Ionic Liquids in Pharmaceutical and Biomedical Applications

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Nanomedicine and Nanotechnology".

Deadline for manuscript submissions: closed (20 October 2023) | Viewed by 22157

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Guest Editor
NanoBioMedical Centre, Adam Mickiewicz University, Wszechnicy Piastowskiej 3, 61-614 Poznan, Poland
Interests: ionic liquids; nanodrug delivery; chemical engineering; green chemistry; biopolymers; polymer nanomaterials; synthesis; nanomaterials; material characterization; polymeric materials; nanomaterials synthesis; nanoparticle synthesis; polymerization
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Special Issue Information

Dear Colleagues,

It is my great pleasure to invite you to contribute research or review articles to a Special Issue of Pharmaceutics entitled Ionic Liquids in Pharmaceutical and Biomedical Applications. The application of ionic liquids (ILs) and deep eutectic solvents (DESs) in the biomedical sphere has gained increasing attention recently, mainly due to their unique properties and tunability, which allows for the development of materials with specific functions that can meet appropriate requirements. In the areas of pharmaceutics and biomedicine, ILs and DESs have already been used as active pharmaceutical ingredients and drug delivery systems, including nanoformulations. Moreover, their unique properties allow them to be used as antimicrobial, antifungal, and antiviral agents, as stabilizers for both drugs and proteins, and in biosensing applications.

This Special Issue aims to present recent trends and developments, including discussions about fundamental aspects and their applicability. Moreover, it will allow us to identify current challenges and future directions in the use of ionic liquids and deep eutectic solvents in pharmaceutics and biomedicine.

Original research papers, communications, review articles, and opinions are welcome.

We look forward to receiving your contributions.

Dr. Roksana Markiewicz
Guest Editor

Manuscript Submission Information

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Keywords

  • ionic liquids
  • deep eutectic solvents
  • active pharmaceutical ingredients (API)
  • drug delivery systems
  • antimicrobial properties
  • drug and protein stabilization
  • nanoformulations
  • biosensing

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Published Papers (10 papers)

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Research

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13 pages, 3248 KiB  
Article
Characterization of Graft Copolymers Synthesized from p-Aminosalicylate Functionalized Monomeric Choline Ionic Liquid
by Aleksy Mazur and Dorota Neugebauer
Pharmaceutics 2023, 15(11), 2556; https://doi.org/10.3390/pharmaceutics15112556 - 30 Oct 2023
Cited by 1 | Viewed by 877
Abstract
An ionic liquid based on the monomeric choline, specifically [2-(methacryloyloxy)ethyl]-trimethylammonium chloride (TMAMA), underwent biofunctionalization through an ion exchange reaction with the model drug anion: p-aminosalicylate (PAS), a primary antibiotic for tuberculosis treatment. This modified biocompatible IL monomer (TMAMA/PAS) was subsequently copolymerized with [...] Read more.
An ionic liquid based on the monomeric choline, specifically [2-(methacryloyloxy)ethyl]-trimethylammonium chloride (TMAMA), underwent biofunctionalization through an ion exchange reaction with the model drug anion: p-aminosalicylate (PAS), a primary antibiotic for tuberculosis treatment. This modified biocompatible IL monomer (TMAMA/PAS) was subsequently copolymerized with methyl methacrylate (MMA) to directly synthesize the well-defined graft conjugates with regulated content of ionic fraction with PAS anions (up to 49%), acting as drug delivery systems. The length of the polymeric side chains was assessed by the monomer conversions, yielding a degree of polymerization ranging from 12 to 89. The density of side chains was controlled by “grafting from” using the multifunctional macroinitiators. In vitro drug release, triggered by the ion exchange between the pharmaceutical and phosphate anions in a PBS medium, occurred in the range of 71–100% (2.8–9.8 μg/mL). Owing to significant drug content and consistent release profiles, these particular graft copolymers, derived from biomodified IL monomers with ionically attached pharmaceutical PAS in the side chains, are recognized as potentially effective drug delivery vehicles. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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21 pages, 3961 KiB  
Article
Cholinium-Based Ionic Liquids as Promising Antimicrobial Agents in Pharmaceutical Applications: Surface Activity, Antibacterial Activity and Ecotoxicological Profile
by María Teresa García, Elena Bautista, Ana de la Fuente and Lourdes Pérez
Pharmaceutics 2023, 15(7), 1806; https://doi.org/10.3390/pharmaceutics15071806 - 24 Jun 2023
Cited by 2 | Viewed by 2020
Abstract
Cholinium-based ionic liquids are compounds increasingly studied in pharmaceutics and biomedicine to enhance bioavailability in drug delivery systems and as bioactive ingredients in pharmaceutical formulations. However, their potential as antimicrobial agents has scarcely been investigated. Herein, we explored the antimicrobial activity of a [...] Read more.
Cholinium-based ionic liquids are compounds increasingly studied in pharmaceutics and biomedicine to enhance bioavailability in drug delivery systems and as bioactive ingredients in pharmaceutical formulations. However, their potential as antimicrobial agents has scarcely been investigated. Herein, we explored the antimicrobial activity of a series of surface-active cholinium-based ionic liquids (Chol-ILs). For this purpose, Chol-ILs with alkyl chains of 10–16 carbon atoms were synthesized and their self-assembly in aqueous medium was investigated. Subsequently, their antimicrobial activity against a panel of clinically relevant bacteria and their ability to eradicate MRSA and P. aeruginosa PAO1 biofilms was evaluated. Finally, we analyzed the ecotoxicological profile of Chol-ILs in terms of susceptibility to aerobic biodegradation and acute aquatic toxicity against D. magna and V. fisheri. Our results reveal that cholinium-based ILs with alkyl chain lengths ≥12 C show a broad spectrum of antibacterial activity. Their antimicrobial efficacy depends on their hydrophobicity, with the C14–C16 homologs being the most effective compounds. These ILs exhibit antimicrobial activity similar to that of imidazolium ILs and quaternary ammonium antiseptics. Moreover, the longer alkyl chain Chol-ILs are able to eradicate established biofilms at concentrations as low as 16–32 µg/mL. The biodegradation rate of cholinium-based ILs decreases with alkyl chain elongation. Our results reinforce the suitability of Chol-ILs as promising multifunctional compounds for application in pharmaceutical and biomedical formulation. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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11 pages, 1907 KiB  
Article
Deep Eutectic Solvents for Efficient Drug Solvation: Optimizing Composition and Ratio for Solubility of β-Cyclodextrin
by Ilan Shumilin, Ahmad Tanbuz and Daniel Harries
Pharmaceutics 2023, 15(5), 1462; https://doi.org/10.3390/pharmaceutics15051462 - 11 May 2023
Viewed by 1754
Abstract
Deep eutectic solvents (DESs) show promise in pharmaceutical applications, most prominently as excellent solubilizers. Yet, because DES are complex multi-component mixtures, it is challenging to dissect the contribution of each component to solvation. Moreover, deviations from the eutectic concentration lead to phase separation [...] Read more.
Deep eutectic solvents (DESs) show promise in pharmaceutical applications, most prominently as excellent solubilizers. Yet, because DES are complex multi-component mixtures, it is challenging to dissect the contribution of each component to solvation. Moreover, deviations from the eutectic concentration lead to phase separation of the DES, making it impractical to vary the ratios of components to potentially improve solvation. Water addition alleviates this limitation as it significantly decreases the melting temperature and stabilizes the DES single-phase region. Here, we follow the solubility of β-cyclodextrin (β-CD) in DES formed by the eutectic 2:1 mole ratio of urea and choline chloride (CC). Upon water addition to DES, we find that at almost all hydration levels, the highest β-CD solubility is achieved at DES compositions that are shifted from the 2:1 ratio. At higher urea to CC ratios, due to the limited solubility of urea, the optimum composition allowing the highest β-CD solubility is reached at the DES solubility limit. For mixtures with higher CC concentration, the composition allowing optimal solvation varies with hydration. For example, β-CD solubility at 40 wt% water is enhanced by a factor of 1.5 for a 1:2 urea to CC mole ratio compared with the 2:1 eutectic ratio. We further develop a methodology allowing us to link the preferential accumulation of urea and CC in the vicinity of β-CD to its increased solubility. The methodology we present here allows a dissection of solute interactions with DES components that is crucial for rationally developing improved drug and excipient formulations. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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23 pages, 18504 KiB  
Article
Effect of Ionic Liquid on Silver-Nanoparticle-Complexed Ganoderma applanatum and Its Topical Film Formulation
by Pattwat Maneewattanapinyo, Wiwat Pichayakorn, Chaowalit Monton, Nattakan Dangmanee, Thaniya Wunnakup and Jirapornchai Suksaeree
Pharmaceutics 2023, 15(4), 1098; https://doi.org/10.3390/pharmaceutics15041098 - 29 Mar 2023
Cited by 5 | Viewed by 1345
Abstract
Imidazolium-based ionic liquids have been widely utilized as versatile solvents for metal nanoparticle preparation. Silver nanoparticles and Ganoderma applanatum have displayed potent antimicrobial activities. This work aimed to study the effect of 1-butyl-3-methylimidazolium bromide-based ionic liquid on the silver-nanoparticle-complexed G. applanatum and its [...] Read more.
Imidazolium-based ionic liquids have been widely utilized as versatile solvents for metal nanoparticle preparation. Silver nanoparticles and Ganoderma applanatum have displayed potent antimicrobial activities. This work aimed to study the effect of 1-butyl-3-methylimidazolium bromide-based ionic liquid on the silver-nanoparticle-complexed G. applanatum and its topical film. The ratio and conditions for preparation were optimized by the design of the experiments. The optimal ratio was silver nanoparticles: G. applanatum extract: ionic liquid at 97:1:2, and the conditions were 80 °C for 1 h. The prediction was corrected with a low percentage error. The optimized formula was loaded into a topical film made of polyvinyl alcohol and Eudragit®, and its properties were evaluated. The topical film was uniform, smooth, and compact and had other desired characteristics. The topical film was able to control the release of silver-nanoparticle-complexed G. applanatum from the matrix layer. Higuchi’s model was used to fit the kinetic of the release. The skin permeability of the silver-nanoparticle-complexed G. applanatum was improved by about 1.7 times by the ionic liquid, which might increase solubility. The produced film is suitable for topical applications and may be utilized in the development of potential future therapeutic agents for the treatment of diseases. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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21 pages, 2842 KiB  
Article
N-Benzylethanolammonium Ionic Liquids and Molten Salts in the Synthesis of 68Ga- and Al18F-Labeled Radiopharmaceuticals
by Yulia A. Kondratenko, Julia S. Shilova, Vladislav A. Gavrilov, Andrey A. Zolotarev, Michail A. Nadporojskii, Tatyana A. Kochina and Dmitrii O. Antuganov
Pharmaceutics 2023, 15(2), 694; https://doi.org/10.3390/pharmaceutics15020694 - 18 Feb 2023
Cited by 2 | Viewed by 1324
Abstract
Ionic liquids (ILs), due to their structural features, have unique physical and chemical properties and are environmentally friendly. Every year, the number of studies devoted to the use of ILs in medicine and pharmaceutics is growing. In nuclear medicine, the use of ILs [...] Read more.
Ionic liquids (ILs), due to their structural features, have unique physical and chemical properties and are environmentally friendly. Every year, the number of studies devoted to the use of ILs in medicine and pharmaceutics is growing. In nuclear medicine, the use of ILs with self-buffering capacity in the synthesis of radiopharmaceuticals is extremely important. This research is devoted to obtaining new ionic buffer agents containing N-benzylethanolammonium (BEA) cations and anions of carboxylic acids. A series of new BEA salts was synthesized and identified by NMR (1H, 13C), IR spectroscopy and elemental and thermal analysis. The crystal structures of BEA hydrogen succinate, hydrogen oxalate and oxalate were determined by x-ray diffraction. Newly synthesized compounds were tested as buffer solutions in 68Ga- and Al18F-radiolabeling reactions with a series of bifunctional chelating agents and clinically relevant peptides used for visualization of malignancies by positron emission tomography. The results obtained confirm the promise of using new buffers in the synthesis of 68Ga- and Al18F-labeled radiopharmaceuticals. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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20 pages, 4958 KiB  
Article
Novel Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles and Biochemical Valuation on F1FO-ATPase and Mitochondrial Permeability Transition Pore Formation
by Vincenzo Algieri, Cristina Algieri, Paola Costanzo, Giulia Fiorani, Antonio Jiritano, Fabrizio Olivito, Matteo Antonio Tallarida, Fabiana Trombetti, Loredana Maiuolo, Antonio De Nino and Salvatore Nesci
Pharmaceutics 2023, 15(2), 498; https://doi.org/10.3390/pharmaceutics15020498 - 2 Feb 2023
Cited by 4 | Viewed by 1928
Abstract
An efficient, eco-compatible, and very cheap method for the construction of fully substituted pyrazoles (Pzs) via eliminative nitrilimine-alkene 1,3-dipolar cycloaddition (ENAC) reaction was developed in excellent yield and high regioselectivity. Enaminones and nitrilimines generated in situ were selected as dipolarophiles and dipoles, respectively. [...] Read more.
An efficient, eco-compatible, and very cheap method for the construction of fully substituted pyrazoles (Pzs) via eliminative nitrilimine-alkene 1,3-dipolar cycloaddition (ENAC) reaction was developed in excellent yield and high regioselectivity. Enaminones and nitrilimines generated in situ were selected as dipolarophiles and dipoles, respectively. A deep screening of the employed base, solvent, and temperature was carried out to optimize reaction conditions. Recycling tests of ionic liquid were performed, furnishing efficient performance until six cycles. Finally, a plausible mechanism of cycloaddition was proposed. Then, the effect of three different structures of Pzs was evaluated on the F1FO-ATPase activity and mitochondrial permeability transition pore (mPTP) opening. The Pz derivatives’ titration curves of 6a, 6h, and 6o on the F1FO-ATPase showed a reduced activity of 86%, 35%, and 31%, respectively. Enzyme inhibition analysis depicted an uncompetitive mechanism with the typical formation of the tertiary complex enzyme-substrate-inhibitor (ESI). The dissociation constant of the ESI complex (Ki’) in the presence of the 6a had a lower order of magnitude than other Pzs. The pyrazole core might set the specific mechanism of inhibition with the F1FO-ATPase, whereas specific functional groups of Pzs might modulate the binding affinity. The mPTP opening decreased in Pz-treated mitochondria and the Pzs’ inhibitory effect on the mPTP was concentration-dependent with 6a and 6o. Indeed, the mPTP was more efficiently blocked with 0.1 mM 6a than with 1 mM 6a. On the contrary, 1 mM 6o had stronger desensitization of mPTP formation than 0.1 mM 6o. The F1FO-ATPase is a target of Pzs blocking mPTP formation. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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20 pages, 10982 KiB  
Article
Studies on the Interaction between Model Proteins and Fluorinated Ionic Liquids
by Márcia M. S. Alves, Manuel N. Melo, Haydyn D. T. Mertens, Ana B. Pereiro and Margarida Archer
Pharmaceutics 2023, 15(1), 157; https://doi.org/10.3390/pharmaceutics15010157 - 3 Jan 2023
Cited by 4 | Viewed by 1567
Abstract
Proteins are inherently unstable, which limits their use as therapeutic agents. However, the use of biocompatible cosolvents or surfactants can help to circumvent this problem through the stabilization of intramolecular and solvent-mediated interactions. Ionic liquids (ILs) have been known to act as cosolvents [...] Read more.
Proteins are inherently unstable, which limits their use as therapeutic agents. However, the use of biocompatible cosolvents or surfactants can help to circumvent this problem through the stabilization of intramolecular and solvent-mediated interactions. Ionic liquids (ILs) have been known to act as cosolvents or surface-active compounds. In the presence of proteins, ILs can have a beneficial effect on their refolding, shelf life, stability, and enzymatic activities. In the work described herein, we used small-angle X-ray scattering (SAXS) to monitor the aggregation of different concentrations of ILs with protein models, lysozyme (Lys) and bovine serum albumin (BSA), and fluorescence microscopy to assess micelle formation of fluorinated ILs (FILs) with Lys. Furthermore, coarse-grained molecular dynamics (CG-MD) simulations provided a better understanding of Lys–FIL interactions. The results showed that the proteins maintain their globular structures in the presence of FILs, with signs of partial unfolding for Lys and compaction for BSA with increased flexibility at higher FIL concentrations. Lys was encapsulated by FIL, thus reinforcing the potential of ILs to be used in the formulation of protein-based pharmaceuticals. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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Review

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28 pages, 4185 KiB  
Review
Recent Advances in Biocompatible Ionic Liquids in Drug Formulation and Delivery
by Rahman Md Moshikur, Rebecca L. Carrier, Muhammad Moniruzzaman and Masahiro Goto
Pharmaceutics 2023, 15(4), 1179; https://doi.org/10.3390/pharmaceutics15041179 - 7 Apr 2023
Cited by 10 | Viewed by 3050
Abstract
The development of effective drug formulations and delivery systems for newly developed or marketed drug molecules remains a significant challenge. These drugs can exhibit polymorphic conversion, poor bioavailability, and systemic toxicity, and can be difficult to formulate with traditional organic solvents due to [...] Read more.
The development of effective drug formulations and delivery systems for newly developed or marketed drug molecules remains a significant challenge. These drugs can exhibit polymorphic conversion, poor bioavailability, and systemic toxicity, and can be difficult to formulate with traditional organic solvents due to acute toxicity. Ionic liquids (ILs) are recognized as solvents that can improve the pharmacokinetic and pharmacodynamic properties of drugs. ILs can address the operational/functional challenges associated with traditional organic solvents. However, many ILs are non-biodegradable and inherently toxic, which is the most significant challenge in developing IL-based drug formulations and delivery systems. Biocompatible ILs comprising biocompatible cations and anions mainly derived from bio-renewable sources are considered a green alternative to both conventional ILs and organic/inorganic solvents. This review covers the technologies and strategies developed to design biocompatible ILs, focusing on the design of biocompatible IL-based drug formulations and delivery systems, and discusses the advantages of these ILs in pharmaceutical and biomedical applications. Furthermore, this review will provide guidance on transitioning to biocompatible ILs rather than commonly used toxic ILs and organic solvents in fields ranging from chemical synthesis to pharmaceutics. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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18 pages, 1098 KiB  
Review
Role and Recent Advancements of Ionic Liquids in Drug Delivery Systems
by Monu Kumar Shukla, Harshita Tiwari, Rachna Verma, Wen-Liang Dong, Shavkatjon Azizov, Brajesh Kumar, Sadanand Pandey and Deepak Kumar
Pharmaceutics 2023, 15(2), 702; https://doi.org/10.3390/pharmaceutics15020702 - 20 Feb 2023
Cited by 20 | Viewed by 3532
Abstract
Advancements in the fields of ionic liquids (ILs) broaden its applications not only in traditional use but also in different pharmaceutical and biomedical fields. Ionic liquids “Solutions for Your Success” have received a lot of interest from scientists due to a myriad of [...] Read more.
Advancements in the fields of ionic liquids (ILs) broaden its applications not only in traditional use but also in different pharmaceutical and biomedical fields. Ionic liquids “Solutions for Your Success” have received a lot of interest from scientists due to a myriad of applications in the pharmaceutical industry for drug delivery systems as well as targeting different diseases. Solubility is a critical physicochemical property that determines the drug’s fate at the target site. Many promising drug candidates fail in various phases of drug research due to poor solubility. In this context, ionic liquids are regarded as effective drug delivery systems for poorly soluble medicines. ILs are also able to combine different anions/cations with other cations/anions to produce salts that satisfy the concept behind the ILs. The important characteristics of ionic liquids are the modularity of their physicochemical properties depending on the application. The review highlights the recent advancement and further applications of ionic liquids to deliver drugs in the pharmaceutical and biomedical fields. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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25 pages, 4269 KiB  
Review
Deep Eutectic Systems as Novel Vehicles for Assisting Drug Transdermal Delivery
by Jinbao Wang, Mingjian Li, Langhuan Duan, Yameng Lin, Xiuming Cui, Ye Yang and Chengxiao Wang
Pharmaceutics 2022, 14(11), 2265; https://doi.org/10.3390/pharmaceutics14112265 - 23 Oct 2022
Cited by 13 | Viewed by 3314
Abstract
In recent years, deep eutectic systems (DES) emerged as novel vehicles for facilitating the transdermal delivery of various drugs, including polysaccharides, proteins, insulin, vaccine, nanoparticles, and herb extracts. The objective of this study is to conduct a comprehensive review of the application of [...] Read more.
In recent years, deep eutectic systems (DES) emerged as novel vehicles for facilitating the transdermal delivery of various drugs, including polysaccharides, proteins, insulin, vaccine, nanoparticles, and herb extracts. The objective of this study is to conduct a comprehensive review of the application of DES to transdermal drug delivery, based on previous work and the reported references. Following a brief overview, the roles of DES in TDDS, the modes of action, as well as the structure–activity relationship of DES are discussed. Particularly, the skin permeation of active macromolecules and rigid nanoparticles, which are the defining characteristics of DES, are extensively discussed. The objective is to provide a comprehensive understanding of the current investigation and development of DES-based transdermal delivery systems, as well as a framework for the construction of novel DES-TDDS in the future. Full article
(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications)
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