Ionic Liquids in Drug Delivery: History
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Sónia N. Pedro
,
Carmen S. R. Freire
,
Armando J. D. Silvestre
,
Mara G. Freire

Ionic liquids (ILs) are molten salts composed of a large organic cation and an organic/inorganic anion. The large dimensions of their ions lead to charge dispersion, which makes difficult the formation of a regular crystalline structure. Due to their unique properties, ILs have been applied in the crystallization of active pharmaceutical ingredients (APIs), as solvents, co-solvents and emulsifiers in drug formulations, as pharmaceuticals (API-ILs) aiming liquid therapeutics, and in the development and/or improvement of drug-delivery-based systems.

  • Active pharmaceutical ingredients
  • Drug delivery
  • Ionic liquids

Pharmaceuticals play a major role in medical care, boosting life quality and expectancy, especially when considering chronic diseases [1]. The global prescription of medicines is forecast to grow up to nearly $1.2 trillion by 2022 [2]. Although active pharmaceutical ingredients (APIs) can be commercialized in several dosage forms, crystalline forms have been the preferred option [3][4]. However, 40 to 70% of the drugs under development present low water-solubility, which may compromise the bioavailability and therapeutic efficacy and, thus, fail in the later stages of development [5][6]. The irregular gastrointestinal absorption of solid forms, along with the low therapeutic efficiency and possible toxicity and side-effects of polymorphs, are major concerns to overcome [7]. For instance, large differences in bioavailability among different polymorphs require different drug dosages [8]. On the other hand, the therapeutic dosage of a certain API can correspond to a toxic or potential lethal dose if the wrong polymorph is administered. Polymorphism issues result in significant economic losses in sales and in R&D to enable novel formulations back into the market [9][10].

Beyond the well-known downsides of polymorphism, the APIs’ solubility in aqueous solution, dissolution, and bioavailability are also dependent on particle size and properties [11]. Attempting to improve the drugs solubility in water as well as their bioavailability, several strategies have been investigated, especially when the oral route is envisaged [5][6]. Nevertheless, most of these strategies still use large quantities of organic solvents in the manufacturing process of these formulations, particularly to induce the crystallization of a given polymorphic form and particle size, having associated health and environmental concerns [12]. Furthermore, solvent molecules can be incorporated into the crystal structure of the API during the crystallization process [13]. Therefore, when considering the use of organic solvents, they must be removed from the API or their levels must be controlled in order to ensure human consumption safety [12]. Despite the existence of extensive literature describing novel and “greener” solvents to this purpose, there is still some reluctance by the pharmaceutical industry to accept and implement these alternatives [14][15][16].

In the above context, liquid forms of APIs are appealing solutions to avoid both polymorphism and improve low-water solubility constraints, while allowing to reduce organic solvents use. The pharmaceutical industry has relied on eutectic mixtures for this purpose, shortly exploring other options for commercialization [17][18]. In addition to these, ionic liquids (ILs) disclose high potential in the pharmaceutical field, which is mainly due to their high versatility in terms of chemical structure design towards a target application. ILs are molten salts that are composed of a large organic cation and an organic/inorganic anion. The large dimensions of their ions lead to charge dispersion, which makes difficult the formation of a regular crystalline structure [19][20]. ILs display a set of unique features, from which is possible to highlight, if properly designed, their high thermal and chemical stability and a strong solvation ability for a wide variety of compounds [21]. The proper selection of cation-anion combinations in ILs enables the use of drugs as ion components, allowing for the conversion of solid active pharmaceutical ingredients into liquid forms (API-ILs). Thus, this strategy solves the problem of polymorphism and provides improved bioavailability, and ideally boosts therapeutic properties [3][22].

Because of the unique properties of ILs, their application in the pharmaceutical field has been extended far beyond the development of novel liquid forms (API-ILs), being investigated as well in other stages of drug development and delivery. The number of publications related to the application of ILs in the pharmaceutical field has grown exponentially in the past 20 years, as illustrated in Figure 1. ILs have been applied in the development of purification platforms for pharmaceuticals for which some recent review manuscripts exist [23][24][25]. Other relevant reviews and book chapters recognizing the advances of ILs in different areas of pharmaceuticals development, spanning from their formulation, biological activity, and application on drug delivery are also available [22][26][27][28][29][30][31][32][33][34].

Figure 1. Number of publications per year in a twenty years perspective related to ILs and active pharmaceutical ingredients (APIs) (number of articles, reviews and book chapters according to a ScienceDirect database search using as keywords “ionic liquids”, “active pharmaceutical ingredients”, and “drug delivery”) (left). Overview of the ILs’ applications in the pharmaceutical field reported hitherto (right).

This entry is adapted from the peer-reviewed paper 10.3390/ijms21218298

References

  1. World Health Organization Medicines Strategy-Contries at the Core. Available online: https://apps.who.int/iris/bitstream/handle/10665/84307/WHO_EDM_2004.5_eng.pdf;jsessionid=0F733DD987692B73A234E9FB8C10D40B?sequence=1 (accessed on 20 May 2020).
  2. Ende, M.T.; Ende, D.J. Chemical Engineering in the Pharmaceutical Industry: Drug Product Design, Development and Modeling, 2nd ed.; Wiley: Hoboken, NJ, USA, 2019.
  3. Shamshina, J.L.; Rogers, R.D. Overcoming the problems of solid state drug formulations with ionic liquids. Ther. Deliv. 2014, 5, 489–491.
  4. Byrn, S.; Pfeiffer, R.; Ganey, M.; Hoiber, C.; Poochikian, G. Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations. Pharm. Res. 1995, 12, 945–954.
  5. Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: Review of recent advances and business prospects. Acta Pharm. Sin. B 2015, 5, 442–453.
  6. Savjani, K.T.; Gajjar, A.K.; Savjani, J.K. Drug Solubility: Importance and Enhancement Techniques. ISRN Pharm. 2012, 2012, 195727.
  7. Brittain, H.G.; Grant, D.J.R. Effects of Polymorphism and Solid-State Solvation on Solubility and Dissolution Rate. In Polymorphism in Pharmaceutical Solids; Taylor and Francis: Abingdon, UK, 2009; pp. 436–480.
  8. Censi, R.; Di Martino, P. Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs. Molecules 2015, 20, 18759–18776.
  9. Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Ritonavir: An Extraordinary Case of Conformational Polymorphism. Pharm. Res. 2001, 18, 859–866.
  10. Hulme, A.T.; Price, S.L.; Tocher, D.A. A New Polymorph of 5-Fluorouracil Found Following Computational Crystal Structure Predictions. J. Am. Chem. Soc. 2005, 127, 1116–1117.
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  13. El-Yafi, A.K.E.Z.; El-Zein, H. Technical crystallization for application in pharmaceutical material engineering: Review article. Asian J. Pharm. Sci. 2015, 10, 283–291.
  14. Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S.M.S. Chemical and biochemical transformations in ionic liquids. Tetrahedron 2005, 61, 1015–1060.
  15. Olivier-bourbigou, H.; Magna, L. Ionic liquids: Perspectives for organic and catalytic reactions. J. Mol. Catal. A Chem. 2002, 183, 419–437.
  16. Cave, G.W.V.; Raston, L.; Scott, J.L. Recent advances in solventless organic reactions: Towards benign synthesis with remarkable versatility. Chem. Commun. 2001, 2001, 2159–2169.
  17. Ehrenström-Reiz, G.; Reiz, S.; Stockman, O. Topical Anaesthesia with EMLA, a New Lidocaine-Prilocaine Cream and the Cusum Technique for Detection of Minimal Application Time. Acta Anaesthesiol. Scand. 1983, 27, 510–512.
  18. Shamshina, J.L.; Kelley, S.P.; Gurau, G.; Rogers, R.D. Develop ionic liquid drugs. Nature 2015, 528, 188–189.
  19. Freire, M.G.; Cláudio, A.F.M.; Araújo, J.M.M.; Coutinho, J.A.P.; Marrucho, I.M.; Canongia Lopes, J.N.; Rebelo, L.P.N. Aqueous biphasic systems: A boost brought about by using ionic liquids. Chem. Soc. Rev. 2012, 41, 4966–4995.
  20. Earle, M.J.; Esperança, J.M.S.S.; Gile, M.; Lopes, J.N.C.; Rebelo, L.P.N.; Magee, J.W.; Seddon, K.R.; Widegren, J.A. The distillation and volatility of ionic liquids. Nature 2005, 439, 831–834.
  21. Cláudio, A.F.M.; Neves, M.C.; Shimizu, K.; Canongia Lopes, J.N.; Freire, M.G.; Coutinho, J.A.P. The magic of aqueous solutions of ionic liquids: Ionic liquids as a powerful class of catanionic hydrotropes. Green Chem. 2015, 17, 3948–3963.
  22. Shamshina, J.L.; Barber, P.S.; Rogers, R.D. Ionic liquids in drug delivery. Expert Opin. Drug Deliv. 2013, 10, 1367–1381.
  23. Castro, L.; Pereira, P.; Freire, M.; Pedro, A. Progress in the Development of Aqueous Two-Phase Systems Comprising Ionic Liquids for the Downstream Processing of Protein- Based Biopharmaceuticals. Am. Pharm. Rev. 2019, 1–6.
  24. Ventura, P.M.; Silva, F.A.; Quental, M.V.; Mondal, D.; Freire, M.G. Ionic-Liquid-Mediated Extraction and Separation Processes for Bioactive Compounds: Past, Present, and Future Trends. Chem. Rev. 2017, 117, 6984–7052.
  25. McQueen, L.; Lai, D. Ionic liquid aqueous two-phase systems from a pharmaceutical perspective. Front. Chem. 2019, 7.
  26. Egorova, K.S.; Ananikov, V.P. Biological Activity of Ionic Liquids Involving Ionic and Covalent Binding: Tunable Drug Development Platform. In Encyclopedia of Ionic Liquids; Springer: Berlin/Heidelberg, Germany, 2019; pp. 1–8. ISBN 9789811067396.
  27. Egorova, K.S.; Gordeev, E.G.; Ananikov, V.P. Biological Activity of Ionic Liquids and Their Application in Pharmaceutics and Medicine. Chem. Rev. 2017, 117, 7132–7189.
  28. Tanner, E.E.L.; Curreri, A.M.; Balkaran, J.P.R.; Selig-wober, N.C.; Yang, A.B.; Kendig, C.; Fluhr, M.P.; Kim, N.; Mitragotri, S. Design Principles of Ionic Liquids for Transdermal Drug Delivery. Adv. Mater. 2019, 31, 1901103.
  29. Dobler, D.; Schmidts, T.; Klingenhöfer, I.; Runkel, F. Ionic liquids as ingredients in topical drug delivery systems. Int. J. Pharm. 2013, 441, 620–627.
  30. Adawiyah, N.; Moniruzzaman, M.; Hawatulaila, S.; Goto, M. Ionic liquids as a potential tool for drug delivery systems. Med. Chem. Commun. 2016, 7, 1881–1897.
  31. Marrucho, I.M.; Branco, L.C.; Rebelo, L.P.N. Ionic Liquids in Pharmaceutical Applications. Annu. Rev. Chem. Biomol. Eng. 2014, 5, 527–546.
  32. Huang, W.; Wu, X.; Qi, J.; Zhu, Q.; Wu, W.; Lu, Y.; Chen, Z. Ionic liquids: Green and tailor-made solvents in drug delivery. Drug Discov. Today 2020, 25, 901–908.
  33. Frizzo, C.P.; Gindri, I.M.; Tier, A.Z.; Buriol, L.; Moreira, D.N.; Martins, M.A.P. Pharmaceutical Salts: Solids to Liquids by Using Ionic Liquid Design. In Ionic Liquids—New Aspects for the Future; IntechOpen: London, UK, 2013; pp. 557–579.
  34. Moniruzzaman, M.; Mahmood, H.; Goto, M. Chapter 15: Ionic Liquid Based Nanocarriers for Topical and Transdermal Drug Delivery. In Ionic Liquid Devices; Royal Society of Chemistry: London, UK, 2017; pp. 390–403.
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