RSM-Based Design and Optimization of Transdermal Film of Ondansetron HCl

  • Rabinarayan ParhiEmail author
  • Tejasri Panchamukhi
Original Article



The main objective of the present investigation was to develop transdermal films of ondansetron HCl (OS) with polyvinyl alcohol (PVA) using Box-Behnken design and to optimize them employing Derringer’s optimization tool.


Design-Expert software was used to investigate the effect of independent variables such as concentration (%, w/w) of glycerol and 1,8-cineole, and number of Freeze-Thaw cycle (F-T cycle) on the dependent variables viz. ultimate tensile strength (UTS) and flux. The F-T cycle followed by solvent casting method was employed to develop films. Universal tensile testing machine and Franz diffusion cell were used to measure tensile strength and flux, respectively.


Quadratic model was found to be best fit model and the effect of concentration of glycerol and the number of F-T cycle significantly influences the tensile strength (p < 0.0001), whereas the concentration of 1,8-cineole significantly (p < 0.0001) influenced the flux. The optimized conditions were found to be 10% (w/w) of glycerol, 4.999 number of F-T cycle, and 7.499% (w/w) of 1,8-cineole using Derringer’s optimization tool. Under these conditions, the predicted tensile strength and flux obtained were 18.322 MPa and 30.697 μg/cm2/h, respectively, with desirability of 0.791. Skin irritation potential study on the rat showed a score of 0.44 ± 0.13 on Draize scoring system. The optimized film was found to be stable for 3 months at room temperature and accelerated conditions (40 ± 2 °C temperature and 75 ± 5% RH).


Above results imply that the optimized film of OS is a safe transdermal drug delivery tool which could be used as a potential alternative to oral dosage form.


Transdermal film Ondansetron HCl Tensile strength Flux Box-Behnken design 



The authors are thankful to Dr. Sanjay Swain, head of CIF, BIT, Mesra, for performing TGA/DTA and mechanical properties of our samples. The authors also thank the management of GITAM Deemed to be University, Visakhapatnam, for providing necessary facilities to carry out the research work.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Teodorescu F, Quéniat G, Foulon C, Lecoeur M, Barras A, Boulahneche S, et al. Transdermal skin patch based on reduced graphene oxide: a new approach for photothermal triggered permeation of OS across porcine skin. J Control Release. 2017;245:137–46.CrossRefGoogle Scholar
  2. 2.
    Ahmed TA, El-Say KM. Transdermal film-loaded finasteride microplates to enhance drug skin permeation: two-step optimization study. Eur J Pharm Sci. 2016;88:246–56.CrossRefGoogle Scholar
  3. 3.
    Advanced Film-Forming Agent for Transdermal Drug Delivery. Available from: Accesses 15 Nov 2017.
  4. 4.
    Dhiman S, Singh GT, Rehni AK. Transdermal patches: a recent approach to new drug delivery system. Int J Pharm Pharm Sci. 2011;3:26–34.Google Scholar
  5. 5.
    Kathe K, Kathpalia H. Film forming systems for topical and transdermal drug delivery. Asian J Pharm Sci. 2017;12:487–97.CrossRefGoogle Scholar
  6. 6.
    Moreira RB, Teixeira JA, Furuyama-Lima AM, de Souza NC, Siqueira AB. Preparation, characterization and evaluation of drug-delivery systems: pectin and mefenamic acid films. Thermochim Acta. 2014;590:100–6.CrossRefGoogle Scholar
  7. 7.
    Ahmed TA, El-Say KM, Aljaeid BM, Fahmy UA, Abd-Allah FI. Transdermal glimperide delivery system based on optimized ethosomal nano-vesicles: preparation, characterization, in vitro, ex vivo and clinical evaluation. Int J Pharm. 2016;500:245–54.CrossRefGoogle Scholar
  8. 8.
    Laitinen R, Räty J, Korhonen K, Ketolainen J, Peiponen KK. Reflectometric monitoring of the dissolution process of thin polymeric films. Int J Pharm. 2017;523:127–32.CrossRefGoogle Scholar
  9. 9.
    Karki S, Kim H, Na S-J, Shin D, Jo K, Lee J. Thin films as an emerging platform for drug delivery. Asian J Pharm Sci. 2016;11:559–74.CrossRefGoogle Scholar
  10. 10.
    Sheshala R, Khan N, Chitneni M, Darwis Y. Formulation and in vivo evaluation of OS orally disintegrating tablets using different superdisintegrants. Arch Pharm Res. 2011;34:1945–56.CrossRefGoogle Scholar
  11. 11.
    Can AS, Erdal MS, Güngör S, Özsoy Y. Optimization and characterization of chitosan films for transdermal delivery of OS. Molecules. 2013;18:5455–71. Scholar
  12. 12.
    Rajabalaya R, Tor L-Q, David S. Formulation and in vitro evaluation of OS hydrochloride matrix transdermal systems using ethyl cellulose/polyvinyl pyrrolidone polymer blends. Int J Med Health Biomed Bioeng Pharm Eng. 2012;6:2012.Google Scholar
  13. 13.
    Takahashi K, Rytting JH. Novel approach to improve permeation of OS across shed snake skin as a model membrane. J Pharm Pharmacol. 2001;53:789–94.CrossRefGoogle Scholar
  14. 14.
    David SRN, Rajabalaya R, Zhia ES. Development and in vitro evaluation of self-adhesive matrix-type transdermal delivery system of ondansetron hydrochloride. Trop J Pharm Res. 2015;14:211–8.CrossRefGoogle Scholar
  15. 15.
    Baptista JGC, Rodrigues SPJ, Matsushita AFY, Vitorino C, Maria TMR, Burrows HD, et al. Does poly(vinyl alcohol) act as an amphiphilic polymer? An interaction study with simvastatin. J Mol Liq. 2016;222:287–94.CrossRefGoogle Scholar
  16. 16.
    Lozinsky VI, Plieva FM. Poly(vinyl alcohol) cryogels employed as matrices for cell immobilization. 3. Overview of recent research and developments. Enzym Microb Technol. 1998;23:227–42.CrossRefGoogle Scholar
  17. 17.
    Martinez YN, Piñuel L, Castro GR, Breccia JD. Polyvinyl alcohol–pectin cryogel films for controlled release of enrofloxacin. Appl Biochem Biotechnol. 2012;167:1421–9.CrossRefGoogle Scholar
  18. 18.
    Anirudha TS, Nair SS, Sekhar VC. Deposition of gold-cellulose hybrid nanofiller on a polyelectrolyte membrane constructed using guar gum and poly(vinyl alcohol) for transdermal drug delivery. J Membr Sci. 2017;539:344–57.CrossRefGoogle Scholar
  19. 19.
    Marwah H, Garg T, Goyal AK, Rath G. Permeation enhancer strategies in transdermal drug delivery. Drug Deliv. 2016;23:1–15.CrossRefGoogle Scholar
  20. 20.
    Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37.CrossRefGoogle Scholar
  21. 21.
    Mohammed D, Hirata K, Hadgraft J, Lane ME. Influence of skin penetration enhancers on skin barrier function and skin protease activity. Eur J Pharm Sci. 2014;51:118–22.CrossRefGoogle Scholar
  22. 22.
    Hwang M-R, Kim JO, Lee JH, Kim YI, Kim JH, Chang SW, et al. Gentamicin-loaded wound dressing with polyvinyl alcohol/dextran hydrogel: gel characterization and in vivo healing evaluation. AAPS PharmSciTech. 2010;11:1092–103.CrossRefGoogle Scholar
  23. 23.
    Emma JW, Gavin PA, Mc Coy CP, Jones DS. The effect of dilute solution properties on poly(vinyl alcohol)films. J Mech Behav Biomed Mater. 2013;28:222–31.CrossRefGoogle Scholar
  24. 24.
    Parhi R, Suresh P, Patnaik S. Formulation optimization of PVA/HPMC cryogel of diltiazem HCl using 3-level factorial design and evaluation for ex vivo permeation. J Pharm Investig. 2015;45:319–27.CrossRefGoogle Scholar
  25. 25.
    Parhi R, Suresh P. Transdermal delivery of diltiazem HCl from matrix film: effect of penetration enhancers and study of antihypertensive activity in rabbit model. J Adv Res. 2016;7:539–50.CrossRefGoogle Scholar
  26. 26.
    Tirunagari M, Jangala VR, Khagga M, Gannu R. Transdermal therapeutic system of isradipine: effect of hydrophilic and hydrophobic matrix on in vitro and ex vivo characteristics. Arch Pharm Res. 2010;33:1025–33.CrossRefGoogle Scholar
  27. 27.
    Schroeder IZ, Franke P, Schaefer UF, Lehr CM. Development and characterization of film forming polymeric solutions for skin drug delivery. Eur J Pharm Biopharm. 2007;65:111–21.CrossRefGoogle Scholar
  28. 28.
    Parhi R, Suresh P. Formulation optimization and characterization of transdermal film of simvastatin by response surface methodology. Mater Sci Eng C. 2016;58:331–41.CrossRefGoogle Scholar
  29. 29.
    Parhi R, Suresh P, Pattnaik S. Application of response surface methodology for design and optimization of reservoir-type transdermal patch of simvastatin. Cur Drug Deliv. 2016;13:742–53.CrossRefGoogle Scholar
  30. 30.
    Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J Pharmacol Exp Ther. 1944;82:377–90.Google Scholar
  31. 31.
    ICH Guideline Q1A(R). Stability testing of new drug substances and products. Geneva: ICH; 2000.Google Scholar
  32. 32.
    Chaudhary H, Rohilla A, Rathee P, Kumar V. Optimization and formulation design of carbopol loaded Piroxicam gel using novel penetration enhancers. Int J Biol Macromol. 2013;55:246–53.CrossRefGoogle Scholar
  33. 33.
    Sarkar G, Saha NR, Roy I, Bhattacharyya A, Bose M, Mishra R, et al. Taro corms mucilage/HPMC based transdermal patch: an efficient device for delivery of diltiazem hydrochloride. Int J Biol Macromol. 2014;66:158–65.CrossRefGoogle Scholar
  34. 34.
    Patel DP, Setty CM, Mistry GN, Patel SL, Patel TJ, Mistry PC, et al. Development and evaluation of ethyl cellulose-based transdermal films of furosemide for improved in-vitro skin permeation. AAPS PharmSciTech. 2009;10:437–42.CrossRefGoogle Scholar
  35. 35.
    Witek-Krowiak A, Chojnacka K, Podstawczyk D, Dawiec A, Pokomeda K. Application of response surface methodology and artificial neural network methods in modelling and optimization of biosorption process. Bioresour Technol. 2014;160:150–60.CrossRefGoogle Scholar
  36. 36.
    Wang C, Zhang J, Wang F, Wang Z. Extraction of crude polysaccharides from Gomphidius rutilus and their antioxidant activities in vitro. Carbohyr Polym. 2013;94:479–86.CrossRefGoogle Scholar
  37. 37.
    Wu H, Zhu J, Diao W, Wang C. Ultrasound-assisted enzymatic extraction and antioxidant activity of polysaccharides from pumpkin (Cucurbita moschata). Carbohyr Polym. 2014;113:314–24.CrossRefGoogle Scholar
  38. 38.
    Maran JP, Manikandan S, Thirugnanasambandham K, Nivetha CV, Dinesh R. Box-Behnken design based statistical modeling for ultrasound-assisted extraction of corn silk polysaccharide. Carbohyr Polym. 2013;92:604–11.CrossRefGoogle Scholar
  39. 39.
    Nesseem DI, Eid SF, El-Houseny SS. Development of novel transdermal self-adhesive films for tenoxicam, an anti-inflammatory drug Demiana. Life Sci. 2011;89:430–8.CrossRefGoogle Scholar
  40. 40.
    Saettone MF, Perini G, Rijli P, Rodriguez L, Cini M. Effect of different polymer–plasticizer combinations on ‘in vitro’ release of theophylline from coated pellets. Int J Pharm. 1995;126:83–8.CrossRefGoogle Scholar
  41. 41.
    Limpongsa E, Umprayn K. Preparation and evaluation of diltiazem hydrochloride diffusion-controlled transdermal delivery system. AAPS PharmSciTech. 2008;9:464M–70M.CrossRefGoogle Scholar
  42. 42.
    Handbook of Pharmaceutical Excipients. 5th edn. In: Rowe RC, Sheskey PJ, Owen SC, editors. 1 Lambeth high street, London SE1 7JN, UK: Pharmaceutical Press; 2006. p. 301–303.Google Scholar
  43. 43.
    Kumara A, Mishra R, Reinwald Y, Bhat S. Cryogels: freezing unveiled by thawing. Mater Today. 2010;13:42–4.CrossRefGoogle Scholar
  44. 44.
    Ricciardi R, Gaillet C, Ducouret G, Lafuma F, Laupretre F. Investigation of the relationships between the chain organization and rheological properties of atactic poly(vinyl alcohol) hydrogels. Polymer. 2003;44:3375–80.CrossRefGoogle Scholar
  45. 45.
    McGuinness GB, Vrana NE, Liu Y. Polyvinvyl alcohol-based cryogels: tissue engineering and regenerative medicine. Encycl Biomed Polym Polym Biomater. 2014;1–11.
  46. 46.
    Pazos V, Mongrain R, Tardif JC. Polyvinyl alcohol cryogel: optimizing the parameters of cryogenic treatment using hyperelastic models. J Mech Behav Biomed Mater. 2009;2:542–9.CrossRefGoogle Scholar
  47. 47.
    Parhi R, Suresh P, Mondal S, Kumar PM. Novel penetration enhancers for skin applications: a review. Curr Drug Deliv. 2012;9:219–30.CrossRefGoogle Scholar
  48. 48.
    Narishetty ST, Panchagnula R. Effect of l-menthol and 1,8-cineole on phase behavior and molecular organization of SC lipids and skin permeation of zidovudine. J Control Release. 2005;102:59–70.CrossRefGoogle Scholar
  49. 49.
    Jiang Q, Wu Y, Zhang H, Liu P, Yao J, Yao P, et al. Development of essential oils as skin permeation enhancers: penetration enhancement effect and mechanism of action. Pharm Biol. 2017;55:1592–600.CrossRefGoogle Scholar
  50. 50.
    Fox LT, Gerber M, Plessis JD, Hamman JH. Transdermal drug delivery enhancement by compounds of natural origin. Molecules. 2011;16:10507–40.CrossRefGoogle Scholar
  51. 51.
    Aqil M, Ahad A, Sultana Y, Ali A. Status of terpenes as skin penetration enhancers. Drug Discov Today. 2007;12:1061–7.CrossRefGoogle Scholar
  52. 52.
    Parhi R, Podilam S, Patnaik S. Physical means of stratum corneum barrier manipulation to enhance transdermal drug delivery. Cur Drug Deliv. 2015;12:122–38.CrossRefGoogle Scholar
  53. 53.
    Parhi R. Development and optimization of pluronic® F127 and HPMC based thermosensitive gel for the skin delivery of metoprolol succinate. J Drug Deliv Sci Technol. 2016;36:23–33.CrossRefGoogle Scholar
  54. 54.
    Ahuja MM. Metronidazole loaded carboxymethyl tamarind kernel polysaccharide-polyvinyl alcohol cryogels: preparation and characterization. Int J Biol Macromol. 2015;72:931–8.CrossRefGoogle Scholar
  55. 55.
    Ahmad A, Alkharfy KM, Wanie TA, Raish M. Application of Box-Behnken design for ultrasonic-assisted extraction of polysaccharides from Paeonia emodi. Int J Biol Macromol. 2015;72:990–7.CrossRefGoogle Scholar
  56. 56.
    Sivakumar T, Manavalan R, Valliappan K. Global optimization using derringer’s desirability function: enantioselective determination of ketoprofen in formulations and in biological matrices. Acta Chromatogr. 2007;19:29–47.Google Scholar
  57. 57.
    de Jesus NAM, de Oliveira AHP, Tavares DC, Furtado RA, de Silva MLA, Cunha WR, et al. Biofilm formed from a tri-ureasil organic−inorganic hybrid gel for use as a cubebin release system. J Sol-Gel Sci Technol. 2018;88:192–201.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.GITAM Institute of PharmacyGITAM (Deemed to be University)VisakhapatnamIndia

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