Ionic liquid: a new direction for drug development

Posted by Tylor on February 25th, 2021

In drug development and production, solid active pharmaceutical ingredients, which are usually made into powders or tablets, are a preferred choice compared with liquid active pharmaceutical ingredients. If solid active ingredients are to be finally marketed, the issue of solubility must be solved. 40-70% of drug development failures are due to poor solubility. This is because drugs of poor solubility cannot be well-absorbed by the body.

Ionic liquids, as an exciting class of compounds that can circumvent the above problems, are being ignored. Half of the drugs currently on the market are salts linked together by ionic bonds. Compared with the solid form, the salt that is liquid at room temperature or body temperature has better solubility, absorption and stability. Ionic liquids can also deliver two or more active ingredients at once. For example, by combining the active ions of the painkiller procaine with non-steroidal anti-inflammatory drug (NSAID) salicylic acid, a liquid salt-procaine salicylate is formed. It can play the medicinal effects of these two compounds more effectively, and at the same time opens up new treatment options.

In the past 20 years, many researchers have proved the great value of ionic liquids. They can be used as solvents, electrolytes and compressor fluids. They are reusable, non-volatile and very safe. However, the vast majority of scientists' research on these compounds is still limited to their original use. For example, dialkylimidazolium, quaternary ammonium and phosphonium salts are still regarded as "green" solvents and electrolytes as they were in the 1990s. In fact, in addition to these most widely recognized properties, ionic liquids have many other properties. Considering that liquid salts are more soluble in the body than solids, the effects of ionic liquids on organisms (such as toxicity) should be further studied.

Current drug development generally requires morphological screening of solid drug. Ionic liquids have great potential to improve drug development, delivery, and efficacy.

Research on ionic liquids

Researchers have begun to study the subtleties of ionic bonds in the liquid state. The exchange of ions can make the salt soluble or insoluble (in a given solvent), volatile or non-volatile, permeable or impermeable, reactive or non-reactive. But there are still many unknowns: how to predict whether a given ion can become a liquid? How to purify active ingredients that have never been crystallized? The precise difference of ionic bonds can be controlled manually. Chemists have studied the effects of proton transfer and hydrogen bonding on the melting point of salts, the ease with which ions pass through cell membranes, and the creation of different types of acid-base complexes.

The industry has also begun to pay attention to ionic liquids. An ionic liquid analgesic patch based on the non-steroidal anti-inflammatory drug (NSAID) etodolac and the analgesic lidocaine for the treatment of back pain has completed Phase III clinical trials. It is necessary to test more combinations of ionic liquids and drugs. For example, ionic liquid drugs loaded on powder can be taken orally, and the dissolution rate of the drug can be changed by changing the properties of the powder carrier.

Laboratory studies have shown that the nature of the drug affects its delivery in the body. For example, the liquid combination of lidocaine (base) and ibuprofen (acid) forms a strong hydrogen bond between the two components, which allows the two drugs to pass through the cell membrane at the same time. Similarly, the permeability of other drugs can also be enhanced. When designing solid pharmaceutical co-crystals, whether hydrogen-bonded complexes are combined or separated in the blood has become a controversial topic.

For the pharmaceutical industry, the most important issue is how to define and standardize ionic liquid drugs. The US Food and Drug Administration's (FDA) Active Pharmaceutical Ingredient Guidelines focus mainly on pure compounds and their stability. Of course, solids are easier to classify and research. The latest guidelines in April 2013 distinguish between crystalline hydrogen-bonded co-crystals and ionized salts. The two may differ only in bonding methods, but there is no difference in biological activity.

Future prospect

As suggested by some chemists, researchers should better define and understand ionic liquids. Chemists in academia and industry need to find techniques that can prove the structure and purity of ionic liquids. There is a need to develop methods to identify certain complexes, free ions, or dissociate acids and bases. At the same time, it is also necessary to define a classification system around the degree of change in ionic bonds and to develop methods for evaluating the purity of ionic liquids. For clinical transformation, the drug delivery mechanism and procedures also need to be clear, such as the shelf life.

Regulators should reduce their attention to the form of materials and pay more attention to their clinical effects. The development of a scientific classification system for ionic liquids based on medicinal performance can enable regulatory agencies to distinguish between laws and regulations.

It is a good starting point to develop ionic liquids based on drugs that have been approved by the FDA. People are more familiar with these drugs that have been successfully marketed and will bring more investment. There is no miracle in the process of designing and researching liquids and a lot has to be done to overcome various chemical, biological, manufacturing, and regulatory issues.