Ionic Liquids in Drug Delivery

Abstract

Ionic liquids (ILs) are molten salts composed of a large organic cation and an organic/inorganic anion. Due to their ionic character, most ILs present advantageous properties over conventional solvents, such as negligible volatility at atmospheric conditions and high thermal and chemical stabilities. The wide variety of IL anion–cation combinations allows these solvents to be designed to display a strong solvation ability for a myriad of active pharmaceutical ingredients (APIs) and (bio)polymers. Given these properties, ILs have been used as solvents and as formulation components in different areas of drug delivery, as well as novel liquid forms of APIs (API-ILs) applied in different stages of development of novel drug delivery systems. Furthermore, their combination with polymers and biopolymers has enabled the design of drug delivery systems for new therapeutic routes of administration.

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs

“…Different cation–anion combinations together with the vast pharmaceutical industry knowledge of salts formulations opens new avenues for ILs as depicted in Figure . − The anions of well-known anti-inflammatory drugs ibuprofen and naproxen as carboxylates are an excellent example with biocompatible cations (e.g., [C16PYR]­[Ibu]). The fluoroquinolones (antibiotics) and valproates (antiepileptic) are developed as more efficient and less toxic novel API-IL medical formulations.…”

Ionic Liquid-Based Materials for Biomedical Applications

“… Applications of ILs in drug delivery systems design and development (APIs: active pharmaceuticals ingredients). Reprinted with permission from [ 118 ]. …”

The Emerging Role of Ionic Liquid-Based Approaches for Enhanced Skin Permeation of Bioactive Molecules: A Snapshot of the Past Couple of Years

“…Given the huge number of possible cation/anion combinations, reports to date cover an immense panoply of different ILs that can be classified in many different ways, depending on the classification criteria ( Figure 9 ), as thoroughly reviewed elsewhere [ 123 ]. In general, three generations of ILs have been recognized, going from the earlier examples of ILs proposed as “greener” surrogates of classical organic solvents to the next generation of ILs whose chemical and physical properties were adjustable to their specific applications (task-specific ILs, or TSILs), and finally to ILs displaying low toxicity, biocompatibility, biodegradability and, in some cases, even bioactivity [ 120 , 121 , 123 , 124 , 125 ].…”

“…ILs are particularly appealing for pharmaceutical applications, given their (i) non-crystalline nature, avoiding fluidity/polymorphism-related liabilities of many drug formulations, and (ii) easy customization and adjustable-properties, through a sensible choice of the ion components [ 12 , 124 , 125 ]. Hence, ILs properties such as vapor pressure, thermal stability, chemical and electrochemical stability, polarity, solubility, amphipathicity, and even bioactivity, can be finely tuned [ 14 ].…”

“…Thus, the CPE action of hydrophilic ILs (e.g., 1-ethyl-3-methylimidazolium-based) has been mostly ascribed to their role as polar enhancers able to (i) increase solubility and partition of hydrophilic drugs, and/or (ii) fluidize the SC by disrupting the tight packing of both proteins and lipids (at the headgroups level— Figure 8 ). In turn, hydrophobic ILs, many of which are SAILs (e.g., CPC, 1-dodecyl-3-methylimidazolium-based ILs), may exert their skin permeation action by (i) increasing solubility and partition of hydrophobic drugs, (ii) inserting into the SC lipid bilayers, causing a disruption of the ordered packing of the phospholipid bilayers or even phase separation or induction of lamellar phases ( Figure 8 ), and/or (iii) extracting SC lipids [ 124 , 128 , 129 , 130 , 131 ]. Interestingly, SC lipid extraction followed by replacement of the extracted lipids with the IL and water has been recently advanced as the mechanism by which CAGE enhances the skin permeation of macromolecules like dextran [ 132 ].…”