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Open AccessArticle

Deep Eutectic Solvents for Efficient Drug Solvation: Optimizing Composition and Ratio for Solubility of β-Cyclodextrin

by

Ilan Shumilin

,

Ahmad Tanbuz

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Daniel Harries

Pharmaceutics 2023, 15(5), 1462; https://doi.org/10.3390/pharmaceutics15051462 - 11 May 2023

Viewed by 646

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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Open AccessArticle

Effect of Ionic Liquid on Silver-Nanoparticle-Complexed Ganoderma applanatum and Its Topical Film Formulation

by

Pattwat Maneewattanapinyo

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Jirapornchai Suksaeree

Pharmaceutics 2023, 15(4), 1098; https://doi.org/10.3390/pharmaceutics15041098 - 29 Mar 2023

Cited by 1 | Viewed by 552

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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Open AccessArticle

N-Benzylethanolammonium Ionic Liquids and Molten Salts in the Synthesis of ⁶⁸Ga- and Al¹⁸F-Labeled Radiopharmaceuticals

by

Yulia A. Kondratenko

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Julia S. Shilova

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Vladislav A. Gavrilov

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Andrey A. Zolotarev

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Michail A. Nadporojskii

,

Tatyana A. Kochina

and

Dmitrii O. Antuganov

Pharmaceutics 2023, 15(2), 694; https://doi.org/10.3390/pharmaceutics15020694 - 18 Feb 2023

Viewed by 637

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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Open AccessArticle

Novel Regioselective Synthesis of 1,3,4,5-Tetrasubstituted Pyrazoles and Biochemical Valuation on F₁F_O-ATPase and Mitochondrial Permeability Transition Pore Formation

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Matteo Antonio Tallarida

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and

Pharmaceutics 2023, 15(2), 498; https://doi.org/10.3390/pharmaceutics15020498 - 02 Feb 2023

Viewed by 900

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 F₁F_O-ATPase activity and mitochondrial permeability transition pore (mPTP) opening. The Pz derivatives’ titration curves of 6a, 6h, and 6o on the F₁F_O-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 (K_i’) 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 F₁F_O-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 F₁F_O-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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Open AccessArticle

Studies on the Interaction between Model Proteins and Fluorinated Ionic Liquids

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Pharmaceutics 2023, 15(1), 157; https://doi.org/10.3390/pharmaceutics15010157 - 03 Jan 2023

Cited by 1 | Viewed by 742

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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Open AccessReview

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 - 07 Apr 2023

Viewed by 753

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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Open AccessReview

Role and Recent Advancements of Ionic Liquids in Drug Delivery Systems

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Sadanand Pandey

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Deepak Kumar

Pharmaceutics 2023, 15(2), 702; https://doi.org/10.3390/pharmaceutics15020702 - 20 Feb 2023

Cited by 2 | Viewed by 1192

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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Open AccessReview

Deep Eutectic Systems as Novel Vehicles for Assisting Drug Transdermal Delivery

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Pharmaceutics 2022, 14(11), 2265; https://doi.org/10.3390/pharmaceutics14112265 - 23 Oct 2022

Cited by 4 | Viewed by 1482

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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