Green Chemistry CRITICAL REVIEW Cite this: Green Chem., 2020, 22, 8116 Received 13th July 2020, Accepted 14th September 2020 DOI: 10.1039/d0gc02387f rsc.li/greenchem Biocompatible ionic liquids and their applications in pharmaceutics Rahman Md Moshikur, † a Md. Raihan Chowdhury, † a Muhammad Moniruzzaman b and Masahiro Goto * a,c,d Ionic liquids (ILs) have been used as solvents or materials, or both, in many applications, including phar- maceutics and medicine due to their exceptional properties consisting of the combination of “green” pro- perties with tunable physicochemical and biological properties. The use of ILs in the pharmaceutical industry can address many challenges associated with the use of conventional organic solvents or water. ILs have been established as potential solvents to solubilize many insoluble or sparingly soluble drugs for formulations or delivery. The use of ILs can also address many of the drawbacks of solid-state drugs, including polymorphism and low solubility, stability, and bioavailability. However, many ILs are inherently toxic, which is the main challenge toward developing IL-based drug formulations and drug delivery systems. The use of second- and third-generation ILs comprising more biocompatible cations and anions, compared with the first-generation ILs, has considerably addressed the toxicity issue. A wide range of biocompatible ILs have been designed to improve the pharmacokinetic and pharmacodynamic properties, as well as the biological activity, of drugs. This review describes the advances in the area of green IL-related research and emphasizes the new conceptual development of ILs in pharmaceutics and medicine. Particular attention is given to the mechanistic knowledge in the synthesis of ILs, as well as to the ecotoxicological and biological impact of biocompatible ILs, stimulating the understanding of innova- tive technologies in IL-based drug delivery systems. 1. Introduction The development of smart drug formulations and delivery systems for the management of various diseases is a challen- ging task for pharmaceutical industries to accomplish without compromising on the safety and efficacy of the drugs. To meet this challenge, many innovative drugs have been developed with new biological properties. For example, in 2018, The Food and Drug Administration (FDA) approved 59 novel drugs: 42 new chemical entities and 17 biologics. 1 However, most drugs in development do not reach the formulation stage because of their insolubility or poor solubility in water and most of the pharmaceutically accepted organic solvents or agents. 2–6 A variety of pharmaceutical approaches, such as using prodrugs or salt formulations, nanoemulsions, micellization, solid dis- persions, cyclodextrin inclusions, hydrate and solvate prep- arations, and nanoparticles have been considered to enable the delivery of water insoluble drugs and have shown promise in enhancing the bioavailability. 6 However, large amounts of organic solvents are used to formulate these drugs, which may be detrimental to human health, as well as ecosystems. 7 Therefore, green techniques are desirable for the effective delivery of such insoluble drugs, with minimal systemic adverse effects. Ionic liquids (ILs) are a topic of scientific interest for researchers and have attracted attention in many areas of modern science since the mid-1990s. 5 In 2018, more than 7000 articles were listed in the Scopus® database, indicating the importance of ILs as a potential “green solvent”. ILs are defined as a class of molten organic salts typically composed of unsymmetrical organic cations and inorganic or organic anions with melting points at or below 100 °C. 5,8,9 The physicochemical properties of ILs can be easily modified by simply changing the combinations of the cations and anions, as well as the substituents on the cations or anions, 3,10 leading to the term “designer solvents”. 11 Currently, the following three generations of ILs are available for various applications. † These authors contributed equally to this work. a Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan. E-mail: m-goto@mail.cstm.kyushu-u.ac.jp; Fax: +81 92 802 2810; Tel: +8192 802 2806 b Chemical Engineering Department, Universiti Teknologi PETRONAS, 32610 Seri Iskandar, Perak, Malaysia c Advanced Transdermal Drug Delivery System Center, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan d Division of Biotechnology, Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan 8116 | Green Chem. , 2020, 22, 8116–8139 This journal is © The Royal Society of Chemistry 2020