Special Issue "Ionic Liquids and Deep Eutectic Solvents for Application in Pharmaceutics"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (31 May 2020).

Special Issue Editors

Dr. Luis Cobra Branco
E-Mail Website
Guest Editor
Departamento de Química, LAQV-REQUIMTE, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2825-149 Caparica, Portugal
Interests: sustainable chemistry; ionic liquids; catalysis; material science; responsive materials; energy; pharmaceuticals
Special Issues and Collections in MDPI journals
Dr. Miguel Santos
E-Mail Website
Guest Editor
Department of Chemistry, Universidade NOVA de Lisboa, Calçada de Alfazina 2, 2825-149 Caparica, Portugal
Interests: active pharmaceutical ingredients as organic salts and ionic liquids; API-OSILs; bioavailability; drug delivery; ionic liquids
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Over the last decades, Ionic Liquids (ILs) and Deep Eutectic Solvents (DES) have been studied academically throughout many fields of chemical and biological research, including pharmaceutical sciences, due to their highly tuneable physical, chemical and physicochemical properties. In the particular area of pharmaceutics, ILs have been studied as alternative green solvents for the preparation, purification and crystallization of active pharmaceutical ingredients (APIs). However, the tailorable properties of ILs and DES render them distinct interactions with cellular membranes and organelles, enabling a myriad of applications ranging from bactericidal agents against pathological microorganisms to innovative materials for transdermal drug and protein delivery. ILs and DES have also found use in the manipulation of naturally occurring matrixes such as polysaccharides, yielding outstanding materials suitable for tissue regeneration and wound healing, as well as gene and drug delivery. Furthermore, the formation of ILs by combination of ionisable APIs with biocompatible organic counter-ions (API-ILs) has shown striking evidence over the last decade as a very capable instrument to enhance the bioavailability of poorly water and/or lipid soluble drugs, in addition to reduce or even eliminate polymorphism, yielding more effective formulations of commercial drugs.

In this Special Issue we focus on revealing fascinating developments covering all applications of Ionic Liquids and Deep Eutectic Solvents in pharmaceutical sciences.

Dr. Luis Branco
Dr. Miguel Santos
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Ionic Liquids (ILs)
  • Deep Eutectic Solvents (DES)
  • Drug Delivery
  • Drug Bioavailability
  • Polymorphism
  • Cytotoxicity
  • Pharmaceutical Ionic Liquids (API-ILs)
  • Therapeutic Deep Eutectic Solvents (THEDES)

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Published Papers (8 papers)

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Editorial

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Editorial
Ionic Liquids and Deep Eutectic Solvents for Application in Pharmaceutics
Pharmaceutics 2020, 12(10), 909; https://doi.org/10.3390/pharmaceutics12100909 - 23 Sep 2020
Cited by 4 | Viewed by 724
Abstract
Over the last few decades, Ionic Liquids (ILs) and Deep Eutectic Solvents (DES) have been studied academically throughout many fields of chemical and biological research, including pharmaceutical sciences, due to their highly tunable physical, chemical and physicochemical properties [...] Full article

Research

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Article
Antimicrobial Activities of Highly Bioavailable Organic Salts and Ionic Liquids from Fluoroquinolones
Pharmaceutics 2020, 12(8), 694; https://doi.org/10.3390/pharmaceutics12080694 - 23 Jul 2020
Cited by 8 | Viewed by 1021
Abstract
As the development of novel antibiotics has been at a halt for several decades, chemically enhancing existing drugs is a very promising approach to drug development. Herein, we report the preparation of twelve organic salts and ionic liquids (OSILs) from ciprofloxacin and norfloxacin [...] Read more.
As the development of novel antibiotics has been at a halt for several decades, chemically enhancing existing drugs is a very promising approach to drug development. Herein, we report the preparation of twelve organic salts and ionic liquids (OSILs) from ciprofloxacin and norfloxacin as anions with enhanced antimicrobial activity. Each one of the fluoroquinolones (FQs) was combined with six different organic hydroxide cations in 93–100% yield through a buffer-assisted neutralization methodology. Six of those were isomorphous salts while the remaining six were ionic liquids, with four of them being room temperature ionic liquids. The prepared compounds were not toxic to healthy cell lines and displayed between 47- and 1416-fold more solubility in water at 25 and 37 °C than the original drugs, with the exception of the ones containing the cetylpyridinium cation. In general, the antimicrobial activity against Klebsiella pneumoniae was particularly enhanced for the ciprofloxacin-based OSILs, with up to ca. 20-fold decreases of the inhibitory concentrations in relation to the parent drug, while activity against Staphylococcus aureus and the commensal Bacillus subtilis strain was often reduced. Depending on the cation–drug combination, broad-spectrum or strain-specific antibiotic salts were achieved, potentially leading to the future development of highly bioavailable and safe antimicrobial ionic formulations. Full article
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Article
Ionic Liquid-In-Oil Microemulsions Prepared with Biocompatible Choline Carboxylic Acids for Improving the Transdermal Delivery of a Sparingly Soluble Drug
Pharmaceutics 2020, 12(4), 392; https://doi.org/10.3390/pharmaceutics12040392 - 24 Apr 2020
Cited by 16 | Viewed by 1420
Abstract
The transdermal delivery of sparingly soluble drugs is challenging due to of the need for a drug carrier. In the past few decades, ionic liquid (IL)-in-oil microemulsions (IL/O MEs) have been developed as potential carriers. By focusing on biocompatibility, we report on an [...] Read more.
The transdermal delivery of sparingly soluble drugs is challenging due to of the need for a drug carrier. In the past few decades, ionic liquid (IL)-in-oil microemulsions (IL/O MEs) have been developed as potential carriers. By focusing on biocompatibility, we report on an IL/O ME that is designed to enhance the solubility and transdermal delivery of the sparingly soluble drug, acyclovir. The prepared MEs were composed of a hydrophilic IL (choline formate, choline lactate, or choline propionate) as the non-aqueous polar phase and a surface-active IL (choline oleate) as the surfactant in combination with sorbitan laurate in a continuous oil phase. The selected ILs were all biologically active ions. Optimized pseudo ternary phase diagrams indicated the MEs formed thermodynamically stable, spherically shaped, and nano-sized (<100 nm) droplets. An in vitro drug permeation study, using pig skin, showed the significantly enhanced permeation of acyclovir using the ME. A Fourier transform infrared spectroscopy study showed a reduction of the skin barrier function with the ME. Finally, a skin irritation study showed a high cell survival rate (>90%) with the ME compared with Dulbecco’s phosphate-buffered saline, indicates the biocompatibility of the ME. Therefore, we conclude that IL/O ME may be a promising nano-carrier for the transdermal delivery of sparingly soluble drugs. Full article
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Article
Anticrystal Engineering of Ketoprofen and Ester Local Anesthetics: Ionic Liquids or Deep Eutectic Mixtures?
Pharmaceutics 2020, 12(4), 368; https://doi.org/10.3390/pharmaceutics12040368 - 17 Apr 2020
Cited by 7 | Viewed by 1537
Abstract
Ionic liquids (ILs) and deep eutectic mixtures (DEMs) are potential solutions to the problems of low solubility, polymorphism, and low bioavailability of drugs. The aim of this work was to develop and investigate ketoprofen (KET)-based ILs/DEMs containing an ester local anesthetic (LA): benzocaine [...] Read more.
Ionic liquids (ILs) and deep eutectic mixtures (DEMs) are potential solutions to the problems of low solubility, polymorphism, and low bioavailability of drugs. The aim of this work was to develop and investigate ketoprofen (KET)-based ILs/DEMs containing an ester local anesthetic (LA): benzocaine (BEN), procaine (PRO) and tetracaine (TET) as the second component. ILs/DEMs were prepared via a mechanosynthetic process that involved the mixing of KET with an LA in a range of molar ratios and applying a thermal treatment. After heating above the melting point and quench cooling, the formation of supercooled liquids with Tgs that were dependent on the composition was observed for all KET-LA mixtures with exception of that containing 95 mol% of BEN. The KET-LA mixtures containing either ≥ 60 mol% BEN or 95 mol% of TET showed crystallization to BEN and TET, respectively, during either cooling or second heating. KET decreased the crystallization tendency of BEN and TET and increased their glass-forming ability. The KET-PRO systems showed good glass-forming ability and did not crystallize either during the cooling or during the second heating cycle irrespective of the composition. Infrared spectroscopy and molecular modeling indicated that KET and LAs formed DEMs, but in the KET-PRO systems small quantities of carboxylate anions were present. Full article
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Article
Alendronic Acid as Ionic Liquid: New Perspective on Osteosarcoma
Pharmaceutics 2020, 12(3), 293; https://doi.org/10.3390/pharmaceutics12030293 - 24 Mar 2020
Cited by 7 | Viewed by 1041
Abstract
Herein the quantitative synthesis of eight new mono- and dianionic Organic Salts and Ionic Liquids (OSILs) from alendronic acid (ALN) is reported by following two distinct sustainable and straightforward methodologies, according to the type of cation. The prepared ALN-OSILs were characterized by spectroscopic [...] Read more.
Herein the quantitative synthesis of eight new mono- and dianionic Organic Salts and Ionic Liquids (OSILs) from alendronic acid (ALN) is reported by following two distinct sustainable and straightforward methodologies, according to the type of cation. The prepared ALN-OSILs were characterized by spectroscopic techniques and their solubility in water and biological fluids was determined. An evaluation of the toxicity towards human healthy cells and also human breast, lung and bone (osteosarcoma) cell lines was performed. Globally, it was observed that the monoanionic OSILs showed lower toxicity than the corresponding dianionic structures to all cell types. The highest cytotoxic effect was observed in OSILs containing a [C2OHMIM] cation, in particular [C2OHMIM][ALN]. The latter showed an improvement in IC50 values of ca. three orders of magnitude for the lung and bone cancer cell lines as well as fibroblasts in comparison with ALN. The development of OSILs with high cytotoxicity effect towards the tested cancer cell types, and containing an anti-resorbing molecule such as ALN may represent a promising strategy for the development of new pharmacological tools to be used in those pathological conditions. Full article
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Article
Synthesis and Antibacterial Activity of Ionic Liquids and Organic Salts Based on Penicillin G and Amoxicillin hydrolysate Derivatives against Resistant Bacteria
Pharmaceutics 2020, 12(3), 221; https://doi.org/10.3390/pharmaceutics12030221 - 02 Mar 2020
Cited by 16 | Viewed by 1828
Abstract
The preparation and characterization of ionic liquids and organic salts (OSILs) that contain anionic penicillin G [secoPen] and amoxicillin [seco-Amx] hydrolysate derivatives and their in vitro antibacterial activity against sensitive and resistant Escherichia coli and Staphylococcus aureus strains is reported. Eleven [...] Read more.
The preparation and characterization of ionic liquids and organic salts (OSILs) that contain anionic penicillin G [secoPen] and amoxicillin [seco-Amx] hydrolysate derivatives and their in vitro antibacterial activity against sensitive and resistant Escherichia coli and Staphylococcus aureus strains is reported. Eleven hydrolyzed β-lactam-OSILs were obtained after precipitation in moderate-to-high yields via the neutralization of the basic ammonia buffer of antibiotics with different cation hydroxide salts. The obtained minimum inhibitory concentration (MIC) data of the prepared compounds showed a relative decrease of the inhibitory concentrations (RDIC) in the order of 100 in the case of [C2OHMIM][seco-Pen] against sensitive S. aureus ATCC25923 and, most strikingly, higher than 1000 with [C16Pyr][seco-Amx] against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300. These outstanding in vitro results showcase that a straightforward transformation of standard antibiotics into hydrolyzed organic salts can dramatically change the pharmaceutical activity of a drug, including giving rise to potent formulations of antibiotics against deadly bacteria strains. Full article
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Article
Ionic Liquid Forms of the Antimalarial Lumefantrine in Combination with LFCS Type IIIB Lipid-Based Formulations Preferentially Increase Lipid Solubility, In Vitro Solubilization Behavior and In Vivo Exposure
Pharmaceutics 2020, 12(1), 17; https://doi.org/10.3390/pharmaceutics12010017 - 22 Dec 2019
Cited by 6 | Viewed by 1385
Abstract
Lipid based formulations (LBFs) are commonly employed to enhance the absorption of highly lipophilic, poorly water-soluble drugs. However, the utility of LBFs can be limited by low drug solubility in the formulation. Isolation of ionizable drugs as low melting, lipophilic salts or ionic [...] Read more.
Lipid based formulations (LBFs) are commonly employed to enhance the absorption of highly lipophilic, poorly water-soluble drugs. However, the utility of LBFs can be limited by low drug solubility in the formulation. Isolation of ionizable drugs as low melting, lipophilic salts or ionic liquids (ILs) provides one means to enhance drug solubility in LBFs. However, whether different ILs benefit from formulation in different LBFs is largely unknown. In the current studies, lumefantrine was isolated as a number of different lipophilic salt/ionic liquid forms and performance was assessed after formulation in a range of LBFs. The solubility of lumefantrine in LBF was enhanced 2- to 80-fold by isolation as the lumefantrine docusate IL when compared to lumefantrine free base. The increase in drug loading subsequently enhanced concentrations in the aqueous phase of model intestinal fluids during in vitro dispersion and digestion testing of the LBF. To assess in vivo performance, the systemic exposure of lumefantrine docusate after administration in Type II-MCF, IIIB-MCF, IIIB-LCF, and IV formulations was evaluated after oral administration to rats. In vivo exposure was compared to control lipid and aqueous suspension formulations of lumefantrine free base. Lumefantrine docusate in the Type IIIB-LCF showed significantly higher plasma exposure compared to all other formulations (up to 35-fold higher). The data suggest that isolation of a lipid-soluble IL, coupled with an appropriate formulation, is a viable means to increase drug dose in an oral formulation and to enhance exposure of lumefantrine in vivo. Full article
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Review

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Review
Ionic Liquids as Potential and Synergistic Permeation Enhancers for Transdermal Drug Delivery
Pharmaceutics 2019, 11(2), 96; https://doi.org/10.3390/pharmaceutics11020096 - 22 Feb 2019
Cited by 32 | Viewed by 2711
Abstract
Transdermal drug delivery systems (TDDS) show clear advantages over conventional routes of drug administration. Nonetheless, there are limitations to current TDDS which warrant further research to improve current TDD platforms. Spurred by the synthesis of novel biodegradable ionic liquids (ILs) and favorable cytotoxicity [...] Read more.
Transdermal drug delivery systems (TDDS) show clear advantages over conventional routes of drug administration. Nonetheless, there are limitations to current TDDS which warrant further research to improve current TDD platforms. Spurred by the synthesis of novel biodegradable ionic liquids (ILs) and favorable cytotoxicity studies, ILs were shown to be a possible solution to overcome these challenges. Their favorable application in overcoming challenges ranging from synthesis, manufacture, and even therapeutic benefits were documented. In this review, said ILs are highlighted and their role in TDDS is reviewed in terms of (a) ILs as permeation enhancers (single agents or combined), (b) ILs in drug modification, and (c) ILs as active pharmaceutical ingredients. Furthermore, future combination of ILs with other chemical permeation enhancers (CPEs) is proposed and discussed. Full article
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