Resolution method of chiral drug

The chiral drug is a pair of enantiomers which are physical and mirror images after the chiral center is introduced into the molecular structure of the drug. Each pair of chemically pure enantiomers has different physical and chemical properties (not only in optical rotation), which can be named R-type or S-type, D-type or L-type, left-handed or right-handed according to different naming rules.

Darwin, Wallace and other naturalists and biologists have paid a lot of attention to macroscopic biological chirality, such as Darwin’s book Movement and Habits of Climbing Plants. In the book, there is a table describing 42 species of climbing plants, most of which have right-handed spirals, while only 11 have left-handed spirals. The most observed in our lives is the left-right growth of plants, morning glory to the “left” plate, and hops to the “right” climb.

 

Why does it have to be about these drugs? Are there any differences between the two? Indeed, chiral drugs are very different from non-chiral drugs. Sometimes the properties of the two pure isomers are similar, but sometimes they are very different, even one is beneficial and the other is harmful in the human body. Then we have to talk about the notorious “Seal” incident here.

Thalidomide was widely used around the world except the United States in the 1950s. Thalidomide can effectively prevent vomiting in the early stages of pregnancy, but it hinders the blood supply of pregnant women to the fetus, resulting in the birth of a large number of “seal deformed babies” without hands and feet. As a result, it was banned as an antiemetic for pregnant women for the next three decades. Later studies found that this tragedy occurred because thalidomide has two structures, left-handed and right-handed, and the left-handed body has a therapeutic effect, which can reduce the early pregnancy reaction of pregnant women. But its chiral partner (right-handed) is teratogenic, leading to the emergence of deformed babies as shown above.

Therefore, it is very important to understand the drug properties of two enantiomers of chiral drugs, which is directly related to the health and safety of users and leads to the concept of chiral resolution. In order to use drugs better and more reasonably, it is necessary to obtain single enantiomers of chiral drugs by resolution, and realize the separation of two pure enantiomers in racemic drugs, which is called “chiral resolution”.

Resolution Methods of Chiral drugs.

The importance of chiral drug resolution is self-evident. As early as 1848, French chemist L. Pasteur used tweezers to separate dextrotaric acid and levotartaric acid under a microscope. So far, under the continuous exploration of countless scientists, the industry has some effective separation methods. The following table summarizes the information, advantages, and disadvantages of several common resolution methods, including mechanical resolution method, sowing crystallization method, crystallization method (direct crystallization method & non-enantiomeric salt resolution method), biological resolution method, chromatographic resolution method, eutectic resolution method.

 

Method. Train of thought Case Advantages Disadvantages
Mechanical splitting

method

Direct Separation of racemic mixtures by tweezers and other equipment As early as 1848, French chemist L. Pasteur used tweezers to separate dextrotaric acid and levotartaric acid under a microscope. Simple operation and low cost The limitation is too big, the applicable material system is few
Seeding crystallization method In the saturated solution of the racemic mixture, an enantiomer is added as a seed to induce one of the enantiomers to crystallize and precipitate in advance, thereby achieving the separation of the parent. The resolution of two enantiomers of glutamic acid by sowing crystallization has been applied in industry. The equipment is simple and easy to realize industrialization. The seed of the supersaturated solution and one of the enantiomers is required to be produced first, and the conditions are harsh.
Direct crystallization

method

It is only suitable for the separation of aggregates composed of mechanical mixtures of two enantiomeric crystals. Large-scale Separation of L-Glutamic Acid for Acrylic Acid production in Industry. The separation efficiency is high and the purity of the product is good. Substances with this structure do not exceed 20% of all racemases.
Non-enantiomeric salt resolution method The separation is carried out by using the reaction rate of a pair of enantiomers with an asymmetric reagent (usually a chiral substance) and the properties of the product produced by the enantiomeric reaction of a pair of enantiomers with an asymmetric reagent (usually a chiral substance). Resolution of ephedrine and pseudoephedrine in industry. Low price. Cannot be used when the target compound cannot be salted
Biological resolution

method

When an enzyme, bacterium, yeast, or microorganism grows in racemase solution, one of the enantiomers destroys quickly and the other slowly, thus completing the separation. L-amino acid decomposition

D-amino acid

High resolution efficiency and speed It is difficult to quickly select strains with high resolution, and a large number of test differences are needed.
Chromatographic

resolution method

Separation of a pair of isomers by using Optical substances (Chiral stationary Phase in chromatographic column) with different adsorption rates. Resolution of left lansoprazole and right lansoprazole The resolution is rapid and efficient, and the enantiomeric purity obtained at the same time is high. The use of expensive special stationary phases is too costly and complex to operate
Eutectic separation

method

The separation of chiral drugs is realized by strong direction-dependent hydrogen bond. The enantiomeric pure API forms eutectic with only one of the two enantiomers of chiral CCF, and does not form enantiomer pairs. Split racemic ibuprofen Split efficiently and quickly, but also at low cost. Need to find the right eutectic agent.

To sum up, with the continuous development of chiral drugs and the deepening of chiral resolution technology, chiral drugs will “do a great deal” in the future!

References

1. Francotte, E., & Lindner, W. (Eds.). (2006). Chirality in drug research. Weinheim: Wiley-VCH.

2. Ali, I., Suhail, M., Lone, M. N., Alothman, Z. A., & Alwarthan, A. (2016). Chiral resolution of multichiral center racemates by different modalities of chromatography. Journal of Liquid Chromatography & Related Technologies39(9), 435-444.