Skip to main content
SpringerLink
Log in

Box-Behnken experimental design in the development of a nasal drug delivery system of model drug hydroxyurea: Characterization of viscosity, in vitro drug release, droplet size, and dynamic surface tension

  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The purpose of the research was to investigate the changes in physicochemical properties and their influence on nasal formulation performance using 5-factor, 3-level Box-Behnken experimental design on the combined responses of viscosity, droplet size distribution (DSD), and drug release. Gel formulations of hydroxyurea (HU) with surface-active polymers (hydroxyethylcellulose [HEC] and polyethylene-oxide [PEO]) and ionic excipients (sodium chloride and calcium chloride) were prepared using Box-Behnken experimental design. The rheology and dynamic surface tension (DST) of the test formulations was investigated using LV-DV-III Brookfield rheometer and T60 SITA tensiometer, respectively. Droplet size analysis of nasal aerosols was determined by laser diffraction using the Malvern Spraytec with the InnovaSystems actuator. In vitro drug release studies were conducted on Franz diffusion cells. With PEO gel, calcium chloride increased the viscosity and DSD and retarded drug release, while sodium chloride decreased the viscosity, DST, and DSD and accelerated the release of HU. With HEC gel, the addition of the above salts resulted in less significant changes in viscosity, DSD, and DST, but both salts significantly increased the release of HU. Droplet size data obtained from a high viscosity nasal pump was dependent on type of polymer, polymer-excipient interactions, and solvent properties. The applications of Box-Behnken experimental design facilitated the prediction and identified major excipient influences on viscosity, DSD, and in vitro drug release.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dayal P, Shaik MS, Singh M. Evaluation of different parameters that affect droplet-size distribution from nasal sprays using the Malvern Spraytec.J Pharm Sci. 2004;93:1725–1742.

    Article  CAS  Google Scholar 

  2. Malmsten M.Surfactants and Polymers in Drug Delivery. Lancaster, PA: Dekker; 2002.

    Google Scholar 

  3. Rotthäuser B, Kraus G, Schmidt PC. Optimization of an effervescent tablet formulation using a central composite design optimization of an effervescent tablet formulation containing spray driedL-leucine and polyethylene glycol 6000 as lubricants using a central composite design.Eur J Pharm Biopharm. 1998;46:85–94.

    Article  Google Scholar 

  4. Nazzal S, Nutan M, Palamakula A, Shah R, Zaghloul A, Khan MA. Optimization of a self-nanoemulsified tablet dosage form of Ubiquinone using response surface methodology: effect of formulation ingredients.Int J Pharm. 2002;240:103–114.

    Article  CAS  Google Scholar 

  5. Poncet-Legrand C, Lafuma F, Audebert R. Rheological behavior of colloidal dispersions of hydrophobic particles stabilized in water by amphiphilic polyelectrolytes.Colloids Surf A: Physicochemical Eng Aspects. 1999;152:251–261.

    Article  CAS  Google Scholar 

  6. Chiotelli E, Pilosio G, Le Meste M. Effect of sodium chloride on the gelatinization of starch: a multimeasurement study.Biopolymers. 2002;63:41–58.

    Article  CAS  Google Scholar 

  7. Box GEP, Behnken DW. Some new 3 level designs for the study of quantitative variables.Technometrics. 1960;2:455–475.

    Article  Google Scholar 

  8. Omelczuk MO, McGinity JW. The influence of thermal treatment on the physical-mechanical and dissolution properties of tablets containing poly(DL-lactic acid).Pharm Res. 1993;10:542–548.

    Article  CAS  Google Scholar 

  9. Pillay V, Fassihi R. Evaluation and comparison of dissolution data derived from different modified release dosage forms: an alternative method.J Control Release. 1998;55:45–55.

    Article  CAS  Google Scholar 

  10. Borodin O, Smith GD. Molecular dynamic simulations of poly (ethylene oxide)/LiI melts. 2. dynamic properties.Macromolecules. 2000;33:2273–2283.

    Article  CAS  Google Scholar 

  11. van Zon A, Bel G-J, Mos B, Verkerk P, de Leeuw SW. Structural relaxation in polyethylene oxide: salt solutions.Comp Mater Sci. 2000;17:265–269.

    Article  Google Scholar 

  12. Smitter LM, Guedez JF, Muller AJ, Saez AE. Interactions between poly(ethylene oxide) and sodium dodecyl sulfate in elongational flows.J Colloid Interface Sci. 2001;236:343–353.

    Article  CAS  Google Scholar 

  13. Dougherty RC. Density of salt solutions: effect of ions on the apparent density of water.J Phys Chem B. 2001;105:4514–4519.

    Article  CAS  Google Scholar 

  14. Leberman R, Soper AK. Effect of high-salt concentrations on waterstructure.Nature. 1995;378:364–366.

    Article  CAS  Google Scholar 

  15. Walrafen GE, Chu YC. Shear viscosity and self-diffusion evidence for high concentrations of hydrogen-bonded clathrate-like structures in very highly supercooled liquid water.J Phys Chem. 1995;99:10635–10643.

    Article  CAS  Google Scholar 

  16. Madan B, Sharp K. Changes in water structure induced by a hydrophobic solute probed by simulation of the water hydrogen bond angle and radial distribution functions.Biophys Chem. 1999;78:33–41.

    Article  CAS  Google Scholar 

  17. Hakem F, Lal J. Polyelectrolyte-like behavior of poly(ethylene-oxide) solutions with added monovalent salt.Europhys Lett. 2003;64:204–210.

    Article  CAS  Google Scholar 

  18. Bernson A, Lindgren J, Weiwei H, Frech R. Coordination and conformation in PEO, PEGM, and PEG systems containing lithium or lanthanum triflate.Polym. 1995;36:4471–4478.

    Article  CAS  Google Scholar 

  19. McCallion ON, Taylor KM, Thomas M, Taylor AY. Nebulization of fluids with different viscosity and surface tension.J Aerosol Med. 1995;8:281–284.

    Article  Google Scholar 

  20. Newman SP, Pellow PG, Clarke SW. Droplets sizes from medical atomizer (nebulizers) for drug solutions of different viscosity and surface tension.Atomization Spray Tech. 1987;3:1–11.

    CAS  Google Scholar 

  21. McCallion ON, Patel MJ. Viscosity effects on nebulization of aqueous solutions.Int J Pharm. 1996;130:245–249.

    Article  CAS  Google Scholar 

  22. Frese Ch, Ruppert S, Sugar M, et al. Adsorption kinetics of surfactant mixtures from micellar solutions as studied by maximum bubble pressure technique.J Colloid Interface Sci. 2003;267:475–482.

    Article  CAS  Google Scholar 

  23. Šarković D, Babović V. Experiments of water aerosol estimations of droplet parameters.Physics, Chemistry and Technology. 2002;2:197–208.

    Google Scholar 

  24. Biswas G, Som SK. Coefficient of discharge and spray cone angle of a pressure nozzle with combined axial and tangential entry of power-law fluids.Appl Sci Res. 1986;43:3–22.

    Article  CAS  Google Scholar 

  25. Rayleigh L. On the instability of jets.Proc Lond Math Soc. 1878;10:4–13.

    Article  Google Scholar 

  26. Squire HB. Investigation of the instability of a moving liquid film.Brit J Appl Phys. 1953;4:167–169.

    Article  Google Scholar 

  27. Thomas GO. The aerodynamic breakup of ligaments.Atomization and Sprays. 2003;13:117–129.

    Article  Google Scholar 

  28. Martin A.Physical Pharmacy: Physical Chemical Principles in the Pharmaceutical Sciences. Philadelphia, PA: Lea & Fabiger; 1993.

    Google Scholar 

  29. Scatena LF, Brown MG, Richmond GL. Water at hydrophobic surfaces: weak hydrogen bonding and strong orientation effects.Science. 2001;292:908–912.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pharmaceutics, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, 32307, Tallahassee, FL

    Pankaj Dayal, R. Jayachandra Babu & Mandip Singh

  2. Division of Pharmaceutics, Department of Pharmacy and Pharmacology, University of the Witwatersrand, Johannesburg, South Africa

    Viness Pillay

Authors
  1. Pankaj Dayal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Viness Pillay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Jayachandra Babu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mandip Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mandip Singh.

Additional information

Published: November 17, 2005

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dayal, P., Pillay, V., Babu, R.J. et al. Box-Behnken experimental design in the development of a nasal drug delivery system of model drug hydroxyurea: Characterization of viscosity, in vitro drug release, droplet size, and dynamic surface tension. AAPS PharmSciTech 6, 72 (2005). https://doi.org/10.1208/pt060472

Download citation

  • Received:

  • Accepted:

  • DOI: https://doi.org/10.1208/pt060472

Keywords

Search

Navigation