Ionic Liquid Forms of Weakly Acidic Drugs in Oral Lipid Formulations: Preparation, Characterization, in Vitro Digestion, and in Vivo Absorption Studies

Abstract

This study aimed to transform weakly acidic poorly water-soluble drugs (PWSD) into ionic liquids (ILs) to promote solubility in, and the utility of, lipid-based formulations. Ionic liquids (ILs) were formed directly from tolfenamic acid (Tolf), meclofenamic acid, diclofenac, and ibuprofen by pairing with lipophilic counterions. The drug-ILs were obtained as liquids or low melting solids and were significantly more soluble (either completely miscible or highly soluble) in lipid based, self-emulsifying drug delivery systems (SEDDS) when compared to the equivalent free acid. In vivo assessment of a SEDDS lipid solution formulation of Tolf didecyldimethylammonium salt and the same formulation of Tolf free acid at low dose (18 mg/kg, where the free acid was soluble in the SEDDS), resulted in similar absorption profiles and overall exposure. At high dose (100 mg/kg), solution SEDDS formulations of the Tolf ILs (didecyldimethylammonium, butyldodecyldimethylammonium or didecylmethylammonium salts) were possible, but the lower lipid solubility of Tolf free acid dictated that administration of the free acid was only possible as a suspension in the SEDDS formulation or as an aqueous suspension. Under these conditions, total drug plasma exposure was similar for the IL formulations and the free acid, but the plasma profiles were markedly different, resulting in flatter, more prolonged exposure profiles and reduced C for the IL formulations. Isolation of a weakly acidic drug as an IL may therefore provide advantage as it allows formulation as a solution SEDDS rather than a lipid suspension, and in some cases may provide a means of slowing or sustaining absorption. The current studies compliment previous studies with weakly basic PWSD and demonstrate that transformation into highly lipophilic ILs is also possible for weakly acidic compounds.

Mechanisms of action of ionic liquids on living cells: the state of the art

“…Whereas the discovery of the toxicity of ILs has broken the dreams of several researchers, it stimulated, on the other hand, a series of new studies interested in taking advantage of the affinity of ILs towards cells for applications in pharmacology, bio-medicine, and bio-nanotechnology (Hough et al 2007 ; Carson et al 2009 ; Stoimenovski et al 2012 ; Marrucho et al 2014 ; Williams et al 2014 ; Egorova et al 2017 ; Sahbaz et al 2017 ; Agatemor et al 2018 ; Benedetto and Ballone 2018a ; Tanner et al 2020 ; Shi et al 2020 ). For example, it has been shown that the oral delivery of a choline-based IL prevents the absorption of fat molecules through intestinal tissue in rats (Nurunnabi et al 2019 ).…”

API ionic liquids: probing the effect of counterion structure on physical form and lipid solubility

“…API ILs when utilised in combination with LBFs have been shown previously to enhance drug exposure. 14,29,30 The conversion to API ILs can enhance solubility in LBFs and ultimately result in greater oral exposure of the API, by exploiting the benets of LBFs described earlier. 25 This may be particularly important during drug development where toxicity screening of lead compounds requires delivery of large doses (up to 2000 mg kg À1 ) where dissolution of standard API forms may not be feasible.…”

Oral Drug Delivery Technologies—A Decade of Developments

“…Porter and coworkers (Williams et al, 2014;Sahbaz et al, 2015Sahbaz et al, , 2017Williams et al, 2018) pioneered ILs for improving the oral delivery of poorly bioavailable drugs. In one of the examples, they demonstrated enhanced solubility of drugs such as danazol and itraconazole using 1-hexyl-3hexyloxycarbonylpyridinium cation and dicyanamide [N(CN) 2 ] anion, resulting in almost ∼100 times increased solubility.…”

“…In another study, some weakly basic drugs such as itraconazole, cinnarizine, and halofantrine were converted to lipophilic ionic liquids using their hydrochloride salts and were combined with lipid systems for improved oral delivery (Sahbaz et al, 2015). Similar studies were conducted using various other high/low soluble or high/poor permeable drugs such as tolfenamic acid, meclofenamic acid, diclofenac, ibuprofen, amlodipine fexofenadine, ranitidine, and metformin (Sahbaz et al, 2017;Williams et al, 2018). Ionic liquids resulted in the possibility of higher dose administration in comparison with parent drugs, specially, in self-emulsifying drug delivery systems or using their lipophilic salts like lauryl sulfate, oleate, and docusate as counter ions.…”