To investigate cyclodextrin-mediated solubilization and physical stabilization of novel 1-indanone thiosemicarbazone (TSC) candidate drugs that display extremely high self-aggregation and precipitation tendency in water.
TSC/CD complexes were produced by co-solvent method, and TSC/CD phase-solubility diagrams were obtained by plotting TSC concentration as a function of increasing CD concentration. Size, size distribution, and zeta-potential of the different TSC/CD complexes and aggregates were fully characterized by dynamic light scattering. The morphology of the structures was visualized by atomic force microscopy.
Results indicated the formation of Type A inclusion complexes; the solubility of different TSCs was enhanced up to 215 times. The study of physical stability revealed that, as opposed to free TSCs that self-aggregate, crystallize, and precipitate in water very rapidly, complexed TSCs remain in solution for at least 1 week. On the other hand, a gradual size growth was observed. This phenomenon stemmed from the self-aggregation of the TSC/CD complex.
1-indanone TSC/CD inclusion complexes improved aqueous solubility and physical stability of these new drug candidates and constitute a promising technological approach towards evaluation of their activity against the viruses hepatitis B and C.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Atwood D, Florence AT. Surfactant Systems: Their Chemistry, Pharmacy and Biology. Chapter 3, Micellization, Chapman and Hall. 72–117 (1983).
Espada R, Valdespina S, Alfonso C, Rivas G, Ballesteros MP, Torrado JJ. Effect of aggregation state on the toxicity of different amphotericin B preparations. Int J Pharm. 2008;361:64–9.
Taboada P, Attwood D, Ruso JM, Sarmiento F, Mosquera V. Self-association of amphiphilic penicillins in aqueous electrolyte solution: a light-scattering and NMR study. Langmuir. 1999;15:2022–8.
Fini A, Fazio G, Feroci G. Solubility and solubilization properties of non-esteroidal anti-inflammatory drugs. Int J Pharm. 1995;126:95–102.
Taboada P, Attwood D, Ruso JM, García M, Mosquera V. Thermodynamic properties of some antidepressant drugs in aqueous solution. Langmuir. 2001;17:173–7.
Attwood D, Mosquera V, Lopez-Fontan JL, Garcia M, Sarmiento F. Self-association of phenothiazine drugs: influence of the counterion on the mode of association. J Colloid Interface Sci. 1996;184:658–62.
Frenkel YV, Clark AD, Das Jr K, Wang Y-H, Lewi PJ, Janssen PAJ, et al. Concentration and pH dependent aggregation of hydrophobic drug molecules and relevance to oral bioavailability. J Med Chem. 2005;48:1974–83.
Fernandez DA, Awruch J, Dicelio LE. Synthesis and photophysical properties of a new cationic water-soluble Zn phthalocyanine. J Photochem Photobiol B. 1997;41:227–32.
López-Nicolás JM, García-Carmona F. Effect of hydroxypropyl-β-cyclodextrin on the aggregation of (E)-resveratrol in different protonation states of the guest molecule. Food Chem. 2010;118:648–55.
Atwood D, Boitard E, Dubés J-P, Tachoire H. A colorimetric study of the influence of temperature on the self-association of amphiphilic antidepressant drugs in aqueous solution. J Colloid Interface Sci. 2000;227:356–62.
Domagk G, Behnisch R, Mietzsch F, Schimidt H. On a new class of compounds effective in vitro against tubercle bacilli. Naturwis. 1946;33:315.
Iakovidou Z, Papageorgiou A, Demertzis MA, Mioglou E, Mourelatos D, Kotsis A, et al. Platinum (II) and Palladium (II) complexes with 2-acetylpyridine thiosemicarbazone: cytogenetic and antineoplastic effects. Anti-Cancer Drugs. 2001;12:65–70.
Sriram D, Yogeeswari P, Dhakla P, Senthilkumar P, Banerjee D. N-Hydroxythiosemicarbazones: synthesis and in vitro antitubercular activity. Bioorg Med Chem Lett. 2007;17:1888–91.
Halve AK, Bhashkar B, Sharma V, Bhadauria R, Kankoriya A, Soni A, et al. Synthesis and in vitro antimicrobial studies of some new 3-[phenyldiazenyl] benzaldehyde N-phenyl thiosemicarbazones. J Enzyme Inhib Med Chem. 2008;23:77–81.
Du X, Guo C, Hansell E, Doyle PS, Caffrey CR, Holler TP, et al. Synthesis and structure–activity relationship study of potent trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain. J Med Chem. 2002;45:2695–707.
Pelosi G, Bisceglie F, Bignami F, Ronzi P, Schiavone P, Re MC, et al. Antiretroviral activity of thiosemicarbazone metal complexes. J Med Chem. 2010;53:8765–9.
Finkielstein LM, Castro E, Fabián LE, Moltrasio GY, Campos RH, Cavallaro LV, et al. New-1-indanone thiosemicarbazone derivatives active against BVDV. Eur J Med Chem. 2008;43:1767–73.
Brousse BN, Massa R, Moglioni AG, Martins Alho M, D’Accorso N, Gutkind G, et al. Antibacterial and antifungal activity of some thiosemicarbazones and 1,3,4-thiadiazolines. J Chil Chem Soc. 2004;49:45–9.
Garcia C, Brousse B, Carlucci M, Moglioni A, Martins Alho M, Moltrasio G, et al. Inhibitory effect of thiosemicarbazone derivatives on Junin virus replication in vitro. Antivir Chem Chemother. 2003;14:99–105.
Finkielsztein LM, Moltrasio GY, Caputto ME, Castro EF, Cavallaro LV, Moglioni AG. What is known about the antiviral agents active against Bovine Viral Diarrhea Virus (BVDV)? Curr Med Chem. 2010;17:2933–55.
Glisoni RJ, Chiappetta DA, Finkielsztein LM, Moglioni AG, Sosnik A. Self-aggregation behaviour of novel thiosemicarbazone drug candidates with potential antiviral activity. New J Chem. 2010;34:2047–58.
Brewster M, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Del Rev. 2007;59:645–66.
Loftsson T, Brewster M. Pharmaceutical Applications of Cyclodextrins. 1. Drug Solubilization and Stabilization. J Pharm Sci. 1996;85:1017–25.
Loftsson T, Másson M, Brewster ME. Self-association of cyclodextrins and cyclodextrin complexes. J Pharm Sci. 2004;93:1091–9.
Loftsson T, Duchêne D. Cyclodextrins and their pharmaceutical applications. Int J Pharm. 2007;329:1–11.
Zouvelekis D, Yannakopoulou K, Mavridis IM, Antoniadou-Vyza E. The self-association of the drug acemetacin and its interactions and stabilization with β-cyclodextrin in aqueous solution as inferred from NMR spectroscopy and HPLC studies. Carbohydrate Res. 2002;337:1387–95.
McIntosh MP, Leong N, Katneni K, Morizzi J, Shackleford DM, Prankerd RJ. Impact of chlorpromazine self-association on its apparent binding constants with cyclodextrins: effect of SBE7-β-CD on the disposition of chlorpromazine in the rat. J Pharm Sci. 2010;99:2999–3008.
Bonini M, Rossi S, Karlsson G, Almgren M, Lo Nostro P, Baglioni P. Self-assembly of β-Cyclodextrin in water. Part 1: Cryo-TEM and dynamic light scattering. Langmuir. 2006;22:1478–84.
He Y, Shen PFX, Gao H. Cyclodextrin-based aggregates and characterization by microscopy. Micron. 2008;39:495–516.
Messner M, Kurlov SV, Jansook P, Loftsson T. Self-assembled cyclodextrin aggregates and nanoparticles. Int J Pharm. 2009;387:199–208.
Szente L, Szejtli J, Kis GL. Spontaneous opalescence of aqueous γ-cyclodextrin solutions: complex formation or self-aggregation? J Pharm Sci. 1998;87:778–81.
Jansook P, Moya-Ortega MD, Loftsson T. Effect of self-aggregation of γ-cyclodextrin on drug solubilization. J Incl Phenom Macrocycl Chem. 2010;68:229–36.
Surfactant micelle characterization using dynamic light scattering. Malvern Instruments. Application Note. (2006).
Martin Del Valle EM. Cyclodextrins and their uses: a review. Proc Biochem. 2004;39:1033–46.
Higuchi T, Connors KA. Phase-solubillity techniques. Adv Anal Chem Instrum. 1965;4:117–212.
Jansook P, Kurkov SV, Loftsson T. Cyclodextrins as solubilizers: formation of complex aggregates. J Pharm Sci. 2010;99:719–29.
Garnero C, Zoppi A, Genovese D, Longhi M. Studies on trimethoprim: hydroxypropyl-β-cyclodextrin: aggregate and complex formation. Carbohydrate Res. 2010;345:2550–6.
Grant DJW, Higuchi T. Solubility Behavior of Organic Compounds. Techniques of Chemistry Volume XXI. Chapter 10. Wiley Interscience (1990).
European Pharmacopeia, 3rd Ed., Supplement 5.4. (Residual solvents), Page 298 (2000).
Mukne AP, Nagarsenker MS. Triamterene-β-cyclodextrin system: preparation, characterization and in vivo evaluation. AAPS PharmSciTech. 2004;5:1–9.
Kim Y-T, Shin B-K, Garripelli VK, Kim J-K, Davaa E, Jo S, et al. A thermosensitive vaginal gel formulation with HPγCD for the pH-dependent release and solubilization of amphotericin B. Eur J Pharm Sci. 2010;41:399–406.
Smith AA, Manavalan R, Kannan K, Rajendiran N. Spectral characteristics of tramadol in different solvents and β-cyclodextrin. Spectrochim Acta Part A. 2009;74:469–77.
Skiba M, Duchêne D, Puisieux F, Wouessidjewe D. Development of a new colloidal drug carrier from chemically-modified cyclodextrins: nanospheres and influence of physicochemical and technological factors on particle size. Int J Pharm. 1996;129:113–21.
Da Silveira AM, Ponchel G, Puisieux F, Duchêne D. Combined poly(isobutylcyanoacrylate) and cyclodextrins nanoparticles for enhancing the encapsulation of lipophilic drugs. Pharm Res. 1998;15:1051–5.
Choi M-J, Scoottitantawat A, Nuchuchua O, Min S-G, Ruktanonchai U. Physical and light oxidative properties of eugenol encapsulated by molecular inclusion and emulsion-diffusion method. Food Res Int. 2009;42:148–56.
Gould S, Scott R. 2-Hydroxypropyl-β-cyclodextrin (HPβ-CD): a toxicology review. Food Chem Toxicol. 2005;43:1451–9.
Li J, Zhang M, Chao J, Shuang S. Preparation and characterization of the inclusion complex of Baicalin (BG) with β-CD and HP-β-CD in solution: an antioxidant ability study. Spectrochim Acta Part A. 2009;73:752–6.
Yavuz B, Bilensoy E, Vural I, Şumnu M. Alternative oral exemestane formulation: improved dissolution and permeation. Int J Pharm. 2010;398:137–45.
Dupuy N, Barbry D, Bria M, Marquis S, Vrielynck L, Kister J. 1H-NMR study of inclusion compounds of phenylurea derivatives in β-cyclodextrin. Spectrochim Acta Part A. 2005;61:1051–7.
Gibaud S, Zirar SB, Mutzenhardt P, Fries I, Astier A. Melarsoprol-cyclodextrins inclusion complexes. Int J Pharm. 2005;306:107–21.
ACKNOWLEDGMENTS & DISCLOSURES
R.J. Glisoni thanks the Ph.D. scholarship of CONICET. AS, AM and DC are staff members of CONICET. The authors thank Dr. Gloria Bonetto (Universidad Nacional de Córdoba, Córdoba, Argentina) for 1D-NMR analysis and Dr. Daniel R. Vega (Departamento Física de la Materia Condensada, CNEA, Buenos Aires, Argentina) for X-ray analysis.
About this article
Cite this article
Glisoni, R.J., Chiappetta, D.A., Moglioni, A.G. et al. Novel 1-indanone Thiosemicarbazone Antiviral Candidates: Aqueous Solubilization and Physical Stabilization by Means of Cyclodextrins. Pharm Res 29, 739–755 (2012). https://doi.org/10.1007/s11095-011-0599-y
- 1-indanone thiosemicarbazone antiviral candidates
- inclusion complexes
- native and modified cyclodextrins