Julia L. Shamshina

Ionic liquid forms of the herbicide dicamba with increased efficacy and reduced volatility

Twenty eight new dicamba (3,6-dichloro-2-methoxybenzoic acid)-based herbicidal salts, have been synthesized and characterized in order to attempt to improve the efficacy of this widely known herbicide used to protect maize, grassland, and other cultures. The new compounds, most of which are ionic liquids by definition and three of which are solids melting above 100 °C, were prepared by pairing quaternary tetraalkyl- or alkoxyammonium, piperidinium, imidazolium, pyridinium, morpholinium, quinolinium, and phosphonium cations with the dicamba anion. Growth chamber and field test data suggested that ionic liquid forms of dicamba offer substantially increased efficacy which would allow less to be applied in the field. Compared to the commercial dicamba free acid product, improved physical properties were observed including higher decomposition temperatures and reduced volatilities, suggesting a potential reduction of overall environmental impact of this herbicide.

Chemistry: Develop ionic liquid drugs

A new realm of potential drugs is hiding in plain sight. Pharmaceutical research, manufacture and regulation focuses on solid active ingredients, delivered as powders or tablets. Liquid forms are neglected and viewed as an intermediate step, rather than an endpoint. Yet many promising solid drug candidates are too insoluble for the body to absorb. Of Develop ionic liquid drugs Update regulation to spur research into drugs that the body absorbs more easily and that could reach market more quickly, urge Julia L. Shamshina and colleagues. the compounds entering development, 40–70% fail because they cannot be modified simply to allow effective release into the bloodstream 1. Meanwhile, ionic liquids, an exciting class of chemical that could bypass these delivery problems, are being ignored 2. Half of all drugs sold are salts 3 that are held together by ionic bonds, among other forces. Salts that are liquid at room or body temperature can have dramatically better solubility, absorba-bility and stability than do solid forms 4. Ionic liquids can also be configured to deliver two or more active ingredients at once. For example, combining active ions from the pain reliever procaine and the non-steroidal anti-inflammatory drug (NSAID) salicylic acid generates a liquid salt, procainium salicylate. It could deliver the medical benefits of both compounds more efficiently and cheaply while opening up new treatment options. With the drug-discovery pipeline clogged, it is time to try alternatives. We call on chemists and the pharmaceutical industry to develop liquid salt forms of drugs. Chemists will need to learn more about the spectrum of interactions in ionic liquids, how to engineer ionic bonds, and how the choice of ions changes the chemical, physical and biological properties of ionic compounds. Regulations must be updated to consider active ingredients in liquid as well as solid states. Why are ionic liquids being ignored? First, most academic and industrial chemists lack understanding and experience of working with them. Chemistry courses and textbooks teach that new molecules are made by manipulating covalent bonds (where electrons are shared between atoms) rather than ionic ones. Second, pharmaceutical companies are conservative. Ionic liquids are unfamiliar , unregulated and felt to be too risky to develop commercially. And there is a perception problem. Over the past 20 years many researchers (including us) have demonstrated the value of ionic liquids as solvents, electrolytes and com-pressor fluids that are reusable, non-volatile and safe. Yet many researchers and journalists …

Effect of the ionic liquid 1-ethyl-3-methylimidazolium acetate on the phase transition of starch: Dissolution or gelatinization?

This work revealed that the interactions between starch, the ionic liquid 1-ethyl-3-methylimidazolium acetate ([Emim][OAc]), and water might contribute to the phase transition (gelatinization, dissolution, or both) of native starch at reduced temperature. Using mixtures of water and [Emim][OAc] at certain ratios (7.2/1 and 10.8/1 mol/mol), both the gelatinization and dissolution of the starch occur competitively, but also in a synergistic manner. At lower [Emim][OAc] concentration (water/[Emim][OAc] molar ratio≥25.0/1), mainly gelatinization occurs which is slightly impeded by the strong interaction between water and [Emim][OAc]; while at higher [Emim][OAc] concentration (water/[Emim][OAc] molar ratio≤2.8/1), the dissolution of starch is the major form of phase transition, possibly restricted by the difficulty of [Emim][OAc] to interact with starch.

Prodrug ionic liquids: functionalizing neutral active pharmaceutical ingredients to take advantage of the ionic liquid form

Neutral, non- or not easily-ionizable active pharmaceutical ingredients can take advantage of the unique property sets of ionic liquids by functionalization with hydrolyzable, charged (or ionizable) groups in the preparation of ionic liquid prodrugs as demonstrated here with the synthesis, characterization, and hydrolysis of cationic acetaminophen prodrugs paired with the docusate anion.

Metsulfuron-Methyl-Based Herbicidal Ionic Liquids

Ten sulfonylurea-based herbicidal ionic liquids (HILs) were prepared by combining the metsulfuron-methyl anion with various cation types including quaternary ammonium ([bis(2-hydroxyethyl)methyloleylammonium](+), [2-hydroxyethyltrimethylammonium](+)), pyridinium ([1-dodecylpyridinium](+)), piperidinium ([1-methyl-1-propylpiperidinium](+)), imidazolium ([1-allyl-3-methylimidazolium](+), [1-butyl-3-methylimidazolium](+)), pyrrolidinium ([1-butyl-1-methylpyrrolidinium](+)), morpholinium ([4-decyl-4-methylmorpholinium](+)), and phosphonium ([trihexyltetradecylphosphonium](+) and [tetrabutylphosphonium](+)). Their herbicidal efficacy was studied in both greenhouse tests and field trials. Preliminary results for the greenhouse tests showed at least twice the activity for all HILs when compared to the activity of commercial Galmet 20 SG, with HILs with phosphonium cations being the most effective. The results of two-year field studies showed significantly less enhancement of activity than observed in the greenhouse; nonetheless, it was found that the herbicidal efficacy was higher than that of the commercial analog, and efficacy varied depending on the plant species.

Understanding the structural disorganization of starch in water-ionic liquid solutions

Using synchrotron X-ray scattering analyses and Fourier transform infrared spectroscopy, this work provides insights into the solvent effects of water : [C2mim][OAc] solutions on the disorganization of a starch semi-crystalline structure. When a certain ratio (10.2 : 1 mol/mol) of water : [C2mim][OAc] solution is used, the preferential hydrogen bonding between starch hydroxyls and [OAc](-) anions results in the breakage of the hydrogen bonding network of starch and thus the disruption of starch lamellae. This greatly facilitates the disorganization of starch, which occurs much easier than in pure water. In contrast, when 90.8 : 1 (mol/mol) water : [C2mim][OAc] solution is used, the interactions between [OAc](-) anions and water suppress the solvent effects on starch, thereby making the disorganization of starch less easy than in pure water. All these differences can be shown by changes in the lamellar and fractal structures: firstly, a preferable increase in the thickness of the crystalline lamellae rather than that of the amorphous lamellae causes an overall increase in the thickness of the semi-crystalline lamellae; then, the amorphous lamellae start to decrease probably due to the out-phasing of starch molecules from them; this forms a fractal gel on a larger scale (than the lamellae) which gradually decreases to a stable value as the temperature increases further. It is noteworthy that these changes occur at temperatures far below the transition temperature that is thermally detectable as is normally described. This hints to our future work that using certain aqueous ionic liquids for destructuration of the starch semi-crystalline structure is the key to realize green processes to obtain homogeneous amorphous materials.

Chitin–calcium alginate composite fibers for wound care dressings spun from ionic liquid solution

Chitin-calcium alginate composite fibers were prepared from a solution of high molecular weight chitin extracted from shrimp shells and alginic acid in the ionic liquid 1-ethyl-3-methylimidazolium acetate by dry-jet wet spinning into an aqueous bath saturated with CaCO3. The fibers exhibited a significant proportion of the individual properties of both calcium alginate and chitin. Ultimate stress values were close to values obtained for calcium alginate fibers, and the absorption capacities measured were consistent with those reported for current wound care dressings. Wound healing studies (rat model, histological evaluation) indicated that chitin-calcium alginate covered wound sites underwent normal wound healing with re-epithelialization and that coverage of the dermal fibrosis with hyperplastic epidermis was consistently complete after only 7 days of treatment. Using a single patch per wound per animal during the entire study, all rat wounds achieved 95-99% closure by day 10 with complete wound closure by day 14.

Simultaneous membrane transport of two active pharmaceutical ingredients by charge assisted hydrogen bond complex formation

Using permeation through a model membrane in a Franz diffusion cell, we have demonstrated that acidic and basic active pharmaceutical ingredients (APIs) in deep eutectic ‘liquid co-crystal’ form can be held tightly together, even in solution, via strong hydrogen bonds or partially ionized interactions, providing simultaneous transport at rates much higher than solutions of their corresponding, commercially available crystalline salts, albeit at rates that are lower than the neutral forms of the individual molecules. It was also shown that the deep eutectic APIs do not have to be premade, but hydrogen-bonded complexes can be formed in situ by mixing the corresponding API–solvent solutions. To understand the behavior, we have extensively studied a range of nonstoichiometric mixtures of lidocaine and ibuprofen spectroscopically and via membrane transport. The data demonstrates the nature of the interactions between the acid and base and provides a route to tune the rate of membrane transport.

Characteristics of starch-based films with different amylose contents plasticised by 1-ethyl-3-methylimidazolium acetate

Starch-based films plasticised by an ionic liquid, 1-ethyl-3-methylimidazolium acetate ([Emim][OAc]), were prepared by a simple compression moulding process, facilitated by the strong plasticisation effect of [Emim][OAc]. The effects of amylose content of starch (regular vs. high-amylose maize) and relative humidity (RH) during ageing of the samples on a range of structural and material characteristics were investigated. Surprisingly, plasticisation by [Emim][OAc] made the effect of amylose content insignificant, contrary to most previous studies when other plasticisers were used. In other words, [Emim][OAc] changed the underlying mechanism responsible for mechanical properties from the entanglement of starch macromolecules (mainly amylose), which has been reported as a main responsible factor previously. The crystallinity of the plasticised starch samples was low and thus was unlikely to have a major contribution to the material characteristics, although the amylose content impacted on the crystalline structure and the mobility of amorphous parts in the samples to some extent. Therefore, RH conditioning and thus the sample water content was the major factor influencing the mechanical properties, glass transition temperature, and electrical conductivity of the starch films. This suggests the potential application of ionic liquid-plasticised starch materials in areas where the control of properties by environmental RH is desired.

A platform for more sustainable chitin films from an ionic liquid process

A versatile platform for the preparation of chitin films with tunable strength, morphology, and efficacy of application has been designed from an ionic liquid process for the production of more sustainable high value materials. Films were prepared by a simple casting method from a solution of chitin in the ionic liquid 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]). The chitin source, the loading in ionic liquid, and the drying methods defined film properties such as strength, porosity, and water absorbency. Only chitin directly extracted from shrimp shells using the ionic liquid (rather than commercially available chitin) could be used to cast films strong enough to be handled and dried. The optimal loading of chitin in the ionic liquid was determined to be 2.5 wt% and different drying methods led to different film properties (e.g., hard and rigid vs. soft and porous). As an exemplary application, loading and release of a model drug (caffeine) was investigated. Interestingly, a burst release of the majority of the caffeine was observed in the first 20 minutes, followed by slow release of the remainder. Although more investigations are needed, the chitin film platform can be thought of as an attractive new tool in the development of packaging materials, biomedical devices, and absorbent materials (M. Rinaudo, Prog. Polym. Sci., 2006, 31, 603–632) made from one of Natures most abundant polymers.