Chiral Drugs and Intermediate Resolution Technologies

The chirality of drug molecules is closely related to the pharmacological activity, toxicity and pharmacokinetic properties of drugs. Since the "tertiary" incident, countries around the world have strengthened the supervision of chiral drugs. For any drug with chirality, the differences in the pharmacodynamics and pharmacokinetic properties of a pair of enantiomers should be evaluated. Compared with the racemates of chiral drugs, single optically active chiral drugs have clear therapeutic targets, higher efficacy and safety, and lower adverse reactions. Currently, there are three main methods to obtain chiral compounds: chiral source synthesis, chiral catalysis, and chiral resolution. Among them, chiral resolution is economical and easy to operate, easy to operate, and easy to realize industrial production. Table 1 summarizes the technical points and advantages and disadvantages of several common resolution methods, including mechanical resolution, seed crystallization, crystallization (direct crystallization & diastereomeric salt resolution), biological resolution, Chromatographic separation, co-crystal separation.

MethodTechnical PointsExamplesAdvantageDisadvantages
Mechanical Disassembly MethodUse tweezers and other equipment to directly achieve the separation of racemic mixturesSeparation of D- and L-tartaric acids with tweezers under the microscopeSimple operation and low costToo many limitations and too few applicable systems
Seed CrystallizationIn the saturated solution of the racemic mixture, an enantiomer is added as a seed crystal to induce one of the enantiomers to crystallize first, so as to achieve the purpose of separationResolution of two enantiomers of glutamic acid by seed crystallizationThe equipment is simple and easy to realize industrializationRequires the production of a supersaturated solution and a seed crystal of one of the enantiomers first, and the conditions are harsh
Direct CrystallizationApplicable only for the resolution of aggregate mixtures that consist of mechanical mixing of two enantiomeric crystalsIndustrial production of large-scale resolution for the preparation of L-glutamic acid from acrylic acidHigh splitting efficiency and good product puritySubstances with this structure do not exceed 20% of all racemates
Diastereomeric Salt ResolutionThe separation is carried out by using a pair of enantiomers and an asymmetric reagent (usually also a chiral substance) with different reaction rates and the properties of the resulting products.Industrially used for the separation of ephedrine and pseudoephedrineLow priceCannot be used when the target compound cannot be salted
Biological SeparationSeparation is accomplished by the use of enzymes, bacteria, yeast or microorganisms grown in a racemate solution to destroy one enantiomer quickly and the other slowlySeparation of racemic ibuprofen by biological enzymesHigh splitting efficiency and fast speedIt is difficult to quickly select strains for efficient splitting, requiring a lot of trial and error
Chromatographic ResolutionSeparation is achieved by different adsorption rates of optically active substances (chiral stationary phases in the chromatographic column) for a pair of isomersSplit Levolansoprazole and DexlansoprazoleFast and efficient resolution while obtaining high enantiomeric purityThe use of expensive special stationary phases is too costly and the operation is more complicated
Eutectic ResolutionThe resolution of chiral drugs is achieved through strong direction-dependent hydrogen bonding. Enantiomerically pure API only forms co-crystals with one of the two enantiomers of chiral CCF, and no enantiomeric pairs are formed.Split racemic ibuprofenSplitting is efficient and fast, and at the same time low costNeed to find the right co-crystal

Table 1. Common chiral drug resolution methods.

1. Crystal Resolution Methods

The crystallization method has the advantages of simple operation, high product purity, and easy industrial production. The disadvantage is that there are fewer compounds suitable for crystallization and resolution. Crystallization resolution does not rely on external chirality sources, and the resolution is achieved by spontaneous crystallization of racemates, including mechanical resolution of racemic mixtures, preferential crystallization, preferential enrichment, crystallization-induced deracemization, and digestion-induced deracemization Racemization, etc. Among them, the combination of crystallization and chiral site racemization is beneficial to improve the resolution efficiency and save production costs.

2. Chemical Resolution Methods

Chemical resolution utilizes chiral resolving agents to resolve racemates into individual optical isomers. Currently, chemical resolution mainly includes diastereomeric salt resolution, co-crystal resolution, inclusion resolution, Dutch resolution and solvent-induced chiral resolution. Chiral resolution reagents can form salt bonds with racemates to obtain diastereomeric salts. According to the differences in physical and chemical properties such as solubility, crystallization methods are used to achieve separation. When the racemate has no ionizable group, the chiral resolving agent can form a diastereomeric co-crystal with the racemate through hydrogen bonding, and then realize the separation according to the difference of physical and chemical properties. Inclusion resolution mainly utilizes chiral resolution agent to form a cage-like structure with chiral cavities, and selectively includes an enantiomer through hydrogen bonding. Dutch resolution and solvent-induced chiral resolution are the perfection and development of diastereomeric salt crystallization and co-crystal resolution methods. Chemical resolution expands the scope of application of crystalline resolution substrates.

3. Kinetic Resolution Methods

Kinetic resolution (KR) is due to the difference in the reaction rate between a pair of enantiomers in the racemate and the chiral catalyst, resulting in one enantiomer being able to generate a product faster and achieving chiral resolution. The resolution efficiency of kinetic resolution depends on the conversion rate (C, 0 < C < 1) and the ratio of the rate constants of the two enantiomeric reactions, which is also known as the stereoselectivity factor s (s=kR/kS). The kinetic resolution effect is better with the increase of s. When s > 10, the resolution effect is significant; when s is small, multiple splits are required. Dynamic kinetic resolution (DKR) is a combination of kinetic resolution and chiral site racemization, which has the characteristics of high enantioselectivity and high yield, and its theoretical yield can reach 100% . The chiral site racemization can be achieved by transition metal catalysis, acid-base catalysis and other methods. Dynamic kinetic resolution needs to meet the following requirements: the rate of racemization should be greater than the rate of chiral catalysis; the racemization reagent and the chiral catalyst are chemically compatible, that is, they work simultaneously without inhibiting the activity of each other; higher conversion and enantioselectivity.

Enzymatic kinetic resolution is the stereoselective catalysis of a pair of enantiomers in the substrate by the enzyme, enabling the enantiomer to generate products faster and achieving chiral resolution. Enzymes commonly used in kinetic resolution include: lipase, transaminase, etc. Among them, lipase is the most widely used in enzyme-catalyzed kinetic resolution due to its easy availability, wide substrate range and high tolerance. Non-enzymatic kinetic resolution catalysts include organometallic complexes and small organic molecules. Organometallic complexes formed by coordination metals and chiral ligands can selectively catalyze the enantioseparation. Coordinating metals are generally transition metals such as titanium, ruthenium, rhodium, and palladium.

4. Chromatographic Resolution Methods

Currently, the chromatographic separation methods of chiral drugs mainly include gas chromatography and liquid chromatography. The resolution selectivity of chiral compounds by gas chromatography mainly depends on the type of chiral stationary phase used and the temperature of chromatographic separation. Generally, gas chromatography is mainly used for the resolution of low-boiling chiral compounds. The resolution of polar chiral compounds such as organic acids and bases generally requires pre-column derivatization to form corresponding esters or amides. Currently, the chiral resolution stationary phases used in gas chromatography are all cyclodextrin derivatives.

The resolution selectivity in liquid chromatography is derived from chiral stationary and mobile phases. Liquid chromatography includes a variety of elution modes, such as normal-phase elution, reversed-phase elution, polar elution, polar ion elution, and gradient elution modes. Most importantly, there are many more types of liquid chromatography columns than gas chromatography chiral stationary phases, including polysaccharide derivatives, cyclodextrin and its derivatives, glycoproteins, macrolide antibiotics and crown ethers chiral stationary phase.

In addition to the above four main resolution techniques, resolution methods such as chiral extraction, membrane resolution, chiral adsorption, and nanoparticle resolution have also been extensively studied in recent years. With advanced equipment and experienced synthetic chemists, BOC Sciences can provide advanced chiral resolution technologies to pharmaceutical companies and academic institutions around the world. If you are interested in our chiral resolution services, please click here for more information.

Chiral Technical Information


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