Exploring an Anti-Crystal Engineering Approach to the Preparation of Pharmaceutically Active Ionic Liquids

Abstract

A series of salts, some of which are ionic liquids, are prepared from cations and anions drawn from Active Pharmaceutical Ingredients (APIs) and Generally Recognized As Safe (GRAS) materials. Using the solid-state structures of the crystalline salts as a basis, an anti-crystal engineering approach to the preparation of “Active Ionic Liquids” (AILs) is explored.

Spotlight on ionic liquids

“…The realization that task-specific ILs can be created via simple and systematic chemical modifications of the constituent ions takes these systems beyond the promise of designer solvents to highly useful systems for diverse applications including drug delivery and as active pharmaceutical ingredients, [1][2][3] solvents for green processing of otherwise insoluble biomolecules such as cellulose, 4,5 highly energetic materials, 1 and novel electrolytes for energy applications such as batteries, fuel cells, and solar photoelectrochemical cells. [6][7][8][9] Plechkova and Seddon 10 estimated that there may be in excess of 10 6 possible ILs if all currently known IL cations and anions were to be paired, and as many as 10 18 if all ternary systems were to be investigated.…”

Evaluation of solubility and partition properties of ampicillin-based ionic liquids

“…For example, the IL propantheline acesulfamate contains the active cation from the API propantheline bromide (an antimuscurinic used to treat a number of conditions such as excessive sweating, cramps, spasms of the stomach, etc.) with acesulfamate, a known artificial sweetener and a pharmaceutical additive (Dean et al, 2009).…”

“…Bica and co-workers studied ILs based on analgesic, anti-pyretic and anti-inflammatory compounds (acetylsalicylic and salicylic acids) . Hough et al (Hough-Troutman et al, 2009) and MacFarlane et al (Dean et al, 2009) reported API-ILs containing various active cations/anions, while Cybulski and co-workers (Cybulski et al, 2011) prepared ILs based on antiseptic/disinfectant cations and enzyme/amino acids anions, which were found to be very effective against bacteria and fungi.…”

“…The use of this modular ionic liquids-based strategy to produce tuneable active pharmaceutical ingredients is very attractive since it allows infinite new possibilities, challenges and opportunities. Besides the elimination of polymorphism and the adjustable solubility, the question of how ionic liquids conjugated with pharmaceutical ingredients could enhance the transport across the membrane is of interest within the APIs context (Dean et al, 2009;Stoimenovski and MacFarlane, 2011;Stoimenovski et al, 2010;Variankaval et al, 2008).…”

The Fields of Crystal Engineering and Ionic Liquids Are Actually Quite Similar

“…The pioneering work of Wilkes and Zaworotko [6] (yes the same one) had set the stage for air stable room temperature liquid salts to find numerous applications and Seddon's use of these caught the imagination of many scientists and engineers. [7] Since the mid 1990s an excess of 15000 papers have appeared using the term 'Ionic Liquids' and only a few have noted the true relationship between this field and Crystal Engineering (one of those by Doug MacFarlane [8] ). Nonetheless, they are quite related.…”