Monash University
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Pharmaceutically active ionic liquids

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posted on 2017-01-31, 04:36 authored by Stoimenovski, Jelena
Many pharmaceutical solids can exist in different physical forms including polymorphs, solvates, hydrates and co-crystals. Polymorphism is observed in more than half of all crystalline pharmaceutical drugs. A drug substance can have multiple polymorphs, each exhibiting different properties including solubility, bioavailability, stability, efficacy etc. Inter-conversion of different polymorphs of a drug during its isolation, manufacture, transport and storage can have profound effects on the quality and performance of the drug product. Therefore, in order to ensure reproducible bioavailability of the drug during its shelf life under a variety of storage conditions, it is desirable to develop the most thermodynamically stable polymorph of that compound, although this is not an easy task. Hence, developing drugs that do not have an inherent tendency to crystallise is a potentially promising avenue of investigation for the pharmaceutical industry. For this reason, liquid drug forms of established active pharmaceutical ingredients (APIs) have been proposed as a new approach towards alleviating the problems associated with polymorphism of solid drugs. Ionic liquids, compounds comprised entirely of ions and that melt below 100 oC, exhibit a lack of crystallisation at ambient temperature and pressure as a result of decreased lattice energies in the crystalline state. These compounds are known for their ability to be tailored, where ions can be chosen to obtain ionic liquids with particular characteristics (e.g. water soluble vs. water insoluble ionic liquids etc.) It is therefore possible to combine pharmaceutically active ions with Generally Recognised as Safe (GRAS) counter ions to obtain liquid salt forms of known APIs. This is the basis of the research discussed within. The concept of dual pharmaceutically active ionic liquids, whereby two APIs with synergistic activities are combined in order to obtain ionic liquids with dual pharmaceutical activity, is also explored. Predicting whether a particular ion pair will generate a liquid at room temperature is difficult due to the number of possible combinations of anions and cations and the intricacies of their interactions. In this project, a concept known as “anti-crystal engineering” was employed in order to aid in the selection of ions most likely to produce liquids, and this approach was successful in generating a wide range of pharmaceutically active ionic liquids. These new compounds have been fully characterised and their physical properties are reported. As most organic acid/base drugs are only sparingly soluble in water, while many of the corresponding salts of these drugs are water soluble, pharmaceutically active protic ionic liquids have also been developed in order to extend this research strategy to a wider number of drugs, rendering them water soluble in most cases. In order to gain more information about their potential behaviour in delivery systems, these compounds were subjected to a number of experimental techniques, such as infrared analysis and transport property studies, where their chemical and physical properties were determined. As protic ionic liquids do not necessarily consist entirely of ions, but may also contain small amounts of the acid/base species they are derived from, it is also imperative to determine the degree of proton transfer in these compounds. For the protic ionic liquid to be considered a “pure” salt, and not a mixture of the starting materials and the salt, the proton transfer should be at least 99 %. We have established a relationship between the presence of certain functional groups, the extent of proton transfer and the level of association between ions, which will be a useful tool for the future design of the most efficient liquid protic drugs. Finally, model membrane transport studies were performed using the pharmaceutically active protic ionic liquids. These have shown very promising initial results, indicating that these compounds can be designed to have enhanced membrane transport when compared to the original solid form of the drug. These results are an important step towards the application of liquid APIs.


Campus location


Principal supervisor

Douglas MacFarlane

Additional supervisor 1

Glen Deacon

Year of Award


Department, School or Centre



Doctor of Philosophy

Degree Type



Faculty of Science

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