Pharmaceutical Research

, Volume 27, Issue 4, pp 521–526

Crystalline vs. Ionic Liquid Salt Forms of Active Pharmaceutical Ingredients: A Position Paper

  • Jelena Stoimenovski
  • Douglas R. MacFarlane
  • Katharina Bica
  • Robin D. Rogers
Commentary

Abstract

Why not consider liquid salt forms of active pharmaceutical ingredients (APIs) as an alternative versatile tool in the pharmaceutical industry? Recent developments have shown that known APIs can be readily converted into ionic liquids and that these novel phases often possess different properties (e.g., improved solubilities and dissolution rates), which may have a direct impact on the pharmacokinetics and pharmacodynamics of the drug. They may also offer the potential of novel and more efficient delivery modes, as well as patent protection for each of the new forms of the drug. Since these pharmaceutically active ionic liquids represent a thermodynamically stable phase, they avoid the troublesome issues surrounding polymorphism and “polymorphic transformation.” In some cases, an active cation and an active anion can be combined to produce a liquid possessing dual functionality. Here we examine and challenge the current industry reliance on crystalline APIs by discussing the breadth and potential impact of liquid salts as a possible approach to phase control.

KEY WORDS

active pharmaceutical ingredient delivery modes ionic liquid polymorphism salt 

REFERENCES

  1. 1.
    Heinrich Stahl P, Wermuth CG, editors. Handbook of Pharmaceutical Salts; Properties, Selection, and Use, VHCA and Wiley-VCH, 2008.Google Scholar
  2. 2.
    Paulekuhn GS, Dressman JB, Saal C. Trends in active pharmaceutical ingredient salt selection based on analysis of the orange book database. J Med Chem. 2007;50:6665–72.CrossRefPubMedGoogle Scholar
  3. 3.
    Brodin A, Nyqvist-Mayer A, Wadsten T, Forslund B, Broberg F. Phase diagram and aqueous solubility of the lidocaine-prilocaine binary system. J Pharm Sci. 1984;73:481–4.CrossRefPubMedGoogle Scholar
  4. 4.
    Byrn SR, Pfeiffer RR, Stephenson G. Solid-State Chemistry of Dugs, Inc. West Lafayette: SSCI; 1999.Google Scholar
  5. 5.
    Peterson ML, Hickey MB, Zaworotko MJ, Almarsson O. Expanding the scope of crystal form evaluation in pharmaceutical science. J Pharm Pharm Sci. 2006;9:317–26.PubMedGoogle Scholar
  6. 6.
    Dean PM, Turanjanin J, Yoshizawa-Fujita M, MacFarlane DR, Scott JL. Exploring an anti-crystal engineering approach to the preparation of pharmaceutically active ionic liquids. Cryst Growth Des. 2009;9:1137–45.CrossRefGoogle Scholar
  7. 7.
    Hough WL, Rogers RD. Ionic liquids then and now: from solvents to materials to active pharmaceutical ingredients. Bull Chem Soc Jpn. 2007;80:2262–9.CrossRefGoogle Scholar
  8. 8.
    Hough WL, Smiglak M, Rodriguez H, Swatloski RP, Spear SK, Daly DT, et al. The third evolution of ionic liquids: active pharmaceutical ingredients. New J Chem. 2007;31:1429–36.CrossRefGoogle Scholar
  9. 9.
    Hough-Troutman WL, Smiglak M, Griffin S, Reichert WM, Mirska I, Jodynis-Liebert J, et al. Ionic liquids with dual biological function: sweet and anti-microbial, hydrophobic quaternary ammonium-based salts. New J Chem. 2009;33:26–33.CrossRefGoogle Scholar
  10. 10.
    Karpinski PH. Polymorphism of active pharmaceutical ingredients. Chem Eng Technol. 2006;29:233–8.CrossRefGoogle Scholar
  11. 11.
    Rodriguez-Spong B, Price CP, Jayasankar A, Matzger AJ, Rodriguez-Hornedo N. General principles of pharmaceutical solid polymorphism. A supramolecular perspective. Adv Drug Delivery Rev. 2004;56:241–74.CrossRefGoogle Scholar
  12. 12.
    Singhal D, Curatolo W. Drug polymorphism and dosage form design: a practical perspective. Adv Drug Delivery Rev. 2004;56:335–47.CrossRefGoogle Scholar
  13. 13.
    Apotex wins latest round in generic Paxil litigation. http://www.nature.com/nrd/journal/v3/n6/full/nrd1423.html, (accessed 27/08/2009) 2004.
  14. 14.
    Draper P. Eutectic liquid drug formulation, (Can.). US: Application; 2007. p. 5.Google Scholar
  15. 15.
    Reichert WM, Holbrey JD, Vigour KB, Morgan TD, Broker GA, Rogers RD. Approaches to crystallization from ionic liquids: complex solvents-complex results, or, a strategy for controlled formation of new supramolecular architectures? Chem Commun. 2006;46:4767–79.CrossRefGoogle Scholar
  16. 16.
    MacFarlane DR, Forsyth SA, Golding J, Deacon GB. Ionic liquids based on imidazolium, ammonium and pyrrolidinium salts of the dicyanamide anion. Green Chem. 2002;4:444–8.CrossRefGoogle Scholar
  17. 17.
    Endres F, MacFarlane D, Abbott A, Editors. Electrodeposition from Ionic Liquids. Wiley-VCH, 2008.Google Scholar
  18. 18.
    Howlett PC, MacFarlane DR, Hollenkamp AF. High lithium metal cycling efficiency in a room-temperature ionic liquid. Electrochem Solid-State Lett. 2004;7:A97–A101.CrossRefGoogle Scholar
  19. 19.
    Armand M, Endres F, MacFarlane DR, Ohno H, Scrosati B. Ionic-liquid materials for the electrochemical challenges of the future. Nat Mater. 2009;8:621–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Welton T. Room-temperature ionic liquids. Solvents for synthesis and catalysis. Chem Rev. 1999;99:2071–83.CrossRefPubMedGoogle Scholar
  21. 21.
    Biswas A, Shogren RL, Stevenson DG, Willett JL, Bhowmik PK. Ionic liquids as solvents for biopolymers: acylation of starch and zein protein. Carbohydr Polym. 2006;66:546–50.CrossRefGoogle Scholar
  22. 22.
    Fujita K, MacFarlane DR, Forsyth M. Protein solubilising and stabilising ionic liquids. Chem Commun. 2005;4804–6.Google Scholar
  23. 23.
    Von Hagen J, Michelsen U. Use of ionic liquids for protein extraction, (Merck Patent G.m.b.H., Germany). DE: Application; 2006. p. 12.Google Scholar
  24. 24.
    Fujita K, Forsyth M, MacFarlane DR, Reid RW, Elliott GD. Unexpected improvement in stability and utility of cytochrome c by solution in biocompatible ionic liquids. Biotechnol Bioeng. 2006;94:1209–13.CrossRefPubMedGoogle Scholar
  25. 25.
    Fujita K, MacFarlane DR, Forsyth M, Yoshizawa-Fujita M, Murata K, Nakamura N, et al. Solubility and stability of cytochrome c in hydrated ionic liquids: effect of Oxo acid residues and kosmotropicity. Biomacromolecules. 2007;8:2080–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Ranke J, Stolte S, Stormann R, Arning J, Jastorff B. Design of sustainable chemical products-the example of ionic liquids. Chem Rev. 2007;107:2183–206.CrossRefPubMedGoogle Scholar
  27. 27.
    Demberelnyamba D, Kim K-S, Choi S, Park S-Y, Lee H, Kim C-J, et al. Synthesis and antimicrobial properties of imidazolium and pyrrolidinonium salts. Bioorg Med Chem. 2004;12:853–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Kumar V, Malhotra SV. Study on the potential anti-cancer activity of phosphonium and ammonium-based ionic liquids. Bioorg Med Chem Lett. 2009;19:4643–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Pernak J, Feder-Kubis J. Synthesis and properties of chiral ammonium-based ionic liquids. Chem-Eur J. 2005;11:4441–9.CrossRefGoogle Scholar
  30. 30.
    Pernak J, Goc I, Mirska I. Antimicrobial activities of protic ionic liquids with lactate anion. Green Chem. 2004;6:323–9.CrossRefGoogle Scholar
  31. 31.
    Pernak J, Sobaszkiewicz K, Foksowicz-Flaczyk J. Ionic liquids with symmetrical dialkoxymethyl-substituted imidazolium cations. Chem-Eur J. 2004;10:3479–85.CrossRefGoogle Scholar
  32. 32.
    Pernak J, Sobaszkiewicz K, Mirska I. Anti-microbial activities of ionic liquids. Green Chem. 2003;5:52–6.CrossRefGoogle Scholar
  33. 33.
    Carson L, Chau PKW, Earle MJ, Gilea MA, Gilmore BF, Gorman SP, et al. Antibiofilm activities of 1-alkyl-3-methylimidazolium chloride ionic liquids. Green Chem. 2009;11:492–7.CrossRefGoogle Scholar
  34. 34.
    Rogers RD, Seddon KR. Ionic liquids: industrial applications to green chemistry. American Chemical Society. 2003.Google Scholar
  35. 35.
    Goho A. The crystal form of a drug can be the secret to its success, 2004. www.sciencenews.org/articles/20040821/bob9.asp (accessed 27/08/2009).
  36. 36.
    Legen I, Salobir M, Kerc J. Comparison of different intestinal epithelia as models for absorption enhancement studies. Int J Pharm. 2005;291:183–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Borka L, Haleblian JK. Crystal polymorphism of pharmaceuticals. Acta Pharm Jugosl. 1990;40:71–94.Google Scholar
  38. 38.
    Schuster D, Laggner C, Langer T. Why drugs fail - a study on side effects in new chemical entities. Curr Pharm Des. 2005;11:3545–59.CrossRefPubMedGoogle Scholar
  39. 39.
    Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Delivery Rev. 2007;59:603–16.CrossRefGoogle Scholar
  40. 40.
    Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Delivery Rev. 2001;48:27–42.CrossRefGoogle Scholar
  41. 41.
    O'Neil MJ, Smith A, Heckelman PE. The Merck Index. Whitehouse Station, NJ: Merck & Co. Inc.; 2001.Google Scholar
  42. 42.
    Zhao H. Are ionic liquids kosmotropic or chaotropic? An evaluation of available thermodynamic parameters for quantifying the ion kosmotropicity of ionic liquids. J Chem Technol Biotechnol. 2006;81:877–91.CrossRefGoogle Scholar
  43. 43.
    Bhargava BL, Klein ML. Initial stages of aggregation in aqueous solutions of ionic liquids: molecular dynamics studies. J Phys Chem B. 2009;113:9499–505.CrossRefPubMedGoogle Scholar
  44. 44.
    Canongia Lopes Jose N, Costa Gomes Margarida F, Padua Agilio AH. Nonpolar, polar, and associating solutes in ionic liquids. J Phys Chem B. 2006;110:16816–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Jiang W, Wang Y, Voth GA. Molecular dynamics simulation of nanostructural organization in ionic liquid/water mixtures. J Phys Chem B. 2007;111:4812–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Nama D, Kumar PGA, Pregosin PS, Geldbach TJ, Dyson PJ. 1H, 19F-HOESY and PGSE diffusion studies on ionic liquids: the effect of co-solvent on structure. Inorg Chim Acta. 2006;359:1907–11.CrossRefGoogle Scholar
  47. 47.
    Zhao Y, Gao S, Wang J, Tang J. Aggregation of ionic liquids [C(n)mim]Br (n = 4, 6, 8, 10, 12) in D2O: a NMR study. J Phys Chem B. 2008;112:2031–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Fraser KJ, Izgorodina EI, Forsyth M, Scott JL, MacFarlane DR. Liquids intermediate between “molecular” and “ionic” liquids: Liquid Ion Pairs? Chem Commun. 2007;3817–9.Google Scholar
  49. 49.
    MacFarlane DR, Forsyth M, Izgorodina EI, Abbott AP, Annat G, Fraser K. On the concept of ionicity in ionic liquids. PCCP. 2009;11:4962–7.PubMedGoogle Scholar
  50. 50.
    Hamamoto H, Miwa Y. Tape preparation comprising etodolac in ionic liquid form, (Medrx Co., Ltd., Japan). WO: Application; 2009. p. 35Google Scholar
  51. 51.
    Fei Z, Geldbach TJ, Zhao D, Dyson PJ. From dysfunction to bis-function: on the design and applications of functionalized ionic liquids. Chem-Eur J. 2006;12:2122–30.CrossRefGoogle Scholar
  52. 52.
    Wan LS. Interaction of salicylic acid with quaternary ammonium compounds. J Pharm Sci. 1968;57:1903–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Duan Z, Gu Y, Zhang J, Zhu L, Deng Y. Protic pyridinium ionic liquids: synthesis, acidity determination and their performances for acid catalysis. J Mol Catal A: Chem. 2006;250:163–8.CrossRefGoogle Scholar
  54. 54.
    Janus E, Goc-Maciejewska I, Lozynski M, Pernak J. Diels-Alder reaction in protic ionic liquids. Tetrahedron Lett. 2006;47:4079–83.CrossRefGoogle Scholar
  55. 55.
    Ogihara W, Kosukegawa H, Ohno H. Proton-conducting ionic liquids based upon multivalent anions and alkylimidazolium cations. Chem Commun. 2006;3637–9.Google Scholar
  56. 56.
    Yoshizawa M, Xu W, Angell CA. Ionic liquids by proton transfer: vapor pressure, conductivity, and the relevance of delta pKa from aqueous Solutions. J Am Chem Soc. 2003;125:15411–9.CrossRefPubMedGoogle Scholar
  57. 57.
    Stoimenovski J, MacFarlane DR. Pharmaceutically active protic ionic liquids, congress on ionic liquids 3. Australia: Cairns; 2009.Google Scholar
  58. 58.
    Johansson KM, Izgorodina EI, Forsyth M, MacFarlane DR, Seddon KR. Protic ionic liquids based on the dimeric and oligomeric anions: [(AcO)xH(x-1)]. PCCP. 2008;10:2972–8.PubMedGoogle Scholar
  59. 59.
    Belieres J-P, Angell CA. Protic ionic liquids: preparation, characterization, and proton free energy level representation. J Phys Chem B. 2007;111:4926–37.CrossRefPubMedGoogle Scholar
  60. 60.
    Kennedy DF, Drummond CJ. Large aggregated ions found in some protic ionic liquids. J Phys Chem B. 2009;113:5690–3.CrossRefPubMedGoogle Scholar
  61. 61.
    Bica K, Rogers RD. Confused ions in ionic liquids—pharmaceutically active ionic liquids composed of oligomers, Congress on Ionic Liquids 3, Cairns, Australia; 2009Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jelena Stoimenovski
    • 1
  • Douglas R. MacFarlane
    • 1
  • Katharina Bica
    • 2
    • 3
  • Robin D. Rogers
    • 2
    • 3
  1. 1.Monash UniversityClaytonAustralia
  2. 2.The Queen’s University of BelfastBelfastUK
  3. 3.The University of AlabamaTuscaloosaUSA

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