Ionic Liquids as Pharmaceutical Salts: A Historical Perspective

Chapter 1

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Ionic Liquids as Pharmaceutical Salts: A Historical Perspective Vineet Kumar and Sanjay V. Malhotra* Laboratory of Synthetic Chemistry, SAIC-Frederick, Inc., National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA *[email protected]

Design and synthesis of pharmaceutically acceptable salts is one of the prime aspect of drug development. An estimated half of all drugs used in medicine are administered as salts. The salt formation of drug candidates has been recognized as an essential preformulation task. Salt formation of APIs can improve their aqueous solubility, industrial processing, safety aspects and sometimes biological properties. These properties can be further enhanced by changing counterion of the active component. Though there is no concerned effort of finding applications of ionic liquids in the pharmaceutical arena in recent years, a detailed survey of the literature shows that pharmaceutical salts having properties now termed as ‘ionic liquids’ have existed for a long time. In this chapter a historical overview of ‘ionic liquid like pharmaceutical salts’, their importance and application in drug development has been described.

Pharmaceutical Salts: An Overview The first nitrogen-containing bases (also known as ‘vegetable alkalis’) extracted from plant materials, and later termed as alkaloids were isolated and purified as well-crystallizing salts. These salts were found to be more stable and water-soluble in comparison to free bases which qualifies them as the preferred forms for use as therapeutic agents e.g. morphine hydrochloride, atropine sulfate, © 2010 American Chemical Society In Ionic Liquid Applications: Pharmaceuticals, Therapeutics, and Biotechnology; Malhotra, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2010.


quinine sulfate, pilocarpine nitrate, codeine phosphate, etc. Among endogenous biological agents, most of the neutrotransmitters biologically derived from amino acids, are also nitrogenous bases able to form salts (1). The salt formation of a drug substance is a critical step in drug development (1, 2). An estimated 50% of all drug molecules are administered as salts. The suboptimal physicochemical or biopharmaceutical properties of a drug can be overcome by pairing a basic or acidic drug molecule with a counterion to create a salt version of the drug. Such salts may offer advantages over the corresponding free drug in terms of physical properties such as melting point (thermal stability), crystallinity, hygroscopicity, dissolution rate, or solubility (bioavailability). From a pharmaceutical viewpoint the melting enthalpy, melting temperature and solubility are of particular importance, both because of their routine measurement and due to their potential influence on processing and bioavailability (3). The process is a simple way to modify the properties of a drug with ionizable functional groups to overcome undesirable features of the parent drug (4). This fact underlines the importance of salt formation for drugs that are designed, developed, and marketed after a rigorous research and development program. Salt forms of drugs have a large effect on quality, safety, and performance of drug. The selected salt ion can significantly influence the pharmacokinetics of a drug candidate, especially the absorption or membrane-transfer process. As a result, the time course of its pharmacodynamic and toxicological effects may undergo a modification or modulation. This can significantly assist chemists and formulators in various aspects of drug discovery and development (5). This is also the reason why regulatory authorities have started to treat the new salt of a registered drug as a new chemical entity (1).

Ionic Liquids: Properties and Applications Main advantages of ionic liquids (ILs) as compared to common molecular organic solvents are their negligible vapour pressure, resulting in reduced inhalatory exposure, absence of flammability, and their high variability concerning chemical structure of headgroups, substituents and anions. These variabilities and combinations thereof lead to an enormous number of theoretically accessible ionic liquids. The possibility to modify structural elements in order to optimise technological features like solvation properties, viscosity, conductivity and thermal as well as electrochemical stability is ideal in terms of technical applicability. Over the years, these neoteric salts have been reviewed extensively for their wide range of applications including organic synthesis, electrochemistry, chromatography, transition metal catalysis, biocatalytic transformations, asymmetric synthesis, polymers, biomaterials and material science, etc. Most of the new applications of ILs take advantage of the unique combinations of chemical and physical properties due to their dual-functional (two component) nature and their inherent design flexibility which allow targeted synthesis of ‘tuned’ material. ILs make a unique architectural platform on which, at least potentially, the properties of both cation and anion can be independentaly modified, enabling 2 In Ionic Liquid Applications: Pharmaceuticals, Therapeutics, and Biotechnology; Malhotra, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2010.


tunability in the design of new functional materials, while retaining the core desired features of an IL (6, 7). However, concerning the risk assessment for man and the environment this structural variability presents an almost insurmountable problem as it is impossible to generate profound knowledge of the effects on human health and the environment for every single compound in this heterogeneous substance group. Therefore, there is a growing attention towards the environmental and mammalian toxicity of these salts. There have been constant efforts in recent years for establishing the structure activity relationship between these vast variety of salts and their toxicity (8). On the subcellular toxicity level of ionic liquids, enzyme inhibition data have been published for the acetylcholinesterase (AChE)(9) and AMP deaminase (10). Other studies of biological effects of ionic liquids on microorganisms and cell cultures in different test systems including HeLa (11), IPC-81 (12), HT-29(13) and CaCo-2(13) cells have also been reported. The results so far show that the most important property of ILs, is their ‘tunability’ which also apply for their toxicity and one can design biodegradable ILs which are non-toxic for humans and environment.

Ionic Liquids as Pharmaceuticals Ionic liquids have been extensively studied for the replacement of VOCs in organic chemistry for the synthesis of biologically active compounds including APIs. However, the pharmaceutical industry does not appear to take ILs seriously as solvents due to issues of their purity, toxicity, and regulatory approval. But the applications of ILs in pharmaceuticals are not limited only as reaction medium. Though there is no concerned effort of finding applications of ILs in the pharmaceutical arena in recent years, a detailed survey of the literature shows that pharmaceutical salts having properties now termed as ‘ionic liquids’ have existed for a long time. There are numerous examples in literature where pharmaceutically active compounds are salts of an acitve ion in combination with a relatively simple and inert counterion. The combined ion pair possess properties that are similar to those compounds now termed as ‘ionic liquids’. Table 1 shows examples of such ‘ionic liquid like pharmaceutical salts’, categorized by their biological activity where the active cation has been combined with an inert anion to give the final drug molecule. On the other hand a suitable drug can be combined with a second active substance by salt formation to give an ionic liquid like compound. Upon dissolution, such a molecular drug combination will dissociate in the body fluids, whereupon the cationic and anionic components follow their independent kinetic and metabolid pathways. This class of pharmaceutical salt pairs i.e. composed of both cation and anion as active ingredients and having ioinc liquid like properties are known in literature for a long time. Exchanging the inert counterion of an active drug with a pharmaceutically active counterion can change their phyisco-chemical properties e.g. melting point, solubility, etc.; and also pharmaceutical properties like bioavailability, stability, permeability. In principle 3 In Ionic Liquid Applications: Pharmaceuticals, Therapeutics, and Biotechnology; Malhotra, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2010.

each component of a drug salt i.e. the active entity and the counter ion (which itself can be an active component with simlar or different effects), can excert its own biological effects on a living organism. The counter-ion can be chosen to synergistically enhance the desired effects or to neutralize unwanted side effects of the active entity. The counter-ion can also be chosen to pharmacologically act independently, but therapeutically in a synergestic manner. Examples of these pharmacutical salts, their biologocal activities and literature references are given in Table 2.


Conclusion and Future Direction Most of the active salts given in Tables 1 and 2 structurally resemble the class of compounds now known as ‘ionic liquids’. It is important to note that some of these salts were reported in literature over a century ago. However, its only during the last two decades that there have been significant efforts to develop an understanding of the physico-chemical of ILs which ahs lead to their wide range of applications. Obviously, much more research has to be done to explore their biomedical applications. Perhaps, we should revisit the ‘ionic liquid-like compounds with pharmaceutical and/or biological application’ already reported in the literature. A better undersating of their properties (especially their toxicity could help the IL community in designing biologically active and useful ILs. A modular IL starategy has the potential to transform the pharmaceutical intustry in ways never expected. This approach can provide a platform for improved activity with new treatment options or even personalized medication.

4 In Ionic Liquid Applications: Pharmaceuticals, Therapeutics, and Biotechnology; Malhotra, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2010.


Table 1. Some examples of pharmaceutical salts having one component as active drug categorised by their biological activities

Continued on next page.



Table 1. (Continued). Some examples of pharmaceutical salts having one component as active drug categorised by their biological activities



Table 2. Some examples of ionic liquid like salt pairs having both cation and anion as active component




Table 2. (Continued). Some examples of ionic liquid like salt pairs having both cation and anion as active component













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12. (a) Stolte, S.; Arning, J.; Bottin-Weber, U.; Matzke, M.; Stock. F.; Thiele, K.; Uerdingen, M.; Welz-Biermann, U.; Jastorff, B.; Ranke, J. Green Chem. 2006, 8, 621. (b) Stolte, S.; Arning, J.; Bottin-Weber, U.; Muller, A.; Pitner, W.-R.; Welz-Biermann, U.; Jastorff, B.; Ranke, J. Green Chem. 2007, 9, 760. 13. Frade, R. F. M.; Matias, A.; Branco, L. C.; Afonso, C. A. M.; Dusrte, C. M. M. Green Chem. 2007, 9, 873.


Ionic Liquids as Pharmaceutical Salts: A Historical Perspective

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