Role of Ionic Liquids in Pharmaceutical Formulation

Ionic liquids (ILs) are liquid mixtures of anions and cations formed under certain conditions according to a certain stoichiometric ratio. Ionic liquids are widely used in various fields because of their simple preparation process, low volatility, high stability, high conductivity and non-flammability.

Increase drug solubility

ILs can increase the solubility of insoluble small molecules and biomacromolecules, and the solubilization effect is affected by external factors and their own factors. Neglecting external factors, the effect of ILs concentration and type on drug solubility should not be underestimated. Different anions and cations have different solubilizing effects on drugs. Small-sized and alkaline anions can improve the solubility of biopolymers, and the synergistic effect of cations contributes to solubilization.

Improvement of drug stability

ILs can improve the stability of drugs. For protein drugs, ILs mainly improve the stability by maintaining their tertiary structure and reducing their denaturation reaction; while the stability of nucleic acid drugs is affected by the concentration of ILs and the nature of cations.

In the case of peptides, ILs often improve stability through the formation of conjugates. Antimicrobial peptide is a kind of alkaline peptide with antimicrobial activity, the relative molecular mass of which is 2,000-7,000. ILs and antimicrobial peptide can form covalent conjugate, which can improve the stability of antimicrobial peptide.

As Pharmaceutical Active Ingredients

In addition to their physicochemical properties, the biological activities of ILs have attracted increasing attention. Some ILs have antimicrobial and anticancer effects, and different compositions of ILs exert different pharmacological activities. In addition, ILs can also be combined with traditional drugs to form a novel API-ILs delivery system, solving the problems of solubility, stability, bioavailability and polycrystalline form.

Composition of API-ILs

Novel drug delivery system In addition to the ILs formed by the combination of common anions and cations, a large number of studies have shown that the formation of ILs containing APIs, i.e., the formation of API-ILs novel drug delivery system by the counter ion of APIs and their counterparts, or the formation of API-ILs by two different APIs, can effectively improve the solubility, stability and permeability of the drugs, and better exert the therapeutic effects of the drugs.

At present, there are three main ways of API-ILs composition:

(i) For APIs in ionic form, they can bind to ions with opposite charges through inter-ionic interactions;

(ii) For neutral APIs, they can covalently bind to ionic compounds;

For neutral APIs, covalent binding with ionic compounds is possible; and (iii) when the components are two different APIs, the first two modes can be combined to produce a system of bi-functional API-ILs.The first major advantage of API-ILs is that they can increase the solubility of the drug and improve the bio-availability of the drug.

For example, ibuprofen is one of the basic drugs used for analgesia and treatment of arthritis, but ibuprofen has poor solubility in gastric fluid, resulting in low clinical bio-availability.

APIs are mostly present in the form of solid crystals in traditional drug formulations to maintain the physicochemical properties of the drug, such as purity, solubility, and stability, but the presence of multiple crystalline forms of certain solid drugs (e.g., Ranitidine and Lidocaine, etc.) limits their bio-availability. The third advantage of the API-ILs system is its ability to liquefy solid drugs, effectively reducing the crystalline form of solid drugs and thus improving their bio-availability.

Summary and Outlook

Compared with the existing means of drug delivery, ILs have the advantages of simple process, low preparation cost and environmental protection, etc. ILs can be applied to solve the problems of low solubility, low bio-availability and poly-crystalline form of traditional drugs, and can also be used as the active ingredient of the drug, which constitutes the novel drug delivery system of API-ILs. The tunability of the components also offers the possibility of preparing ILs with specific functions, making ILs a great potential for development in the pharmaceutical field.

Although studies on ILs have increased substantially in the last 5 years, a systematic understanding of drug-ILs interactions, the mechanism of action of ILs with in vivo barriers, and the bio-compatibility of ILs has yet to be developed, and more in-depth studies are urgently needed.