Solubilization of ibuprofen for freeze dried parenteral dosage forms

Maja Preskar 1 , Tomislav Vrbanec 1 , Franc Vrečer 1 , 2 , Primož Šket 3 , Janez Plavec 3 ,  and Mirjana Gašperlin 2
  • 1 , SI- 8000, Novo mesto, Slovenia
  • 2 University of Ljubljana, Faculty of Pharmacy, SI- 1000, Ljubljana, Slovenia
  • 3 Slovenian NMR Center, National Institute of Chemistry, , SI- 1000, Ljubljana, Slovenia

Abstract

Ibuprofen, a weakly acidic non-steroidal anti-inflammatory drug having poor aqueous solubility, is a challenging drug for the development of pharmaceutical formulations, resulting in numerous research attempts focusing on improvement of its solubility and consequently bioavailability. Most studies have been done for solid dosage forms, with very little attention paid to parenterals. Hence, the main purpose of the present study was to enhance ibuprofen solubility as a result of formulation composition and the freeze drying process. Moreover, the purpose was to prepare a freeze dried dosage form with improved ibuprofen solubility that could, after simple reconstitution with water for injection, result in an isotonic parenteral solution. Solubility of ibuprofen was modified by various excipients suitable for parenteral application. Drug interactions with selected excipients in the final product/lyophilisate were studied by a combined use of XRPD, DSC, Raman and ss-NMR. Analyses of lyophilized samples showed solubility enhancement of ibuprofen and in situ formation of an ibuprofen salt with the alkaline excipients used.

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  • 1. P. Khadka, J. Ro, H. Kim, I. Kim, J. T. Kim, H. Kim, J. M. Cho, G. Yun and J. Lee, Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability, Asian J. Pharm. Sci. 9 (2014) 304–316; https://doi.org/10.1016/j.ajps.2014.05.005

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

  • 3. A. Kotar, M. Kotar, P. Šket and J. Plavec, Potential of solid-state NMR and SEM in characterization of tablets of ibuprofen, Curr. Pharm. Anal. 11 (2015) 124–130; https://doi.org/10.2174/1573412910666141111231325

  • 4. 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

  • 5. 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

  • 6. 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

  • 7. 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

  • 8. A. Tan, N. G. Eskandar, S. Rao and C. A. Prestidge, First in man bioavailability and tolerability studies of a silica-lipid hybrid (Lipoceramic) formulation: A phase I study with ibuprofen, Drug. Deliv. Trans. Re. 4 (2014) 212–221; https://doi.org/10.1007/s13346-013-0172-9

  • 9. S. G. Potta, S. Minemi, R. K. Nukala, C. Peinado, D. A. Lamprou, A. Urquhart and D. Douroumis, Preparation and characterization of ibuprofen solid lipid nanoparticles with enhanced solubility, J. Microencapsul. 28 (2011) 74–81; http://doi.org/10.3109/02652048.2010.529948

  • 10. S. Melzig, D. Niedbalka, C. Schilde and A. Kwade, Spray drying of amorphous ibuprofen nanoparticles for the production of granules with enhanced drug release, Colloids Surf. A Physicochem. Eng. Asp. 536 (2018) 133–141; https://doi.org/10.1016/j.colsurfa.2017.07.028

  • 11. D. Bolten, R. Lietzow and M. Türk, Solubility of ibuprofen, phytosterol, salicylic acid, and naproxen in aqueous solutions, Chem. Eng. Technol. 36 (2013) 426–434; https://doi.org/10.1002/ceat.201200510

  • 12. A. A. Mamun, A. Masum, F. Sharmin, A. Islam and S. Reza, Enhancement of solubility and dissolution characteristics of ibuprofen by solid dispersion technique, Dhaka University, J. Pharm. Sci. 11 (2012) 1–6; https://doi.org/10.3329/dujps.v11i1.12480

  • 13. M. M. Gupta, M. G. Patel, N. S. Patel and M. Kedawat, Enhancement of dissolution rate of ibuprofen by preparing solid dispersion using different methods, Int. J. Pharm. Pharm. Sci. 3 (2011) 204–206.

  • 14. R. P. Dugar, B. Y. Gajera and R. H. Dave, Fusion method for solubility and dissolution rate enhancement of ibuprofen using block copolymer poloxamer 407, AAPS PharmSciTech. 17 (2016) 1428–1440; http://doi.ord/10.1208/s12249-016-0482-6

  • 15. M. Dixit, P. Kulkarni, P. Selvam and S. Mohsin, Preparation and characterization of freeze dried crystals of ibuprofen, Int. Res. J. Pharm. 2 (2011) 255–258.

  • 16. Karsono, J. Tanuwijaya and D. Fatma, Formulation of ibuprofen orally disintegrating tablets (ODTs) by lyophilization method using gelatin and mannitol, Int. J. PharmTech. Res. 6 (2014) 996–1002.

  • 17. M. Di Cagno, P. C. Stein, N. Skalko-Basnet, M. Brandl and A. Bauer-Brandl, Solubilization of ibuprofen with β-cyclodextrin derivatives: Energetic and structural studies, J. Pharm. Biomed. Anal. 55 (2011) 446–451; https://doi.org/10.1016/j.jpba.2011.02.022

  • 18. K. Kagkadis, D. M. Rekkas, P. Dallas and N. H. Choulis, A freeze-dried injectable form of ibuprofen: development and optimisation using response surface methodology, PDA J. Pharm. Sci. Technol. 50 (1996) 317–323; https://doi.org/10.1016/S0378-5173(97)00332-3

  • 19. S. K. Patel, D. Kumar, A. P. Waghmode and A. S. Dhabale, Solubility enhancement of ibuprofen using hydrotopic agents, Int. J. Pharm. Life Sci. 2 (2011) 542–545.

  • 20. S.-H. Park and H.-K. Choi, The effects of surfactants on the dissolution profiles of poorly water-soluble acidic drugs, Int. J. Pharm. 321 (2006) 35–41; https://doi.org/10.1016/j.ijpharm.2006.05.004

  • 21. S. H. Soltanpour and A. Jouyban, Solubility of acetaminophen and ibuprofen in binary and ternary mixtures of polyethylene glycols 200 and 400, propylene glycol, and water at 25 °C, Chem. Eng. Commun. 201 (2014) 1606–1619; https://doi.org/10.1080/00986445.2013.821609

  • 22. M. A. Filippa and E. I. Gasull, Ibuprofen solubility in pure organic solvents and aqueous mixtures of cosolvents: Interactions and thermodynamic parameters relating to the solvation process, Fluid Phase Equilibr. 354 (2013) 185–190; https://doi.org/10.1016/j.fluid.2013.06.032

  • 23. M. G. Volonte, P. D. Valora, A. Cingolani and M. Ferrara, Stability of ibuprofen in injection solutions, Am. J. Health-Syst. Ph. 62 (2005) 630–633.

  • 24. T. Lee and Y. W. Wang, Initial salt screening procedures for manufacturing ibuprofen, Drug Dev. Ind. Pharm. 35 (2009) 555–567; https://doi.org/10.1080/03639040802459452

  • 25. U.S. Food and Drug Administration; FDA Approved Drugs; Ibuprofen http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=ibuprofen&SearchType=BasicSearch; access date April 2017.

  • 26. The ABDA – Federal Union of German Associations of Pharmacists; access date April 2017.

  • 27. Highlights of prescribing information; NDA 022348 Caldolor; https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022348s010lbl.pdf; access date May 25, 2018.

  • 28. J. Manrique and F. Martinez, Solubility of ibuprofen in some ethanol + water cosolvent mixtures at several temperatures, Lat. Am. J. Pharm. 26 (2007) 344–354.

  • 29. M. L Hart, D. P Do, R. A Ansari and S.A A. Rizvi, Brief overview of various approaches to enhance drug solubility, J. Dev. Drugs 2 (2013) 1–7; https://doi.org/10.4172/2329-6631.1000115

  • 30. J. N. Patel, D. M. Rathod, N. A. Patel and M. K. Modasiya, Techniques to improve the solubility of poorly soluble drugs, Int. J. Pharm. Life Sci. 3 (2012) 1459–1469.

  • 31. G. G. Z. Zhang, S. Y. L. Paspal, R. Suryanarayanan and D. J. W. Grant, Racemic species of sodium ibuprofen: Characterization and Polymorphic Relationships, J. Pharm. Sci. 92 (2003) 1356–1366; https://doi.org/10.1002/jps.10393

  • 32. 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; https://doi.org/10.1016/j.ejpb.2011.03.010

  • 33. R. C. Rowe, P. J. Sheskey and M. E. Quinn, Mannitol, Sodium chloride, Dextrose and Succrose, in Handbook of Pharmaceutical Excipients (Ed. R. C. Rowe), 6th ed., Pharmaceutical Press and American Pharmacists Association, London/Washington, UK/USA 2009, pp. 426, 641, 224 and 704.

  • 34. S. R.-Royo, A. Martin, A. L. Simplicio, A. Matias, G. Bansaghi and M. J. Cocero, Separation of ibuprofen enantiomers by diastereomic salt formation and antisolvente precipitation in supercritical carbon dioxide, Poster 89, http://www.isasf.net/fileadmin/files/Docs/Graz/HtmlDir/Papers/P89.pdf; access date May 25, 2018

  • 35. M. Geppi, S. Guccione, G. Mollica, R. Pignatello and C. Veracini, Molecular properties of ibuprofen and its solid dispersions with eudragit RL100 studied by solid state nuclear magnetic resonance, Pharm. Res. 22 (2005) 1544–1555; https://doi.org/10.1007/s11095-005-6249-5

  • 36. F. G. Vogt, Characterization of pharmaceutical compounds by solid-state NMR, eMagRes. 4 (2015) 255–268; https://doi.org/10.1002/9780470034590.emrstm1393

  • 37. R. K. Harris, Applications of solid-state NMR to pharmaceutical polymorphism and related matters, J. Pharm. Pharmacol. 59 (2007) 225–239; https://doi.org/10.1211/jpp.59.2.0009

  • 38. T. Kitak, A. Dumičić, O. Planinšek, R. Šibanc and S. Srčič, Determination of solubility parameters of ibuprofen and ibuprofen lysinate, Molecules 20 (2015) 21549–21568; https://doi.org/10.3390/molecules201219777

  • 39. P. Bustamante, M. A. Peña and J. Barra, The modified extended Hansen method to determine partial solubility parameters of drug containing a single hydrogen bonding group and their sodium derivatives: benzoic acid/Na and ibuprofen/Na, Int. J. Pharm. 194 (2000) 117–124; https://doi.org/10.1016/S0378-5173(99)00374-9

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