Ionic liquids: A pharmaceutical perspective

Chapter I ONIC L IQUIDS : A P HARMACEUTICAL P ERSPECTIVE Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva REQUIMTE, Department of Chemistry, Faculty of Pharmacy, University of Porto, Portugal A BSTRACT In the last decades, ionic liquids (ILs) progressed from chemical curiosities to interesting biological compounds apprehending the attention of researchers of distinct areas, from chemistry to pharmacology. Initially, ILs were explored as materials for diverse applications due to the possibility of synthesize compounds with targeted chemical properties combined with selected physical properties. More recently, the emergence of ILs with biological activity revolutionized the scientific focus of these compounds and opened interesting perspectives regarding their pharmaceutical application. From the pharmaceutical point of view, an IL approach, in the design of novel active pharmaceutical ingredients (APIs), appears to be appropriate as it enables the chemical manipulation of the compounds with specific objectives related with the manufacturing process, the stability of the formulation, bioavailability and eventual adverse effects. Furthermore, even though crystallinity confers advantages during isolation, processing and storage of the drug, it is known that solid forms of APIs often suffer from low solubility and polymorphic conversion which can influence negatively the bioavailability of the drug and ultimately its therapeutic effect. On a distinct perspective, the possibility of engineering the properties of ILs by manipulating anion-cation combinations, in association with their solvent properties and in some cases water-miscibility, are considered promising characteristics regarding the applicability of ILs as solvents or carriers of pharmaceutical drugs. In this chapter it is intended to expose the pharmaceutical potential of ILs through the discussion of their utilization either as APIs or solvents/carriers of pharmaceutical drugs. The discussion will be centered on the benefits of the IL approach for the development of novel drug candidates considering not only physico-chemical aspects but also the pharmaceutical profile of the developed active pharmaceutical ingredients with IL properties. Considering the utilization of ILs as solvents of drugs or as part of drug delivery systems, it is anticipated that the discussion will be focused on the efficiency and toxicity of the systems and on their influence on the pharmacokinetics and Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva 2 pharmacodynamics of the vehiculated drugs. It is also planned to debate the motivations for the pharmaceutical usage of ILs as well as their peculiar properties that launched them in this context. Currently, the pharmaceutical utilization of ILs is one of the most relevant applications of these solvents, with impact on the safety and effectiveness of the involved processes and with benefits in terms of pharmaceutical formulations and pharmacological activity. It is our belief that this chapter is adequate for the book in project and can greatly enhance its acceptance and interest by readers in distinct research areas. A BBREVIATIONS Ionic Liquid(s) IL(s) Research and Development R&D GlaxoSmithKlein GSK Active pharmaceutical ingredient(s) API(s) Ethylammonium nitrate EtNH 3 [NO 3 ] 1-butylpyridinium chloride-aluminum chloride bmpy [Cl]-AlCl 3 Tetrafluoroborate BF 4 Hexafluorophosphate PF 6 Generally recognized as safe GRAS Volatile organic solvent(s) VOCs Food and Drug Administration FDA 1-butyl-3-methylimidazolium tetrafluoroborate bmim [BF 4 ] NSAID(s) non-steroidal antiinflammatory drug(s) Ring closing metathesis RCM Triethylammonium acetate TEAA Support ionic liquid phase SILP 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide bmim [NTf 2 ] n-propyl-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)amide dmim [[NTf 2 ] DPEN (R,R)-1,2 diphenylethylenediamine 1-hexyl-3-methylimidazolium tetrafluoroborate hmim [BF 4 ] 1-ethyl-3-methylimidazolium tetrafluoroborate emim [BF 4 ] 1-butyl-2,3-dimethylimidazolium hexafluorophosphate dbmim [PF 6 ] 1-ethyl-3-methylimidazolium chloride-aluminum chloride emim [Cl]-AlCl 3 1-butyl-3-methylimidazolium chloride-iron chloride bmim [Cl]-FeCl 3 1-butyl-3-methylimidazolium chloride-aluminum chloride bmim [Cl]-AlCl 3 1-butyl-3-methylimidazolium chloride-zinc chloride bmim [Cl]-ZnCl 2 1-ethylpyridinium tetrafluoroborate-zinc chloride etpy [BF 4 ]-ZnCl 2 1-butyl-3-methylimidazolium hexafluorophosphate bmim [PF 6 ] 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide emim [NTf 2 ] methyltrioctylammonium bis(trifluoromethylsulfonyl)imide moma [NTf 2 ] Ionic Liquids: A Pharmaceutical Perspective 3 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide bmpyr [NTf 2 ] 1-hexyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide hmpyr [NTf 2 ] methyl tert-butyl ether MTBE 1-methylimidazolium acetate mim [OAc] 1-methoxyethyl-3-methylimidazolium methanesulfonate moemim [Ms] 1-methoxyethyl-3-methylimidazolium trifluoroacetate moemim [TFa] 1-butyl-3-methylimidazolium trifluoroacetate bmim [TFa] 1-butyl-3-methylimidazolium methanesulfonate bmim [Ms] 1-butyl-3-methylimidazolium hydroxide bmim [OH] dimethylimidazolium dimethylphosphate dmim [(CH 3 O) 2 PO 2 ] 1-hexyl-3-methylimidazolium acetate hmim [OAc] 1-ethyl-3-methylimidazolium acetate emim [OAc] 1-methylimidazolium hydrogen sulfate hmim [SO 4 ] 1-butylimidazolium tetrafluoroborate hbim [BF 4 ] 1-hexyl-3-methylimidazolium hexafluorophosphate hmim [PF 6 ] 1-octyl-3methylimidazolium hexafluorophosphate omim [PF 6 ] 1-ethyl-3-methylimidazolium methanesulfonate emim [Ms] 1-ethyl-3-methylimidazolium trifluoromethanesulfonate emim [TfMs] dimethylimidazolium dimethylphosphate dmim [(CH 3 O) 2 PO 2 ] 1-hexyl-3-methylimidazolium chloride hmim [Cl] 1-tetradecyl-3-methylimidazolium bromide tmim [Br] 1-hexyl-3-methylimidazolium bromide hmim [Br] Ionic liquid(s) with pharmaceutical activity IL-API(s) 1. I NTRODUCTION The pharmaceutical industry faces nowadays unprecedented challenges and amendments. Drug development became a question of millions of dollars and the emergence of generic drugs led to dramatic decreases on the sales of huge market successes [1]. With this, the investment on research and development (R&D) tends to decelerate since the risks associated with drug discovery seem to not be in accordance with the current economic demands. It is known that 95% of the experimental drugs that reach clinical trials fail to be both effective and safe. Before this, 40% of the novel drug candidates never reach this stage due to poor pharmaceutical properties such as reduced solubility or diminished permeation of the bloodbrain barrier [2]. Additionally, the demands regarding the environmental impact of drug discovery are on the frontline of the guidelines of Green Chemistry [3]. In this scenario, the pharmaceutical industry has been struggling to keep the high standards of R&D whit the demands of preserving economically viability and integrate environmental sustainability. Novel approaches and management models have been implemented and at the same time the academic community started to invest on innovative pathways for the development and synthesis of novel drug candidates. Additionally, there has Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva 4 been also investment on the reformulation of old synthetic and production processes to make them more adequate to the current economic and environmental demands. Some pharmaceutical companies are nowadays sensitive to this matter and are aware of the environmental consciousness of the general population. Companies like Pfizer and GlaxoSmithKlein (GSK) created internal guidelines (in accordance with the Green Chemistry principles) that aim, among others, the reduction of greenhouse emissions, the minimization of the impact of R&D (from drug discovery to usage and disposal) and the sustainable utilization of water. On the chemical perspective, one of the most obvious and intuitive approach is the search for greener alternative solvents in research, development, and manufacturing of novel active pharmaceutical ingredients (APIs) [4]. In this context, ionic liquids (ILs) emerged as a new class of compounds with properties that empower their pharmaceutical application in a variety of strands. In April 2000, industry and academia joined efforts and ideas on a NATO Advanced Research Workshop on the topic of “Green Industrial Applications of Ionic Liquids” opening interesting perspectives regarding the future utilization of these compounds. Even though the industrial applications in this field are still scarce, the peculiar properties of ILs envision immense and successful possibilities illustrated by an increasing number of literature examples [5]. ILs are being explored as solvents or reagents in a variety of pharmaceutical processes and as reaction media for common synthetic routes of both known and novel drugs [6]. Additionally, ILs can be part of distinct drug delivery systems for drugs with reduced bioavailability [7-10]. Ultimately, the biological activity of ILs can be explored to form active pharmaceutical ingredients (APIs) with tunable physico-chemical and biological properties [11-14]. Still, changes at the industrial level demand a strict and rigid protocol in order to guarantee the safety and viability of the developed drugs. Figure 1. Current demands of the pharmaceutical industry. Ionic Liquids: A Pharmaceutical Perspective 5 Figure 2. Pharmaceutical applications of ILs. So, aspects like pharmaceutical profile, safety and human toxicity, environmental impact and biodegradability must be deeply addressed and explored to promote the acceptance of ILs by pharmaceutical industry. The following discussion will be focused on the evolution of the IL concept to justify the pharmaceutical potential of these solvents. The main features and advantages of the abovementioned pharmaceutical possibilities will be emphasized and where possible, literature and industrial examples will be explored and debated. 2. H ISTORICAL P ERSPECTIVE OF I LS Most documents focused of the history of ILs go back to the 19 th century, to the “red oil” obtained from Friedel-Crafts reactions and to 1914 where the first IL of history, ethylammonium nitrate (EtNH 3 [NO 3 ]), was synthesized [15]. However, ILs as we know them today can find their origin in the 1960´s when U.S Air Force Academy started a project based on the replacement of LiCl-KCl molten salt electrolyte in thermal batteries [6]. By that time, the involved researchers managed to synthesize and characterize a totally ionic, nonaqueous solvent, 1-butylpyridinium chloride-aluminum chloride (bmpy [Cl]-AlCl 3 ), an alkylchloroaluminate that triggered the interest of chemists on ILs, especially those on the electrochemistry field. This was the first compound fitting the definition of IL that has been accepted for almost a century since Waldens´ studies in 1914: a salt which melts at or below 100ºC. This IL constitutes the first element of the so called first generation of ILs that was mainly composed of dialkylimidazolium and alkylpyridinium cation derivatives combined with chloroaluminate and other metal halides anions. These compounds were largely studied by Osteryoung group [16, 17] and other researchers for their tunable and unique physical properties such as density, viscosity and thermal stability, among others. However, the Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva 6 majority of these compounds are liquid only on a very narrow composition range and demand particular conditions of handling since chloroaluminates are water and oxygen sensitive. Additionally, the typical cations are very prone to reduction. Thus, these ILs are not suitable to be applied in biotransformations and not surprisingly the investigations on this field advanced to the synthesis of air and water stable compounds with wider liquid range. This was achieved initially through the combination of alkylimidazolium cations (less predisposed to reduction than the pyridinium ones) with water–stable anions like tetrafluoroborate (BF 4 ), hexafluorophosphate (PF 6 ) and acetate, among many others. These ILs gathered wide attention from the scientific community not only because of their low reactivity with water but also because of their large electrochemical window. These properties enabled the synthesis of novel ILs with tunable chemical properties combined with selected physical properties and that could be used as materials for diverse applications. These compounds constitute the second generation of ILs and are known for their lower melting points, negligible vapor pressure and moderate polarity. The boost on ILs research occurred between 1999 and 2000 after the emergence of this second generation, with an exponential increase of applications in a variety of fields from biocatalysis to nanotechnology. The major drawback of these ILs is still their toxicity that even though can be modulated is inherent to the majority of the compounds and can be similar to that of chlorinated and aromatic solvents. As expected, the investigations followed the route to non-toxicity. This conducted to the utilization of stable, safe and biodegradable ions sometimes with biological activity and derived from materials generally recognized as safe (GRAS). The third generation of ILs is then composed of ILs with tunable chemical and physical properties and with reduced toxicity, like for instance ILs based on amino acids. Considering these particularities it is not unexpected that this new generation of ILs broadened the applicability of these compounds and triggered the investigation of their biotechnological and pharmaceutical potential. In this historical perspective it is important to highlight that even though the biological and pharmaceutical properties of ILs were explored before, namely through the investigation of antimicrobial, antifungal and anti-cancer activities of imidazolium, ammonium and phosphonium ILs [18-21], only at this stage this property was explored on purpose and recurring to selected materials. Figure 3. Historical perspective of the evolution of ILs according to their properties and applications. Ionic Liquids: A Pharmaceutical Perspective 7 3. A PPLICABILITY OF IL S IN THE P HARMACEUTICAL F IELD As stated before, the peculiar properties of ILs make them suitable for distinct pharmaceutical applications and only their toxicity has hindered major developments in earlier years. Still, there are several situations in which toxicity can be modulated and others where toxicity can be a desirable property. With the forthcoming of the 3 rd generation of ILs novel possibilities arose. This chapter will focus on the major possible applications of ILs in the pharmaceutical perspective: reaction media for the synthesis of APIs, as vehicles of drugs (solvents and drug delivery) and as APIs themselves. 3.1. Synthesis of Pharmaceutical Drugs in IL Media In the pharmaceutical industry the use of volatile organic solvents (VOCs) is common and most of the times these solvents are an important part of the whole process from synthesis of APIs (or intermediates) to manufacturing operations like granulation and extraction [22, 23]. Considering that solvent use is about 80-90% of mass utilization in a typical pharmaceutical industry, the use of VOCs becomes a serious concern either from the human or environmental perspective as the toxicity of the production process is largely dependent on the nature of the selected solvents [24]. Moreover, the final formulations will unavoidably contain residual amounts of solvent. Even though there are strict rules and residual solvents limits improved by Food and Drug Administration (FDA) and other organizations and Pharmacopoeias, the risks and adverse effects of VOCs on human health are well known [25, 26]. It is then desirable that novel approaches could be implemented, as it has been already stated on the introduction section. The current concerns of both academia and industry resulted already on several attempts to substitute VOCs by ILs in drug´s synthetic procedures [27, 28]. This approach is based on the demonstrated ability of ILs to drastically change the rate and selectivity of organic chemical reactions [6]. Currently, it is demonstrated that behind the environmental and safety issues, ILs can have also impact on the reactivity of the species involved in organic synthesis due to a fine balance of entropic and enthalpic contributions that involve the interactions inside the IL and between the ions and dissolved species. In fact, ILs can interact with solutes through dipolar and dispersion forces and act as strong hydrogen-bond acceptors [6]. The most important properties that set ILs apart from other solvents include: − existing as molten salts, in many cases even below room temperature − highly polar − negligable vapor pressure − nonflammable − wide liquid range (typically > 300 °C grade) − electrically conducting − noteworthy dissolution properties (of both organic and inorganic compounds) − high thermostability. Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva 8 Table 1. Synthesized compounds with pharmaceutical interest through the implementation of organic reaction in IL Synthesized Compound Biological activity Reaction Ionic Liquid Ref Isoxazoline derivatives Antimicrobial Diels-Alder bmim [BF 4 ] [32] Pyrrole-fused polycyclic heterocycles (alkaloyds) Alkaloids Diels-Alder bmim [BF 4 ] [33] Pyrano/Thiopyrano fused polycyclic heterocycles Bactericide Diels-Alder TEAA [34] Regioselective arylated products Pharmaceutical intermediates Palladium catalyzed bmim [PF 6 ] bmim [BF 4 ] [35] Arylboronates Pharmaceutical intermediates Anti-tumoral Palladium catalyzed bmim [PF 6 ] bmim [BF 4 ] hmim [BF 4 ] emim [BF 4 ] [30] (S)-Naproxen NSAID RCM bmim [BF 4 ] [36] Hydrogenated aromatic ketones Pharmaceutical intermediates RCM Imidazolium ILs [37] Pravadoline NSAID Friedel-Crafts Imidazolium (PF 6 and chloroaluminate) catalysts [38] Substituted indoles Pharmaceutical intermediates Friedel-Crafts Imidazolium chloroaluminate catalysts [39] Benzophenone derivatives Pharmaceutical intermediates Sunscreens components Friedel-Crafts Imidazolium chloroaluminate catalysts [40] Benzophenone derivatives Pharmaceutical intermediates Sunscreens components Friedel-Crafts Imidazolium chloroindate(III) catalysts [41] Coenzyme Q10 Antioxidant Friedel-Crafts Pyridinium chloroaluminate catalysts [42] Kinetic resolution of ibuprofen NSAID Biocatalysis (Candida rugosa lipase) bmim [PF 6 ] bmim [BF 4 ] bmim [MeSO 4 ] mmim [MeSO 4 ] bmim [OctylSO 4 ] (C 6 H 13 ) 3 C 14 H 29 PN 3 (C 4 H 9 ) 3 CH 3 PTOs [43] Kinetic resolution of ibuprofen NSAID Biocatalysis (lipases fromAspergillus niger AC-54, Candida antarctica, Candida rugosa, Rhizomucor miehei and Thermomyces lanuginose bmim [PF 6 ] bmim [BF 4 ] [44] Caffeic acid phenethyl ester analogues Anti-tumoral Biocatalysis (Candida antarctica lipase) bmim [NTf 2 ] [45] (R)-1-(4chlorophenyl)ethanol Pharmaceutical intermediate Whole cell biocatalysis (Lactobacillus kefir) bmim [PF 6 ] bmim [NTf 2 ] moma [NTf 2 ] [46] (R)-1-(4chlorophenyl)ethanol Pharmaceutical intermediate Escherichia coli Saccharomyces cerevisiae bmim [PF 6 ] bmim [NTf 2 ] moma [NTf 2 ] hmim [PF 6 ] hmim [NTf 2 ] [47, 48] Ionic Liquids: A Pharmaceutical Perspective 9 Synthesized Compound Biological activity Reaction Ionic Liquid Ref bmpyr [NTf 2 ] hmpyr [NTf 2 ] Chiral alcohols Pharmaceutical intermediate [PF 6 ], [NTf 2 ] and [FAP] based hydrophobic ILs [49] (S)-3-chloro-1-phenyl-1propanol Pharmaceutical intermediate E. coli bmim [PF 6 ] bmim [NTf 2 ] emim [BF 4 ] mmim [MeSO 4 ] [50] Nucleosides derivatives Pharmaceutical intermediates momim [Ms] momim [TFa] bmim [TFa] bmim [Ms] [51, 52] [53, 54] 2,3-Disubstituted-1,3thiazolinin-4-one derivatives Antiparasitic Three component condensation (aldehyde, amine and mercaptoacetic acid) bmim [BF 4 ] bmim [PF 6 ] [55] 2-Aryl-4,5-diphenyl imidazoles, pyrazole derivatives, oximes Pharmaceutical intermediates Sonochemical organic synthesis bmim [OH] emim [OAc] hmim [SO 4 ] [56-58] Quinoline derivatives Sonochemical organic synthesis hbmim [BF 4 ] [59] The possibility of developing tailor-made ILs for particular purposes offers exciting opportunities in the organic chemistry field enabling the creation of tasks specific compounds. Moreover, ILs can often form biphasic systems with classic VOCs which allows the simple isolation of reaction products by extraction of the ionic liquid layer. Their ionic nature enables immobilisation and recycling of many transition metal catalysts. Many organic reactions have been studied in IL media sometimes with remarkable results [6, 29]. In a small number of cases the registered differences were small, not meeting anticipated high expectations or justifying extra expense. Herein we intend to focus on chemical reactions that can have significant utility at the pharmaceutical level and that in fundamental literature studies are not always immediately linked to that type of application. The selected reactions were: Dies-Alder, transition metal catalysed (including Heck reaction and ring-closing metathesis), Friedel-Crafts reactions not forgetting enzyme catalysed synthesis. Some examples of successful attempts to perform synthesis of APIs in ILs will be presented and discussed. The abovementioned reactions have been extensively studied in IL media [6, 27, 29-31]. Considering that nowadays drug synthesis can be based on the concept of convergent synthesis, according to which several fragments are prepared in parallel paths and combined at the end of the process, the informations collected from those reactions if not totally adequate to a whole synthesis process can be important in one of those parallel paths. The most important achievements in this field are compiled in Table 1. 3.1.1. Diels-Alder Reaction The Diels-Alders reaction is an organic chemical reaction, more specifically, a cycloaddition, between a conjugated diene and a substituted alkene to form a substituted cyclohexene system [60]. This reaction enables the synthesis of complex polycyclic molecules with adequate control of stereochemistry. Even though this type of reaction accounts for only 5 to 11 % of C-C bond-forming reactions performed under Good Manufacturing Practice in the pharmaceutical industry [61], it is largely explored by scientists in academic drug development and thus deserves a special attention on this chapter. Among Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva 16 for ibuprofen due to the differences registered between S-(+)-ibuprofen and R-(-)-ibuprofen, with the latter being 100-160 times less active than the first one. For this study, the authors selected seven ILs with structural variability and compared the results with those obtained with isooctane. Bmim [PF 6 ] improved both the kinetic resolution and the enantioselectivity with high enzyme stability. Studies of the time course conversion and enzyme stability as a function of time in both isooctane and bmim [PF 6 ] confirmed that this IL is a valid alternative for the kinetic resolution of ibuprofen. Later on, several types of lipases (from Aspergillus niger AC-54, Candida antarctica, Candida rugosa, Rhizomucor miehei and Thermomyces lanuginose) were studied to perform the resolution of (RS)-ibuprofen in two-phase systems containing bmim [PF 6 ] and bmim [BF 4 ] [44]. It was noticed that C. rugosa lipase conducted to the best results in terms of conversion degree, enantiomeric excess of remaining acid and E-value in a two phase system composed of bmim [PF 6 ] and isooctane. The influence of the IL was more pronounced on the E-value being less significant regarding the conversion degree. A similar tendency was observed with A. niger lipase. Acceptable results were also attained with C. antarctica lipase in terms of esterification activity and enantioselectivity. This enzyme can also be used for the synthesis of nucleoside drugs esters resorting to an IL as additive [107]. The lipase catalyzed transterification of ribavirin was performed in mixtures of acetone and increasing concentrations of imidazolium ILs (bmim [BF 4 ], bmim [PF 6 ] and emim [BF 4 ]). The best results in terms of transterification extent were obtained with bmim [BF 4 ] 10%, with an increase of the reaction rate of about 3.5 times when compared with the assay in the absence of IL. These observations were correlated to the increase of solubility of the nucleoside analogue due to the presence of the IL and to enzyme conformational changes. In the presence of bmim [BF 4 ] the nucleoside synthesis was carried out with excellent regioselectivity, fast reaction rate and high yield. Resorting also to C. antarctica lipase, Kurata and co-workers performed the synthesis of caffeic acid phenethyl ester analogues, with antiproliferative effect on tumor cells, in bmim ILs with variable anions [45]. The transesterification reaction of methyl caffeate with various alcohols to produce the abovementioned analogues is favored in the presence of bmim [NTf 2 ]. Considering the registered changes in activity, it was concluded that the activity of enzyme is anion dependent. The optimized synthetic system resulted on the production of 2cyclohexylethyl caffeate and 3-cyclohexylpropyl caffeate with conversion yields of 97.6 and 93.8%, respectively. Both compounds exhibit antiproliferative activity higher than caffeic acid and comparable to 5-fluorouracil. In the field of biocatalysis, it is also important to highlight whole cell catalyzed processes which can present major advantages over the use of isolated enzymes [108]. In biotransformations involving more than one enzyme, the use of whole-cell biocatalysts (recombinant or not) is almost mandatory as it avoids costly and time consuming enzyme purification. OH OH OCH 3 O + R O OH OH OR O Lipase bmim [NTf 2 ] Scheme 4. Synthesis of caffeic acid phenethyl ester in IL media [45]. Ionic Liquids: A Pharmaceutical Perspective 17 In addition, the use of cofactors can be avoided and the process can benefit from the intracellular regeneration of cofactor when the membrane of the whole-cell biocatalyst remains stable during the catalytic route. This approach is generally very adequate to asymmetric synthesis due to low water solubility of substrates or products and inhibitory effects of the reactants on the biocatalyst. Considering the issue of membrane integrity, the selection of the solvent in whole cell biocatalysis is of the most importance and can enhance or highlight the mentioned advantages of this catalytic methodology. In this context, it has been demonstrated that ILs can be successfully employed in whole cell biocatalysis in replacement of VOCs [46-49, 108]. Most of the referred applications of whole cell biocatalysis in IL media have pharmaceutical interest. This approach has been mainly applied to the asymmetric synthesis of chiral alcohols [46-50] which are frequently employed as pharmaceutical intermediates [109]. Pfruender and co-workers demonstrated for the first time that a cellular cofactor regeneration system can be active in the presence of water-immiscible imidazolium and ammonium ILs (bmim [PF 6 ], bmim [NTf 2 ] and methyltrioctylammonium– NTf 2 , moma [NTf 2 ]) [46]. This important demonstration is a result of the study of the Lactobacillus kefir catalyzed asymmetric reduction of chloroacetone to (R)-1-(4chlorophenyl)ethanol in ILs, used as substrate reservoir and extracting agent. The results of the synthetic process were compared with those obtained with commonly used VOCs, like noctanol and methyl tert-butyl ether (MTBE). In the presence of bmim [NTf 2 ] the chemical yield of the synthesis of the chiral alcohol can be doubled and the purity of the product is excellent. With the other tested ILs the results are very acceptable comparing with MTBE. It was also evidenced that the tested ILs do not affect L. kefir membrane integrity and can even enhance it, probably due to changes in morphology. Similar results were obtained in a study of the same process catalyzed by Escherichia coli and Saccharomyces cerevisiae [47, 48] confirming that the selected ILs can be applied on the whole cell biocatalyzed production of pharmaceutical chiral alcohols. A set of other commercially available ILs proved to be also good options for the asymmetric reduction of ketones using recombinant E. coli as biocatalyst [49, 110]. As before, the tested compounds do not affect negatively the intracellular regeneration of NADH nor cell membrane integrity. More recently, Choi and co-workers confirmed the adequacy of imidazolium ILs, with special focus on bmim [NTf 2 ], for the production of chiral alcohols through the E. coli catalyzed synthesis of (S)-3-chloro-1-phenyl1-propanol, a chiral precursor of anti-depressant drugs [50]. 3.1.5. Other Applications Nucleoside chemistry is one of the most important areas in pharmaceutical research providing compounds with wide application in cancer and viral chemotherapy. The problems associated with the insolubility of nucleoside derivatives have hindered the development of novel strategies and ILs soon started to be explored as reaction media for the solubilization and synthesis of these compounds [51-55, 111]. Uzagare et al. performed a deep study of the solubility of 2´-deoxyribonucleosides in several imidazolium ILs [51]. The IL 1methoxyethyl-3-methyl imidazolium methanesulfonate (moemim [Ms]) proved to be a better option for the solubilization of the nucleosides than any other IL or VOC. The acylation and peracylation of the 2´-deoxyribonucleosides can be performed in this IL with good isolation of the reaction product with yields between 89 and 95%. The same IL was used for the selective benzoylation of nucleosides using benzoyl cyanide [52]. Highly efficient benzoylations in mild reaction conditions (25ºC) are achieved with selective benzoylation of Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva 18 sugar hydroxyl groups over amine groups and preferential production of O-benzoylated derivatives. The major drawback of this strategy is the formation of the highly toxic HCN, as reaction by-product. As an alternative, the authors studied the process in the presence of 1methoxyethyl-3-methylimidazolium trifluoroacetate (moemim [TFa]) which exhibits the ability to dissolve both deoxyriboand ribonucleosides [111]. This IL is a good alternative for the selective benzoylation of nucleosides with high yields, under ambient conditions. These results were of the most importance for the development of three nucleoside based anti-viral drugs namely stavudine, brivudine and trifluridine in three ILs, moemim [Ms], moemim [TFa] and bmim [TFa] [53]. In all cases, the selected ILs showed better solvent properties than the commonly used VOCs like N,N-dimethylacetamide. Moreover, the amount of required solvent is reduced due to the high solubility of the synthesized compounds in the ILs. Higher reaction rates are attained with this strategy. The same ILs, with the addition of bmim [Ms], were also applied to the synthesis of antiviral 5-halouracil nucleosides which can be also used as building blocks for the synthesis of other antiviral drugs [54]. As in the abovementioned studies, ILs proved to be good reaction media for this synthesis and in this case could be recovered up to 4 cycles without loss of yield. Two imidazolium ILs were also selected as reaction media for the synthesis of 2,3disubstituted-1,3-thiazolinin-4-one derivatives with antiparasitic activity [55]. The synthesis yield is low at room temperature but by increasing the temperature up to 80 or 90ºC the reaction yield increases to 87 and 74% with bmim [PF 6 ] and bmim [BF 4 ], respectively. Tests performed with bmim [PF 6 ] demonstrate that the IL can be recovered and efficiently reused. This section could not be completed if the works of Zang et al. on sonochemical organic synthesis in IL media were not mentioned. Several compounds including 2-aryl-4,5-diphenyl imidazoles [56], pyrazole derivatives [57] and oximes [58] with pharmaceutical interest. For the synthesis of these compounds, the authors combined bmim [OH] [58], emim [OAc] [56] or hmim [SO 4 ] [57] with ultrasonic irradiation. In all the tested conditions, the reaction time was reduced and the synthesis occurred efficiently with high yields, under mild conditions. Similarly, Heravi managed to synthesize quinolines derivatives, with pharmacological activity, through the combination of hbim [BF 4 ] and ultrasound, resorting to methanol as cosolvent [59]. To finish this section, two applications with immense potential to be implemented in pharmaceutical synthesis must be highlighted due to their importance on the safety and therapeutics perspective. Firstly, the oxidation of ketones, largely applied to the synthesis of antibiotics and steroids, was already performed in IL media resorting to imidazolium ILs as an alternative to the commonly used dichloromethane, chloroform and acetonitrile [112]. The most promising ILs were bmim [BF 4 ] and 1-methylimidazolium acetate (mim [OAc]) providing yields of lactone and ester synthesis between 65 and 95%. R 2 R 1 O NH 2 + R 3 O R 4 R2 R1 R4 R3 hbim [BF 4 ] MeOH, RT, 10-35 min Scheme 5. Condensation of ketones to produce quinolone derivatives in the presence of hbim [BF 4 ] [59]. Ionic Liquids: A Pharmaceutical Perspective 19 Again, ILs could be recycled 3 times without loss of yield. Finally, we highlight the major importance of the work of Hwang and co-workers regarding the formation of amyloid from α-synuclein in IL media. There are a number of amyloid related diseases that largely depend on the development of novel therapeutic strategies based on amyloid formation. However, amyloid formation is usually a very slow process which hinders more effective developments on this field. In this work, a set of imidazolium ILs and one pyridinium IL were tested and in all cases the ILs acted as stimulators of amyloid formation with decrease of the lag time of the process. Amongst the tested compounds, emim [NTf 2 ] is a stronger promoter when compared with other ILs. 3.2. ILs as Drug Vehicles Solubility is one of the most important properties during drug development. It limits the concentration that a dosage form can incorporate and the rate at which the molecule dissolves from the solid form. It is then a key property for gastro-intestinal absorption of orally administered drugs. In fact, poor aqueous solubility of drugs is one of the major causes for low systemic exposure and, consequently, lack of in vivo activity [2, 113]. From the total amount of new chemical entities developed in the pharmaceutical industry, 40% fail to reach higher development levels due to solubility problems [114, 115]. The importance of solubility during drug development is illustrated by the Biopharmaceutics Classification System (BCS) which is basically a guide for the prediction of the intestinal drug absorption, provided by the U.S. FDA [116]. In this classification system, prediction relies in only two major parameters: solubility and intestinal permeability. In this context, it is not surprising that the search for novel strategies to increase the solubility of new drug candidates is one of the biggest concerns of both industry and academic researchers. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, among others. The selection of the strategy to be adopted is highly dependent on drug´s property, site of absorption, and characteristic of the dosage form [117]. ILs are well-known for their solvation properties that make them able to dissolve a wide range of organic and inorganic compounds [118]. This property has been associated with the fact that ILs form a highly solvating and little coordinating media. Additionally, the short range repulsive interactions between anions and cations enhance the solvent power of ILs [119]. In the pharmaceutical field, it has been demonstrated that ILs are capable of dissolving several drugs that are insoluble or poorly soluble in water and in the solvents commonly used in these applications [8, 13, 51, 111, 120-126]. Additionally, their inherent tunability associated with the possibility of designing a specific IL for a specific application are major attractions of these compounds in this field. Generally, there is an increase of the solvency of ILs with the increase of the alkyl side chain of the cation [127]. The studies with nucleoside derivatives of Kumar and co-workers illustrate the importance of solubility studies in a stage prior to synthesis [52, 53, 111]. As described in section 1.3.1.5, imidazolium ILs present better solvent properties for both deoxyriboand ribonucleosides than the commonly used VOCs. These findings opened new perspectives regarding the synthesis of nucleoside derivatives in IL media. Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva 20 The pioneering researches of Professor´s A.T. Florence group boosted the pharmaceutical utilization of ILs as solvents or drug reservoirs [121-123]. This application is mainly related with the ability of ILs to dissolve poorly water-soluble molecules drugs like albendazole and danazol [122], dexamethasone [121, 123], penicillin V, progesterone and dehydroepiandrosterone [123]. For instance, the solubility of albendazole increased more than 20,000 times in hmim [PF 6 ] and more than 10,000 in bmim [PF 6 ]. The issue of IL´s water miscibility was also explored during this evaluation considering the preferential utilization of aqueous systems during drug´s formulation. The water miscibility of poorly water-miscible ILs, like bmim [PF 6 ], can be enhanced through the addition of a more water miscible IL with higher effects for more hydrophilic ILs. The variation of danazol solubility is far more significant with very good results in the water miscible IL bmim [BF 4 ]. Hexafluorophosphate ILs of the imidazolium group were tested as solvents and reservoirs of progesterone, dehydroepiandrosterone, dexamethasone, sucrose and penicillin V [123]. It should be highlighted that the solubility decreases with the increase of the alkyl chain length from bmim to omim. All the ILs are adequate for the entrapment and release of solubilized drugs. Distinctly, the same ILs were utilized to evaluate the release rate of solubilized hydrophilic and hydrophobic drugs by means of the passage of an electric current through the immiscible ILs [121]. The application of electric current to the ILs increases the release of both solubilized drugs with the highest variation being registered for omim [PF 6 ]. Similarly, Smith et al. studied the solubility of ibuprofen and paracetamol in bmim [PF 6 ] and hmim [PF 6 ] at different temperatures. Even though both ILs are good solvents of both drugs, the solubilities are higher in hmim [PF 6 ] than in bmim [PF 6 ]. ILs with trifluoromethanesulfonate and NTf 2 anions were selected to dissolve isoniazide [124], N-acetyl-L-cysteine, coumarin and 4hydroxycoumarin [125]. Trifluoromethanesulfonate ILs are better solvents for isoniazide [124], N-acetyl-L-cysteine and 4-hydroxycoumarin than NTf 2 ones [125]. The inverse was observed for coumarin [125]. The solubility of isoniazide was also studied in ammonium ILs, together with other antibiotic drug pyrazinecarboxamide [128]. Amongst the tested compounds, didecyldimethylammonium nitrate is the best solvent for both drugs with isoniazid exhibiting higher solubility than pyrazinecarboxamide in all the tested ILs. ILs can also be design to provide tunable and adequate hydrophilic-lipophilic balance to enhance water solubility of poorly soluble APIs [126]. This was evidenced recently on a study with amphotericin B and itraconazole, two complex, amphiphilic drugs with reduced water solubility. The selection of the anions and cations took in consideration not only the desired hydrophilic-lipophilic balance but also safety issues keeping in mind that they must be approved for consumption. Thus, acetate ILs based on short-chain fatty amines were synthesized (by choosing complementary functionality in one or both ions) and their effectiveness as solvents was evaluated. The adopted strategy proved to be a good option not only for the solubilization of drugs in the ILs but also to solubilize and maintain the drug in aqueous media. Also on the perspective of the use of ILs as solvents of pharmaceuticals, there are already informations on the influence on drug´s properties that determine their pharmaceutical profile and in vivo behavior [129]. These informations were gathered during the study of imidazolium ILs as solvents of nimesulide, a widely used NSAID with reduced water solubility. The binding of nimesulide to human serum albumin (HSA) as well as its interaction with micelles of hexadecylphosphocholine to calculate partition coefficients, were studied in the presence and in the absence of emim [Ms] and emim [TfMs] 1%. As in aqueous Ionic Liquids: A Pharmaceutical Perspective 21 media, in the presence of the selected ILs, nimesulide binds strongly to HSA by means of spontaneous interactions. The studied drug-IL systems exhibit properties that favor the interaction with biological membranes, evidenced by the high Kp values. Thus, there are good perspectives for the effective absorption and distribution in vivo. ILs can also be incorporated in IL-in-oil microemulsions to be used as carriers of poorly soluble drugs [7-10]. Microemulsions are self-assembled structures widely recognized as vehicles for encapsulation, stabilization, and delivery of pharmaceutical drugs [130]. They are thermodynamically stable colloidal dispersions formed by water and oil and stabilized by an interfacial film or surfactant. The initial report on this topic was elaborated by Professor´s Goto group and involved a four component system composed of dimethylimidazolium dimethylphosphate (dmim [(CH 3 O) 2 PO 2 ]), isopropyl myristate, polyoxyethylene sorbitan (Tween-80) and sorbitan laurate (span-20) for the delivery of acyclovir [8, 9]. The IL was selected as the most adequate compound on solubility studies that were performed with seven imidazolium ILs. The increase of IL content on the micelle conducts to an increase of micelle volume and the incorporation of acyclovir results on a slight decrease of the mean diameter. The efficiency of the proposed delivery system was studied in vitro recurring to a porcine skin model using Franz-type diffusion cells. Skin permeability and the transdermal permeation of acyclovir increases when IL based microemulsions are used. The insertion of IL 4%wt in the microemulsion leads to a reduction of less than 20% in cell viability (human epidermal model LabCyte TM EPI-MODEL 12). With these pioneering studies, the authors confirmed the adequacy of these microemulsions to perform transdermal drug delivery. In continuation, the authors studied a set of imidazolium ILs as dispersed phase [7]. It was noticed that hydrophilic ILs with coordinating anions can be solubilized on the core of Tween-80/ span-20/ isopropyl myristate micelles and form stable microemulsion droplets more effectively. It is important to highlight that the solubility of the ILs in the microemulsion follow the same tendency as in water. The potentialities of the delivery system were further explored with methotrexate and dantrolene, two poorly water soluble drugs. The solubility of both drugs is enhanced in microemulsions with dmim [(CH 3 O) 2 PO 2 ] with further increase by higher IL concentration. Similarly, Dobler and co-workers prepared oil-in-water and water-in-oil microemulsions containing hmim [Cl] and bmim [PF 6 ] and evaluated the influence of the ILs on the properties of the micellar systems [131]. The ILs can be successfully incorporated in the micelles and due to their antimicrobial activity can have the effect of a preservative. As related above, skin permeation is enhanced in the presence of ILs. Other microemulsion systems were explored as vehicles of insoluble drugs such as curcumin [132], dopamine and acetylcholine [133]. The hydrophilic IL bmim [BF 4 ] increases about 7 times the association of curcumin with CTAB and induces a decrease of association in the case of cationic surfactants like sodium dodecylsulfate (SDS), acting like a modulator of drug´s solubilization in micellar systems. On a distinct perspective, the micellization and surface behavior of 1-tetradecyl-3-methylimidazolium bromide (tmim [Br]) was studied in the presence of dopamine and acetylcholine aiming the evaluation of the applicability of the micellar system in drug delivery [133]. The selected IL exhibits better surface activity and better drug carrier performance than the structurally similar cationic surfactant, tetradecyltrimethylammonium bromide. Imidazolium ILs are also good solvents for the release of APIs from styrene-divinylbenzene polymeric vehicles as demonstrated by RamosRodriguez and co-workers [127]. The studies conducting to this conclusion were based on atomistic and mesoscopic simulations that evaluated solubility parameters and the diffusion Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva 22 of albendazole from the polymeric vehicle to an aqueous medium modified with bmim [BF 4 ], bmim [PF 6 ] or hmim [Br]. The diffusion of albendazole was related with the solvent power of the studied ILs, with bmim [PF 6 ] inducing higher release from the vehicle than bmim [BF 4 ] or hmim [Br] due to the higher polarity of [PF 6 ]. The evolution of the research on this field has been only foreclosed by one of the most delicate issues that concerns with ILs: toxicity. Further developments on the use of ILs as carriers or solvents of drugs are largely dependent on the preparation of safer ILs with reliable toxicity data that could be readily accepted as GRAS and used as excipients in pharmaceutical formulations. 3.3. ILs as Active Pharmaceutical Ingredients Despite the technological advances of the last decades, nowadays there is still a significant rate of failure during drug development in the pharmaceutical industry. A study conducted between 1990 and 2002 revealed that only 40% of the drugs that pass phase I and II clinical trials will reach the market [134]. Failure was associated with lack of efficacy (50%), safety concerns (30%) or both (20%). The issue of efficacy is quite intriguing considering that this is the major concern of phase II clinical trials. Drug´s efficacy is tightly associated with bioavailability that in turns is dependent on fundamental properties such as solubility, dissolution rate and lipophilicity. Besides economical and judgmental reformulations, the strongest possibilities to overcome this failure rates are to profile druglike properties as early as possible and work on lower-risk compounds. Typically, the pharmaceutical industry is based on solid and crystalline forms of APIs with claimed advantages in terms of purity, solubility and thermal stability [135, 136]. It is also commonly accepted that solid forms of APIs facilitate isolation, manufacturing and product handling with reduction of the costs of the overall production process. This tendency is further encouraged by a vast amount of guidelines, most of them provided by FDA, concerning the manufacturing and quality control of solid pharmaceuticals with a notorious lack of guiding principles for liquid dosage forms. However, solid forms of APIs often suffer from low solubility and polymorphic conversion which can influence negatively the bioavailability of the drug and ultimately its therapeutic effect [136]. Polymorphism is the ability of a compound to exist as two or more crystalline phases that exhibit distinct arrangements and/or conformations of the molecule in the crystal lattice [135, 137, 138]. Thus, polymorphs display different physical, thermodynamic, spectroscopic, interfacial and mechanical properties. Moreover, the different lattice energies of polymorphs can originate different solubilities and dissolution rates, affecting the bioavailability of pharmaceutical drugs. Polymorphism is one of the major concerns of the pharmaceutical industry during drug development due its impact during formulation and on pharmacological effect, as the conversion can occur throughout drug manufacturing or storage [138]. During drug development, if polymorphs are detected the most active and stable is selected. As examples, acetaminophen (paracetamol) can be presented in two forms with distinct compression properties [137] and the antiviral drug ritonavir has an inactive polymorph that exhibits the ability to inactive the active polymorph [139]. Ranitidine hydrochloride has been subject of deep discussion and legal litigation due to an attempt to approve a more active polymorph than the patented and commercialized by GSK. However and despite all the concerns on this topic, problems with commercialized drugs can still occur. Ionic Liquids: A Pharmaceutical Perspective 23 Particle size is another problem related to solid forms of pharmaceuticals, so that there are rigid guidelines concerning this aspect. It is known that particle size influences several parameters that determine drugs´ bioavailability and stability [140]. In this context one cannot also forget the problems of solubility of the majority of the novel drug candidates that hinder their future commercialization [113]. It is then important to control critically polymorphism, solubility and particle size during the development of solid APIs to avoid failures in posterior phases. 3.3.1. Control and Modulation of Physico-Chemical and Biological Properties of Pharmaceutically Active ILs The most common strategy of the pharmaceutical industry to overcome inadequate physico-chemical properties is salt formation [13, 135, 136]. Recent estimations indicate that around 50% of all drugs utilized in the pharmaceutical industry are salts with improved properties regarding the corresponding neutral molecules. As for neutral drugs, FDA has got lists of approved conterions which include organic and inorganic ones. Even though this strategy hinders some of the abovementioned problems, the possible combinations are relatively small and the industry recurs systematically to the same ions. In this context, an IL approach, in the design of novel APIs, appears to be appropriate as it enables uncountable possible cation-anion combinations while providing distinctive properties unreachable in solid salts namely enhanced solubility and absence of polymorphic forms [12, 14, 141]. In this pharmaceutically active ILs (IL-APIs), the cation and the anion can both present biological activity or the counterion can have the ability to reduce the adverse effects of the active ingredient or change its solubility, for example. The possibility of combining more than two ions in the same compound cannot be forgotten as it can provide an additional biological activity or property. In these cases, the total charge of the cations is balanced by the total charge of the anions [142, 143]. Even though not predictable, synergistic or additive effects must also be considered as they may provide novel treatment possibilities and distinct drug delivery options. Furthermore, the assertive combination of appropriate anions and cations empowers the chemical manipulation of the compounds with specific objectives related with the manufacturing process, the stability of the formulations, their bioavailability and eventual adverse effects. In this perspective, it is important to highlight that small modification of an API can result on dramatic changes of its properties and eventually on its classification in the BCS. Thus, the IL approach can be profitable not only from the technological perspective but also on the pharmacological point of view since the possibility of modulate the abovementioned properties can facilitate the interaction of the compounds with biological membranes with consequent increase in their bioavailability and higher probabilities to actuate in vivo. 3.3.2. Synthesis and Profiling of Active Pharmaceutical Ingredients with IL Properties The synthesis of APIs with IL properties is based on the evident similarity between ILforming cations and APIs and on the assumption that the majority of bioactive ions present properties to form low melting salts, namely adequate size, diffuse charge and asymmetry. The initial developments on this field demanded a deep knowledge not only of the biological action of the ions but also of their ability to form ILs. Even though a critical ion selection is not a guarantee for IL formation, the most determining aspect during IL-APIs´ synthesis is Paula C.A.G. Pinto and M. Lúcia M.F.S. Saraiva 24 definitely ion selection. Independently from the objective, the ions must be GRAS compounds with properties to be incorporated in pharmaceutical formulations either as APIs or excipients. At this point, it is notorious that the research in this field is still mainly focused on the synthesis of novel compounds through the association of ions of distinct pharmacological groups or with diverse excipient properties. This is related with the relatively easy implementation of synthetic procedures based on metathesis reactions after the selection of ions with pharmaceutical interest. Moreover, the intensive investment on novel APIs with IL properties is still motivated by the enthusiasm related with the possibility of associating ions with the objective of modulate the pharmacological activity and physico-chemical properties while obtaining dual activity compounds. The research group of Professor Rogers developed pioneer work regarding the synthesis and characterization of APIs with IL properties with a significant amount of papers and patents on this topic [12, 13, 141-147]. The first experiences on this field were reported on an interesting article exploring the so called third evolution of ILs [14]. Table 2 summarizes the most significant IL-APIs synthesized in the last years as well as their main properties and pharmacological activity. Ranitidine docusate, lidocaine docusate and didecyldimethylammonium ibuprofenate can be synthesized through simple metathesis reactions to overcome issues of polymorphism, solubility and bioactivity [14]. The compounds exhibit dual activity since they incorporate well-known and widely used pharmaceutical ions and counterions with emollient (docusate) or antibacterial properties (didecyldimethylammonium). The association of docusate to lidocaine results on a hydrophobic API with increased thermal stability and enhanced bioactivity from topical application, possibly due to a slower release profile and higher skin permeability associated to the presence of the emollient. The three IL-APIs present low surface tension and low contact angles due to weak cation-anion interactions [161]. The IL-API approach enables the synthesis of compounds based on specifically selected ions. For instance benzalkonium and didecyldimethylammonium can form a dual active IL by combination with ibuprofen with applicability for the treatment of inflammation caused by bacterial infections [12]. Benzalkonium can also be used to form ILs with anions with similar activity, such as sulfacetamide. The result is an IL-API with enhanced antibiotic activity that can potentially reduce bacterial resistance. Similarly acetylsalicylic acid and salicylic acid can be combined with antimicrobial (cetylpyridinium, benzethonium, benzalkonium and hexetidinium), analgesic (tramadolium), local anesthetic (lidocainium and procainium) and antiarrhythmic (procainiumamide) cations to obtain dual activity IL-APIs with advantages in terms of solubility and functionality [145]. These combinations result in low melting or liquid salts at room temperature. However, acetylsalicylate IL-APIs suffer from low stability and their therapeutic application can only be guarantee if moisture is rigorously controlled. From the selected combinations, salicylate IL-APIs incorporating antibacterial actions, such as benzalkonium salicylate and cetylpyridinium salicylate exhibit promising physical and chemical properties that foresee their utilization in antimicrobial applications. This was further confirmed through the study of protein binding affinity, partition coefficients and surfactant properties of benzalkonium salicylate, cetylpyridinium salicylate and emim salicylate [148]. Ionic Liquids: A Pharmaceutical Perspective 25 Table 2. Pharmacological activity and main features of IL-APIs IL-API Anion Cation Pharmacological activity Main features Ref. Ranitidine docusate O O OH O 3 - S OH CH 3 CH 3 CH 3 CH 3 O N + CH 3 CH 3 H S NH NH NO 2 CH 3 Histamine H 2 receptor antagonist Emollient - Absence of polymorphs - Low surface tension - Low contact angles [14] Lidocainium docusate O O OH O 3 - S OH CH 3 CH 3 CH 3 CH 3 CH 3 NH N + CH 3 CH 3 H O CH 3 Local anesthetic Emollient - Higher skin permeation Didecyldimethylammonium ibuprofenate CH 3 CH 3 CH 3 O O - N + CH 3 CH 3 n n CH 3 CH 3 n=7 Antibacterial Antiinflammatory - Anion with primary biological activity Benzalkonium ibuprofenate CH 3 CH 3 CH 3 O O - N + n CH 3 CH 3 CH 3 Antibacterial Antiinflammatory - Appropriate to combat inflammation associated to bacterial infections [12] Didecyldimethylammonium ibuprofenate CH 3 CH 3 CH 3 O O - N + CH 3 CH 3 n n CH 3 CH 3 n=7 Antibacterial Antiinflammatory - Appropriate to combat inflammation associated to bacterial infections Benzalkonium sulfacetamide O O OH O 3 - S OH CH 3 CH 3 N + n CH 3 CH 3 CH 3 Antibacterial Anti-acne - Reduction of bacterial resistance Cetylpyridinium salicylate O - O OH N + C 16 H 33 Antibacterial Antiinflammatory - Improved solubility - Strong bind to HSA - High partition coefficient - Slightly toxic (aquatic toxicity) [145, 148, 149] Cetylpyridinium acetylsalicylate O - O O CH 3 O N + C 16 H 33 Antibacterial Antiinflammatory - Water sensitive - Low stability [145] Benzethonium salicylate O - O OH O O N + CH 3 CH 3 CH 3 CH 3 CH 3 Antibacterial Antiinflammatory - Improved solubility [145, 149] Benzethonium acetylsalicylate O - O O CH 3 O O O N + CH 3 CH 3 CH 3 CH 3 CH 3 Antibacterial Antiinflammatory - Water sensitive - Low stability [145] Benzalkonium salicylate O - O OH N + n CH 3 CH 3 CH 3 Antibacterial Antiinflammatory - Improved solubility - Strong bind to HSA - High partition coefficient - Slightly toxic (aquatic toxicity) [145, 148, 149] Paula C.A.G. 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