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The Role of Ionic Liquids in the Pharmaceutical Field: an Overview of Relevant Applications

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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]. ILs display and a set of unique features,improve fromlow-water which solubility is possible constraints, to highlight, while allowing if properly to reduce designed, organic solvents their highuse. The thermal and pharmaceutical industry has relied on eutectic mixtures for this purpose, shortly exploring other options chemical stabilityfor commercialization and a strong [17,18]. solvation In addition ability to these, for ionic a wide liquids variety (ILs) disclose of compounds high potential [21 in]. the The proper selection ofpharmaceutical cation-anion field, combinations which is mainly indue ILs to their enables high versatility the use in of terms drugs of chemical as ion components,structure design allowing for the conversiontowards a target of solid application. active ILs pharmaceutical are molten salts that ingredients are composed into of liquida large organic forms cation (API-ILs). and an Thus, this strategy solvesorganic/inorganic the problem anion. ofThe polymorphism large dimensions of and their provides ions lead improvedto charge dispersion, bioavailability, which makes and ideally difficult the formation of a regular crystalline structure [19,20]. ILs display a set of unique features, from boosts therapeutic properties [3,22]. which is possible to highlight, if properly designed, their high thermal and chemical stability and a strong Becausesolvation of the ability unique for a wide properties variety of compounds of ILs, their [21]. application The proper selection in the of pharmaceuticalcation-anion combinations field has been extended farin ILs beyond enables the the developmentuse of drugs as of ion novel components, liquid formsallowing (API-ILs), for the conversion being investigatedof solid active as well in other stagespharmaceutical of drug development ingredients into and liquid delivery. forms The(API-ILs). number Thus, ofthis publications strategy solves related the problem to the of application of ILs in thepolymorphism pharmaceutical and provides field hasimproved grown bioavailability, exponentially and ideally in the boos pastts therapeutic 20 years, properties as illustrated [3,22]. in Figure1. Because of the unique properties of ILs, their application in the pharmaceutical field has been ILs have beenextended applied far beyond in the the development development of novel purification liquid forms platforms (API-ILs), for being pharmaceuticals investigated as well (an in application out of the scopeother stages of this of drug review), development for which and delivery. some recent The number review of manuscriptspublications related exist to [ the23– application25]. Other relevant reviews andof ILs book in the chapterspharmaceutical recognizing field has grown the exponentially advances of in ILsthe past in 20 di ffyears,erent as illustrated areas of in pharmaceuticals Figure development,1. ILs spanning have been fromapplied their in the formulation, development biologicalof purification activity, platforms and for application pharmaceuticals on drug (an delivery application out of the scope of this review), for which some recent review manuscripts exist [23–25]. are also availableOther relevant [22, 26reviews–34]. and However, book chapters most recogniz of theseing focusthe advances on a specificof ILs in applicationdifferent areas of of ILs in the pharmaceuticalpharmaceuticals field. On development, the other hand,spanning this from review their formulation, compiles andbiological discusses activity, the and most application relevant works and overallon applicationsdrug delivery are of also ILs available in the [22,26–34]. pharmaceutical However, most field, of namelythese focus on on thea specific role application of ILs as solvents, reagents, andof ILs/or in catalyststhe pharmaceutical in the APIs’ field. On synthesis, the other hand, in the this APIs review crystallization, compiles and discusses as solvents, the most co-solvents, relevant works and overall applications of ILs in the pharmaceutical field, namely on the role of ILs and emulsifiersas solvents, to improve reagents, and/or drugs catalysts solubility, in the as APIs’ a way synthesis, of producing in the APIs liquidcrystallization, forms as of solvents, APIs, and in the developmentco-solvents, of drug and delivery emulsifiers systems.
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    (19) & (11) EP 2 219 642 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/357 (2006.01) A61P 1/16 (2006.01) 21.09.2011 Bulletin 2011/38 A61P 31/12 (2006.01) (21) Application number: 08849759.9 (86) International application number: PCT/EP2008/009659 (22) Date of filing: 14.11.2008 (87) International publication number: WO 2009/062737 (22.05.2009 Gazette 2009/21) (54) SILIBININ COMPONENT FOR THE TREATMENT OF HEPATITIS SILBININKOMPONENTE ZUR BEHANDLUNG VON HEPATITIS COMPOSANT DE SILIBININE POUR LE TRAITEMENT DE L’HÉPATITE (84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR WO-A-02/067853 GB-A- 2 167 414 HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR • POLYAK STEPHEN J ET AL: "Inhibition of T- cell inflammatory cytokines, hepatocyte NF-kappa B (30) Priority: 15.11.2007 EP 07022187 signaling, and HCV infection by standardized 15.11.2007 US 988168 P silymarin" GASTROENTEROLOGY, vol. 132, no. 25.03.2008 EP 08005459 5, May 2007 (2007-05), pages 1925-1936, XP002477920 ISSN: 0016-5085 (43) Date of publication of application: • MAYER K E ET AL: "Silymarin treatment of viral 25.08.2010 Bulletin 2010/34 hepatitis: A systematic review" JOURNAL OF VIRAL HEPATITIS 200511 GB, vol. 12, no. 6, (60) Divisional application: November 2005 (2005-11), pages 559-567, 11005445.9 XP002477921 ISSN: 1352-0504 1365-2893 • CHAVEZ M L: "TREATMENT OF HEPATITIS C (73) Proprietor: Madaus GmbH WITH MILK THISTLE?" JOURNAL OF HERBAL 51067 Köln (DE) PHARMACOTHERAPY, HAWORTH HERBAL PRESS, BINGHAMTON, US, vol.