Ionic Liquids: From Solvents to Materials to Active Pharmaceutical Ingredients

Ionic liquids (ILs) have evolved from salts studied primarily for their physical properties (low melting salts
which could be used as solvents) to tunable materials based upon the physical, chemical, and even biological
properties that can be introduced through either ion. Interesting evolution work in this growing field can
lead to possible future directions, such as the use of ILs as Active Pharmaceutical Ingredients (APIs).

Ionic liquids (ILs) are defined as salts composed solely of ions, with a melting point below 100° C. Although
compounds fitting this definition have been known for over a century, it has been only relatively recently,
first with the utilization of ILs as electrochemical solvents and later with the suggestion that ILs could be
‘‘green solvents,’’ that a phenomenal growth in industrial and academic interest has occurred.

Biologically active cations such as quaternary ammonium compounds and anions such as acesulfamate and
saccharinate have previously been used to form ILs. These were paired with traditional IL-forming counter
ions to control physical properties, especially melting point, but with a focus on preparing ILs, not on
preparing biologically active salts. Specific ILs with biologically active ions have been prepared and shown to
retain their biological activity; specifically, IL salts of anti-bacterial quaternary ammonium cations were
shown to be active against various types of bacteria and in some cases, an increased anti-bacterial effect was

Since ILs are composed of a minimum of two ions (a cation and an anion), both may impart biological activity
to the resulting salt. This dual functionality inherent in ILs is rarely exploited. Given that polymorphism and
solvate formation cannot be predicted; that the exact crystalline state affects chemical (e.g., dissolution rate,
solubility), biological (e.g., bioavailability, pharmacokinetics), mechanical, and physical properties, as well as,
manufacturing processes; and that polymorphs and solvates may inconveniently interconvert—what are
needed are chemical compositions that a) are effective for their intended purpose; b) have controlled and
tunable chemical, biological, and physical properties, c) are in a form that is not subject to polymorphism,
and d) for which controlled tunable dissolution and solubility are possible, which are basic traits of ionic

A modular IL strategy could potentially revolutionize the pharmaceutical and medical industries and provide
a platform for improved activity, new treatment options, or even personalized medication; or it could lead
to such complexity that these materials would never be accepted as pharmaceuticals. The possibility to
overcome problems such as polymorphism, solubility, and bioavailability, that have stopped the use of many
proposed pharmaceuticals, might give abandoned APIs a second life; or speed the adoption of new candidate
drugs. While the future of ILs as potential APIs cannot be certainly predicted, the pharmaceutical industry
should join the growing number of other industries that are considering the use of ILs as materials for many
different process options, and not just as solvents.


Crystal engineering of active pharmaceutical ingredients helps improve solubility and dissolution ra... Drug molecules with limited aqueous solubility are becoming increasingly prevalent in the research and development portfolios of discovery focussed pharmaceutical companies. Molecules of this type can provide a number of challenges in pharmaceutical development and may potentially lead to slow dissolution in biological fluids, insufficient and ...