International Journal of Molecular Sciences Review The Role of Ionic Liquids in the Pharmaceutical Field: An Overview of Relevant Applications Sónia N. Pedro , Carmen S. R. Freire, Armando J. D. Silvestre and Mara G. Freire * Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal; [email protected] (S.N.P.); [email protected] (C.S.R.F.); [email protected] (A.J.D.S.) * Correspondence: [email protected] Received: 25 September 2020; Accepted: 2 November 2020; Published: 5 November 2020 Abstract: Solubility, bioavailability, permeation, polymorphism, and stability concerns associated to solid-state pharmaceuticals demand for effective solutions. To overcome some of these drawbacks, ionic liquids (ILs) have been investigated as solvents, reagents, and anti-solvents in the synthesis and 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. The present review focuses on the use of ILs in the pharmaceutical field, covering their multiple applications from pharmaceutical synthesis to drug delivery. The most relevant research conducted up to date is presented and discussed, together with a critical analysis of the most significant IL-based strategies in order to improve the performance of therapeutics and drug delivery systems. Keywords: active pharmaceutical ingredients; drug delivery systems; formulations; ionic liquids; solubility; permeability 1. Introduction 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 Int. J. Mol. Sci. 2020, 21, 8298; doi:10.3390/ijms21218298 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 8298 2 of 50 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 [14–16]. 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 optionsInt. J. Mol. for Sci. commercialization 2020, 21, x FOR PEER REVIEW [17 ,18]. In addition to these, ionic liquids (ILs)2 discloseof 51 high potential in the pharmaceutical field, which is mainly due to their high versatility in terms of chemical must be controlled in order to ensure human consumption safety [12]. Despite the existence of structure designextensive towards literature a targetdescribing application. novel and “greener” ILs are molten solvents salts to this that purpose, are composed there is still of asome large organic cation andreluctance an organic by the/inorganic pharmaceutical anion. industry The largeto accept dimensions and implement of theirthese alternatives ions lead [14–16]. to charge dispersion, which makesIn di theffi cultabove the context, formation liquid forms of of a APIs regular are appealing crystalline solutions structure to avoid both [19, polymorphism20]. 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