lett. 2014;349(1):8–14. doi:10.1016/j.canlet.2014.04.003

Chen W, MookJr RA, Premont RT, Wang J. Niclosamide: Beyond an antihelminthic drug. Cell Signal. 2018;41:89–96. doi:10.1016/j.cellsig.2017.04.001

Xu J, Shi PY, Li H, Zhou J. Broad spectrum antiviral agent niclosamide and its therapeutic potential. ACS infectious diseases. 2020;6(5):909–915. doi:10.1021/acsinfecdis.0c00052

Campbell WC,Rew RS. Chemotherapy of parasitic diseases. Berlin: Springer Science & Business Media. 2013:654. doi:10.1007/978-1-4684-1233-8

Schweizer MT, Haugk K, McKiernan JS, Gulati R, Cheng HH, Maes JL, Dumpit RF, Nelson PS, Montgomery B, McCune JS, Plymate SR. A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer. PloS one. 2018;13(6):0198389. doi:10.1371/journal.pone.0198389

PubChem. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information;PubChem Compound Summary for CID 4477, Niclosamide [Internet]. 2004 [cited 2023]. English. Available from:, Accessed on 27 June 2023.

Al-Hadiya BMH. Niclosamide: comprehensive profile. Profiles of Drug Subst, Excip and Relat Methodol. 2005;32:67–96. doi:10.1016/S0099-5428(05)32002-8

Ye Y, Zhang X, Zhang T, Wang H, Wu B. Design and evaluation of injectable niclosamide nanocrystals prepared by wet media milling technique. Drug Development and Industrial Pharm. 2015;41(9):1416–1424. doi:10.3109/03639045.2014.954585

Zhirnik AS, Semochkina YP, Moskaleva EY, Krylov NI, Tubasheva IA, Kuznetsov SL, Vorontsov EA. Molecular mechanisms of antitumor activity of the polymeric form of niclosamide with respect to human colorectal cancer cells. Biochem (Moscow), SupplSer B: Biomed Chem. 2017;11:301–307. doi:10.1134/S1990750817030131

Grifasi F, Chierotti MR, Gaglioti K, Gobetto R, Maini L, Braga D, Dichiarante E, Curzi M. Using salt cocrystals to improve the solubility of niclosamide. Cryst Growth & Des. 2015;15(4):1939–1948. doi:10.1021/acs.cgd.5b00106

Xie Y, Yao Y. Octenylsuccinate hydroxypropyl phytoglycogen enhances the solubility and in-vitro antitumor efficacy of niclosamide. Int J Pharm. 2018;535(1–2):157–163. doi:10.1016/j.ijpharm.2017.11.004

Rehman MU, Khan MA, Khan WS, Shafique M, Khan M. Fabrication of Niclosamide loaded solid lipid nanoparticles: in vitro characterization and comparative in vivo evaluation. Artif Cells Nanomed Biotechnol. 2018;46(8):1926–1934. doi:10.1080/21691401.2017.1396996

Bayrakcı M,Ertul S, Yilmaz M. Phase solubility studies of poorly soluble drug molecules by using O-phosphorylated calixarenes as drug-solubilizing agents. J Chem Eng Data. 2012;57(1):233–239. doi:10.1021/je200992c

Khalikov SS, Dushkin AV. Strategies for solubility enhancement of anthelmintics. Pharm Chem J. 2020;54:504–508. doi:10.1007/s11094-020-02229-4

Dushkin AV. Potential of mechanochemical technology in organic synthesis and synthesis of new materials. Chem Sustain Develop. 2004;12(3):251–273.

Arhipov IA, Sadov KM, Limova YuV, Varlamova AI, Khalikov SS, Dushkin AV, Chistyachenko YS, authors; Scientific Research Institute Parasitology named after K.I. Skryabin, assignee. Supramolekulyarnyj kompleks s niklozamidom i sposob ego polucheniya. Russian Federation patent RU 2588368 C1. 2016 June 27.

Kashapov RR, Razuvayeva YS, Ziganshina AY, Mukhitova RK, Sapunova AS, Voloshina A.D, Syakaev VV, Latypov SK, Nizameev IR, Kadirov MK, Zakharova LY. N-methyl-d-glucamine–calix [4] resorcinarene conjugates: Self-assembly and biological properties. Molec.2019;24(10):1939. doi:10.3390/molecules24101939

Needham D. The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology: Motivation for Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, Its Variants and Other Viral Infections. Pharm Res. 2022;39(1):115–141. doi:10.1007/s11095-021-03112-x

Xu W, Sun Y, Du L, Chistyachenko YS, Dushkin AV, Su W. Investigations on solid dispersions of valsartan with alkalizing agents: Preparation, characterization and physicochemical properties. J Drug Delivery Sci Technol. 2018;44:399–405. doi:10.1016/j.jddst.2018.01.012

Wei W, Evseenko VI, Khvostov MV, Borisov SA, Tolstikova TG, Polyakov NE, Dushkin AV, Xu W, Min L, Su W. Solubility, permeability, anti-inflammatory action and in vivo pharmacokinetic properties of several mechanochemically obtained pharmaceutical solid dispersions of nimesulide. Molec.2021;26(6):1513. doi:10.3390/molecules26061513

Saokham P, Muankaew C, Jansook P, Loftsson T. Solubility of cyclodextrins and drug/cyclodextrin complexes. Molec. 2018;23(5):1161. doi:10.3390/molecules23051161

Hao X, Sun X, Zhu H, XieL, Wang X, Jiang N, Fu P, Sang M. Hydroxypropyl-β-cyclodextrin-complexed resveratrol enhanced antitumor activity in a cervical cancer model: In vivo analysis. Front Pharm. 2021;12:573909. doi:10.3389/fphar.2021.573909

Lodagekar A, Borkar RM, Thatikonda S, Chavan RB, Naidu VG, Shastri NR, Srinivas R, Chella N. Formulation and evaluation of cyclodextrin complexes for improved anticancer activity of repurposed drug: Niclosamide. Carbohydr Polym. 2019;212:252–259. doi:10.1016/j.carbpol.2019.02.041

Pistone M, Racaniello GF, Arduino I, Laquintana V, Lopalco A, Cutrignelli A, Rizzi R, Franco M, Lopedota A, Denora N. Direct cyclodextrin-based powder extrusion 3D printing for one-step production of the BCS class II model drug niclosamide. Drug Deliv and Translational Res. 2022;12(8):1895–1910. doi:10.1007/s13346-022-01124-7

Chistyachenko YS, Dushkin AV, Polyakov NE, et al. Polysaccharide arabinogalactan from larch Larixsibirica as carrier for molecules of salicylic and acetylsalicylic acid: preparation, physicochemical and pharmacological study. Drug Deliv. 2015;22:400–407. doi:10.3109/10717544.2014.884655

Emsley JW, Freeney J, Sutcliffe LH. High Resolution Nuclear Magnetic Resonance Spectroscopy. Vol 1. Oxford: Pergamon Press. 1967: 663 p.

Popova MV, Tchernyshev YS, Michel D. NMR Investigation of the Short-chain Ionic Surfactant− Water Systems. Langmuir. 2004;20(3):632–636. doi:10.1021/la035465s

Kerns EH, Di L, Petusky S, Farris M, Ley R, Jupp P. Combined application of parallel artificial membrane permeability assay and Caco-2 permeability assays in drug discovery. J Pharm Sci. 2004;93:1440–1453. doi:10.1002/jps.20075

Kansy M, Senner F, Gubernator K. Physicochemical high throughput screening: Parallel artificial membrane permeation assay in the description of passive absorption processes. J Med Chem. 1998;41:1007–1010. doi:10.1021/jm970530e

Mccallum MM. High-Throughput Approaches for the Assessment of Factors Influencing Bioavailability of Small Molecules in Pre-Clinical Drug Development [dissertation]. Milwaukee (USA) University of Wisconsin; 2013. 259 p.


Article Metrics

Metrics Loading ...

Metrics powered by PLOS ALM

Copyright (c) 2023 Elizaveta S. Meteleva, Elizaveta A. Roenko, Nikolay E. Polyakov

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Scopus logo WorldCat logo DOAJ logo CAS logo BASE logo eLibrary logo

Chimica Techno Acta, 2014-2023
ISSN 2411-1414 (Online)
Copyright Notice