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 One11 (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. Drugs2 (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 Poster89http://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 Molecules20 (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