Progress in the Enantioseparation of β-Blockers by Chromatographic Methods

Abstract

β-adrenergic antagonists (β-blockers) with at least one chiral center are an exceedingly important class of drugs used mostly to treat cardiovascular diseases. At least 70 β-blockers have been investigated in history. However, only a few β-blockers, e.g., timolol, are clinically marketed as an optically pure enantiomer. Therefore, the separation of racemates of β-blockers is essential both in the laboratory and industry. Many approaches have been explored to obtain the single enantiomeric β-blocker, including high performance liquid chromatography, supercritical fluid chromatography and simulated moving bed chromatography. In this article, a review is presented on different chromatographic methods applied for the enantioseparation of β-blockers, covering high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC) and simulated moving bed chromatography (SMB).

′Ab Ovo′ Chiral Phases and Chiral Reagents for Liquid Chromatographic Separation and Isolation of Enantiomers

“…The review by Yang et al, [9] in 2021, discussed application of only a few CDRs and that too only a few of those reported by our laboratory. Different CDRs that were used for enantioseparation of β-adrenergic blocking agents are mentioned below.…”

“…It is interesting to mention that the CDRs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) were not capable of forming diastereomeric derivatives of (RS)salbutamol. [70a] As reported earlier, the diastereomeric derivatives of (RS)-carvedilol prepared with (1, 2), (6)(7)(8)(9), and (11,12) were not separated [70a] while the MLC was capable of providing enantioseparation of its derivatives prepared with (S)-Kpf based reagents. The MLC was also capable of providing enantioseparation of (RS)-salbutamol and carvedilol by indirect mode though their enantiomers were not separated by using CSPs in HPLC.…”

“…Egginger et al ., reviewed [28] a few examples of stereoselective pharmacodynamics and pharmacokinetics of seven popular β‐adrenolytics involving application of CDRs, CSPs and CAMP. In 2021, Yang et al ., listed [9] historically 70 β‐adrenolytics (mostly with one stereogenic center) and presented a review for the enantioseparation of a few of them by supercritical fluid chromatography (SFC), simulated moving bed chromatography (SMB) and HPLC (mainly using eight types of CSPs) with no coverage of TLC. During 2018–19, Batra and Bhushan reviewed enantioseparation methods related only to atenolol [29] and only to propranolol [30] which covered direct approach using chiral columns, and TLC, and LC separation of their diastereomeric derivatives prepared by using different CDRs based on Marfey's reagent (MR) and CC.…”

“…Historically, nearly 70 β‐adrenolytics have been investigated for their stereochemical impact on pharmacodynamics and pharmacokinetics [9] but none of the papers published so far has been able to cover all the 70 molecules for their enantioseparartion. Time to time, there appeared review papers or chapters each covering a few commonly used β‐adrenolytics.…”

“…The discussion gives historical context, while the main focus is on a selection of methods (reported on enantioseparation of β‐adrenergic blocking agents) from well documented experiments published from the laboratory of the author who has an experience of more than three decades in the area of enantioseparation of commonly used racemic pharmaceuticals (and DL‐amino acids and their derivatives). It has been mentioned in literature that “Bhushan and his team have done a lot in this area ” [9] of enantioseparation of β‐adrenergic blocking agents. The methods presented in this paper are useful for scientists of interdisciplinary readership in industry, academia and service laboratories.…”