Investigation of design space for freeze-drying injectable ibuprofen using response surface methodology

Maja Preskar 1 , 2 , Danijel Videc 1 , Franc Vrečer 1 , 2 ,  and Mirjana Gašperlin 2
  • 1 , Krka d.d. SI-8000, Novo mesto, Slovenia
  • 2 University of Ljubljana, Faculty of Pharmacy, SI-1000, Ljubljana, Slovenia

Abstract

This study explores the use of a statistical model to build a design space for freeze-drying two formulations with ibuprofen. A 2 × 3 factorial experimental design was used to evaluate independent variables (filling volume and annealing time) and responses as residual moisture content, specific surface area and reconstitution time. A statistical model and response surface plots were generated to define the interactions among the selected variables. The models constructed for both formulations suggest that 1 mL of filled volume and no annealing should be used to achieve optimal residual moisture content, specific surface area and reconstitution time. The proposed models were validated with additional experiments, in which the responses observed were mainly in close agreement with the predicted ones. Additionally, the established models demonstrate the reliability of the evaluation procedure in predicting the selected responses.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. A. R. Fernandes, N. R. Ferreira, J. F. Fangueiro, A. C. Santos, F. J. Veiga, C. Cabral, A. M. Silva and E. B. Souto, Ibuprofen nanocrystals developed by 22 factorial design experiment: A new approach for poorly water-soluble drugs, Saudi Pharm. J. 25 (2017) 1117–1124; https://doi.org/10.1016/j.jsps.2017.07.004

  • 2. J. Nerurkar, J. W. Beach, M. O. Park and H. W. Jun, Solubility of (±)-ibuprofen and S (+)-ibuprofen in the presence of cosolvents and cyclodextrins, Pharm. Dev. Technol. 10 (2005) 413–421; https://doi.org/10.1081/PDT-54446

  • 3. K. Stoyanova, Z. Vinarov and S. Tcholakova, Improving ibuprofen solubility by surfactant-facilitated self-assembly into mixed micelles, J. Drug. Deliv. Sci. Tec. 36 (2016) 208–215; https://doi.org/10.1016/j.jddst.2016.10.011

  • 4. M. Preskar, T. Vrbanec, F. Vrečer, P. Šket, J. Plavec and M. Gašperlin, Solubilization of ibuprofen for freeze dried parenteral dosage forms, Acta Pharm. 69 (2019) 17–32; https://doi.org/10.2478/acph-2019-0009

  • 5. K. T. Savjani, A. Gajjar and J. K. Savjani, Drug solubility: Importance and enhancement techniques, ISRN Pharm. 12 (2012) Article ID 195727; http://dx.doi.org/10.5402/2012/195727

  • 6. S. M. Patel and M. J. Pikal, Lyophilization process design space, J. Pharm. Sci. 102 (2013) 3883–3887; https://doi.org/10.1002/jps.23703

  • 7. S. Roy, C. Ruitberg and A. Sethuraman, Troubleshooting during the manufacture of lyophilized drug product – Being prepared for the unexpected, Am. Pharm. Rev. 15 (2012).

  • 8. T. R. M. De Beer, M. Wiggenhorn, A. Hawe, J. C. Kasper, A. Almeida, T. Quinten, W. Friess, G. Winter, C. Vervaet and J. P. Remon, Optimization of a pharmaceutical freeze-dried product and its process using experimental design approach and innovative process analyzers, Talanta 83 (2011) 1623–1633; https://doi.org/10.1016/j.talanta.2010.11.051

  • 9. K. Naelepaa, P. Veski, H. Gjelstrup, J. Rantanen and P. Bertelsen, Building quality into a coating process, Pharm. Dev. Technol. 15 (2010) 35–45; https://doi.org/10.3109/10837450902882377

  • 10. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals and Human use, ICH Harmonised Tripartite Guidelines: Pharmaceutical development Q8 (R2), Current Step 4 version, August 2009; https://database.ich.org/sites/default/files/Q8_R2_Guideline.pdf; access date, September 20, 2018.

  • 11. V. K. Mourya, Y. Choudhari and M. Padame, Quality by Design: Impact of product variables and their interaction on the particle size in lyophilization of sodium fluoride, Soft Nanosci. Let. 6 (2016) 1–10; http://dx.doi.org/10.4236/snl.2016.61001

  • 12. J. Sundaram, Y-H. M. Shay, S. U. Sane and C. C. Hsu, Design space development for lyophilization using Doe and process modelling, Biopharm. Int. 23 (2010) 26–36;

  • 13. V. R. Koganti, E. Y. Shalaev, M. R. Berry, T. Osterberg, M. Youssef, D. N. Hiebert, F. A. Kanka, M. Nolan, R. Barrett, G. Scalzo, G. Fitzpatrick, N. Fitzgibbon, S. Luthra and L. Zhang, Investigation of design space for freeze-drying: Use of modeling for primary drying segment of a freeze-drying cycle, AAPS PharmSciTech. 12 (2011) 854–861; https://doi.org/10.1208/s12249-011-9645-7

  • 14. A. G. Martinez, B. E. Rodrigez, A. P. Roca and A. M. Ruiz, Intravenous ibuprofen for treatment of post-operative pain: A multicenter, double blind, placebo-controlled, randomized clinical trial, PloS One 11 (2016) 1–16; https://doi.org/10.1371/journal.pone.0154004

  • 15. D. Awotwe-Otto, C. Agarabi and M. A. Khan, An integrated process analytical technology (PAT) approach to monitoring the effect of supercooling on lyophilization product and process parameters of model monoclonal antibody formulations, J. Pharm. Sci. 103 (2014) 2042–2052; https://doi.org/10.1002/jps.24005

  • 16. S. M. Patel, S. L. Nail, M. J. Pikal, R. Geidobler, G. Winter, A. Hawe, J. Davagnino and S. R. Gupta, Lyophilized drug product cake appearance: What is acceptable, J. Pharm. Sci. 106 (2017) 1706–1721; http://dx.doi.org/10.1016/j.xphs.2017.03.014

  • 17. J. C. Kasper and W. Friess, The freezing step in lyophilisation: Physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals, Eur. J. Pharmaceut. Biopharmaceut. 78 (2011) 248–263; http://doi.org/10.1016/j.ejpb.2011.03.010

  • 18. E. Meister, A significant comparison between collapse and glass transition temperatures, Eur. Pharm. Rev. 13 (2008) 73–79.

  • 19. J. Horn and W. Friess, Detection of collapse and crystallization of saccharide, protein and mannitol formulations by optical fibers in lyophilization, Front. Chem. 6 (2018) 1–9; https://doi.org/10.3389/fchem.2018.00004

  • 20. G. Assegehegn, E. B.- de la Fuente, J. M. Franco and C. Gallegos, The importance of understanding the freezing step and its impact on freeze-drying process performance, J. Pharm. Sci. 108 (2019) 1378–1395; https://doi.org/10.1016/j.xphs.2018.11.039

  • 21. S. M. Patel, C. Bhugra and M. J. Pikal, Reduced Pressure Ice Fog technique for controlled ice nucleation during freeze-drying, AAPS PharmSciTech 10 (2009) 1406–1411; https://doi.org/10.1208/s12249-009-9338-7

  • 22. W. Abdelwahed, G. Degober and H. Fessi, Freeze-drying of nanocapsules: Impact of annealing on the drying process, Int. J. Pharm. 324 (2006) 74–82; https://doi.org/10.016/j.ijpharm.2006.06.047

  • 23. M. S. Arshad, Application of through-vial impedance spectroscopy as a novel process analytical technology for freeze drying, Phd Thesis, Leicester School of Pharmacy, De Montfort University, 2014; https://www.dora.dmu.ac.uk/xmlui/bitstream/handle/2086/10407/PhD%20Thesis%20So-hail%20Muhammad%20Arshad%20After%20corrections%20KW_JB_WS_GS%20approved.pdf;sequence=1, access date August 2, 2018.

  • 24. G. Smith, M. S. Arshad, E. Polygalov and I. Ermolina, Through-vial impedance spectroscopy of the mechanisms of annealing in the freeze-drying of maltodextrin: The impact of annealing hold time and temperature on the primary drying rate, J. Pharm. Sci. 103 (2014) 1799–1810; https://doi.org/10.1002/jps.23982

  • 25. P. Fonte, S. Reis and B. Sarmento, Facts and evidences on the lyophilisation of polymeric nanoparticles for drug delivery, J. Control. Release 225 (2016) 75–86; https://doi.org/10.1016/j.jconrel.2016.01.034

  • 26. X. Tang and M. J. Pikal, Design of freeze-drying processes for pharmaceuticals: practical advice, Pharm. Res. 21 (2004) 191–200; https://doi.org/10.1023/b:pham.0000016234.73023.75

  • 27. X. Lu and M. J. Pikal, Freeze-drying of mannitol-trehalose-sodium chloride-based formulations: The impact of annealing on dry layer resistance to mass transfer and cake structure, Pharm. Dev. Technol. 9 (2004) 85–95; https://doi.org/10.1081/PDT-120027421

  • 28. L. Rey and J. C. May, Freeze Drying/Lyophilization of Pharmaceutical and Biological Products, 3rd ed., Informa Healthcare, New York, London 2011.

  • 29. G. Smith, E. Polygalov, M. S. Arshad, T. Page, J. Taylor and I. Ermolina, An impedance-based process analytical technology for monitoring the lyophilisation process, Int. J. Pharm. 449 (2013) 72–83; http://dx.doi.org/10.1016/j.ijpharm,2013.03.060

  • 30. J. Frost, Multiple Regression Analysis: Use Adjusted R-Squared and Predicted R-Squared to Include the Correct Number of Variables; https://statisticsbyjim.com/regression/interpret-adjusted-r-squared-predicted-r-squared-regression/; access date November 11, 2019

  • 31. A. Hayes, R-Squared Definition, Updated May 8, 2019 https://www.investopedia.com/terms/r/r-squared.asp; access date November 11, 2019

  • 32. S. Raissi and R.-E. Farsani, Statistical process optimization through multi-response surface methodology, Int. J. Math.Comput. Sci. 3 (2009) 197–201.

  • 33. D. Bas and I. H. Boyaci, Modelling and optimization I: Usability of response surface methodology, J. Food Eng. 78 (2007) 836–845; https://doi.org/10.1016/j.jfoodeng.2005.11.024

OPEN ACCESS

Journal + Issues

Search