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Significance
Chiral resolution is the process of separating a racemic mixture of enantiomers into its individual components. Enantiomers are molecules that have the same chemical formula and structure, but differ in the spatial arrangement of their atoms. They are mirror images of each other and cannot be superimposed. Enantiomers often have different biological activities and properties, which makes chiral resolution important for various applications, especially in pharmaceuticals. One of the most common methods for chiral resolution is diastereomeric salt formation. This method involves converting a pair of enantiomers into a pair of diastereomers by reacting them with a chiral resolving agent. Diastereomers are stereoisomers that are not mirror images of each other and have different physical and chemical properties. Therefore, they can be separated by conventional techniques such as crystallization, filtration, chromatography, etc.
Racemic Ibuprofen is a mixture of two enantiomers, or mirror-image molecules, of Ibuprofen. One enantiomer is a (S)-enantiomer and the other is an (R)-enantiomer. Enantiomers can have different biological activities and may have different effects on the human body. Therefore, it is important to separate racemic ibuprofen into its individual enantiomers to study their individual properties. Separating racemic ibuprofen into its enantiomers is important in pharmaceutical research and development because it allows researchers to determine the biological activity and therapeutic potential of each enantiomer. It also allows for the development of more effective and targeted drugs, as one enantiomer may be more effective or less toxic than the other. Additionally, the separation of enantiomers is important in the manufacturing of drugs, as different enantiomers can have different pharmacokinetic properties, such as absorption, distribution, metabolism, and excretion, which can affect the safety and efficacy of the drug. By separating the enantiomers, manufacturers can ensure that only the desired enantiomer is present in the final product, which can improve the drug’s safety and efficacy.
In a new study published in the peer-reviewed Journal Industrial & Engineering Chemistry Research, Professor Tu Lee and his research group from the National Central University in Taiwan developed a new green and strategic method for the chiral resolution of racemic ibuprofen by diastereomeric salt formation with a chiral resolving agent, (S)-(−)-α-methylbenzylamine (S-MBA), in the presence or absence of a nonchiral agent, potassium hydroxide (KOH). The reported innovative method may provide practical guidelines for the future development of similar processes
The research team showed that the chiral resolution of racemic ibuprofen by diastereomeric salt formation with a chiral resolving agent, (S)-(−)-α-methylbenzylamine (S-MBA), in the presence or absence of a nonchiral agent, potassium hydroxide can achieve high diastereomeric excess (%de), yield, and enantiomeric excess (%ee) of the S-enriched ibuprofen under optimal conditions. The formation of diastereomeric salts of racemic ibuprofen with S-MBA and KOH was influenced by the equivalent ratio of the three components. The optimal ratio was found to be 1:0.5:0.5 for racemic ibuprofen: S-MBA:KOH, which resulted in the highest recovery% (21%) derived from %de (40%) and yield (53%) of the diastereomeric salts. The addition of KOH increased the solubility of racemic ibuprofen and S-MBA in water, facilitating the formation of diastereomeric salts. The %de and yield decreased when the ratio deviated from the optimal value, due to the formation of undesired by-products or incomplete reactions. The resolution by cooling crystallization of diastereomeric salts with 40-50 %de was affected insignificantly by the solvent and the temperature range. The optimal solvent was found to be ethyl acetate, which gave the common %de (80%) but the highest yield (71%) of the diastereomeric salt crystals. Ethyl acetate had a lowest solubility power for the diastereomeric salts, allowing for sufficient supersaturation and crystallization, and solvent recycling. The optimal temperature range was found to be 70-25 °C, which provided a suitable driving force for crystallization without causing excessive solubility loss or secondary nucleation. The yield, size and crystallinity of S-enriched ibuprofen from diastereomeric salt crystals was influenced by the solvent-to-antisolvent ratio, the aging time, and the addition rate of antisolvent. The optimal solvent-to-antisolvent ratio was found to be 1:6 for methanol-to-water, which resulted in the highest %ee (80%) and yield (95%) of S-enriched IBU. The addition of water as an antisolvent simply decreased the solubility of ibuprofen, favoring the precipitation of S-enriched ibuprofen. The optimal aging time was found to be 2 h, which allowed for sufficient crystallization without causing excessive dissolution or racemization. The optimal addition rate of antisolvent was found to be 3 mL/min, which provided a suitable nucleation and growth rate without causing excessive supersaturation or agglomeration or poorer degree of crystallinity.
In conclusion, Professor Tu Lee and co-workers demonstrated that diastereomeric salt formation with S-MBA and KOH is a simple, efficient, scalable, and green method for chiral resolution of ibuprofen, which can be applied to other racemic drugs that can form diastereomeric salts with chiral amines. The new method can also provide practical guidelines for optimizing each step of the chiral resolution process by diastereomeric salt formation.
Reference
Lee HL, Hung YL, Amin A, Pratama DE, Lee T. Green and Strategic Approach for Chiral Resolution by Diastereomeric Salt Formation: The Study of Racemic Ibuprofen. Industrial & Engineering Chemistry Research. 2023 Jan 18.
