Katharina Bica

Crystalline vs. Ionic Liquid Salt Forms of Active Pharmaceutical Ingredients: A Position Paper

Why not consider liquid salt forms of active pharmaceutical ingredients (APIs) as an alternative versatile tool in the pharmaceutical industry? Recent developments have shown that known APIs can be readily converted into ionic liquids and that these novel phases often possess different properties (e.g., improved solubilities and dissolution rates), which may have a direct impact on the pharmacokinetics and pharmacodynamics of the drug. They may also offer the potential of novel and more efficient delivery modes, as well as patent protection for each of the new forms of the drug. Since these pharmaceutically active ionic liquids represent a thermodynamically stable phase, they avoid the troublesome issues surrounding polymorphism and “polymorphic transformation.” In some cases, an active cation and an active anion can be combined to produce a liquid possessing dual functionality. Here we examine and challenge the current industry reliance on crystalline APIs by discussing the breadth and potential impact of liquid salts as a possible approach to phase control.

Confused ionic liquid ions—a “liquification” and dosage strategy for pharmaceutically active salts

We present a strategy to expand the liquid and compositional ranges of ionic liquids, specifically pharmaceutically active ionic liquids, by simple mixing with a solid acid or base to form oligomeric ions.

Polarisabilities of alkylimidazolium ionic liquids

The molar polarisability and molar volume for 71 ionic liquids were extracted from 157 measurements of their refractive index and density, which were then further deconstructed into atomic contributions by means of a Designed Regression analysis. Using this approach, the density and refractive index for any chosen ionic liquid with alkyl-substituted imidazolium cations can be predicted in good agreement with experimental data.

Ionic liquids and fragrances – direct isolation of orange essential oil

We present the dissolution of fresh fragrance biomass in ionic liquids for the isolation of essential oils and compare direct distillation with solvent extraction. Orange essential oil was distilled from orange peels dissolved in ionic liquid media, thus allowing a simple, efficient, and mild isolation of fragrance and flavor components with complete recovery of the ionic liquid.

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.

From plant to drug: ionic liquids for the reactive dissolution of biomass

We present an ionic liquid (IL) strategy for the reactive dissolution of star anise seeds using different Bronsted-acidic ionic liquids as the solvent and reaction media towards the isolation of important pharmaceutical intermediates; this procedure provides a single-step, higher yielding and environmentally benign strategy towards the synthesis of the anti-influenza drug Tamiflu™.

New aspects for biomass processing with ionic liquids: towards the isolation of pharmaceutically active betulin

By utilising ionic liquids the pharmaceutically active triterpene betulin can be extracted from biomass with significantly improved extraction yield and purity. The recovery of the ionic liquid 1-ethyl-3-methylimidazolium acetate via azeotropic distillation of EtOH/H2O was successfully demonstrated.

Surface-active Ionic Liquids for Micellar Extraction of Piperine from Black Pepper

We present the application of ionic liquid-aqueous micellar solutions as isolation media for the pharmaceutically active ingredient piperine from black pepper. Several surface-active ionic liquids including a biodegradable betaine derivative were used for the extraction of piperine, and a strong correlation between extraction yield and the critical micelle concentration of the respective ionic liquid was found. A scaled strategy for the isolation of piperine was developed that allowed recovery and recycling of the aqueous ionic liquid micellar solution for five runs without any loss in extraction efficiency. Graphical Abstract Surface-active Ionic Liquids for Micellar Extraction of Piperine from Black Pepper

Exploring ionic liquid–biomass interactions: towards the improved isolation of shikimic acid from star anise pods

Based on shikimic acid – the starting material for the important anti-influenza drug Tamiflu (oseltamivir phosphate) – we present that the dissolution properties of ionic liquids can lead to better access to the valuable ingredient embedded in the biopolymer. Different imidazolium-based ionic liquids were investigated, and the extraction yield of shikimic acid was correlated with their hydrogen-bonding properties via polarizable MD simulations, indicating that the hydrogen bonding of the IL anion to shikimic acid is responsible for a good extraction performance. A scale-up strategy for the isolation of shikimic acid with the ionic liquid 1-ethyl-3-methylimidazolium acetate ([C2mim]OAc) was developed based on ion-exchange resins, thus allowing isolation of shikimic acid in up to 10 wt% yield with complete recovery of the ionic liquid.

Active pharmaceutical ingredients based on salicylate ionic liquids: insights into the evaluation of pharmaceutical profiles

This work is based on the evaluation of the protein binding affinity, partition coefficients (with a biomimetic membrane) and surfactant properties of three pharmaceutically active ionic liquids based on the salicylate anion. Fluorescence spectroscopy was used for the evaluation of the binding of ionic liquids to human serum albumin and for the determination of critical micelle concentrations. Partition coefficients were determined using micelles of hexadecylphosphocholine and UV-Vis derivative spectroscopy. The results indicate that all the compounds bind strongly and spontaneously to human serum albumin and exhibit the ability to form micelles. The determined partition coefficients were up to 6 times higher than those of the starting materials, evidencing that the ionic liquid form has greater affinity for the lipid phase than the inorganic salt form of salicylate. Generally, the studied salicylate ionic liquids exhibit an interesting pharmaceutical profile presenting favorable properties regarding the incorporation of the compounds in antimicrobial pharmaceutical formulations. It was evidenced that the tested ionic liquids can exert direct effects on cell membranes as indicated by their surfactant properties and high ability to partition to hydrophobic environments.