Gas Chromatographic Separation of the Diastereomers of Labetalol as n-Butylboronate

Abstract

Labetalol (LA) is a new antihypertensive agent that consists of 2 racemic mixtures, LA-1 (R.cntdot.S + S.cntdot.R) and LA-2 (R.cntdot.R + S.cntdot.S). These racemic mixtures show a difference in their pharmacological activity. The separative determination of LA-1 and LA-2 by gas chromatography clarified the difference in their excretion and metabolism in humans. LA was heated with n-butylboronic acid in pyridine at 60.degree. C for 2 h and the reaction mixture injected into gas chromatograph (1.5% OV-1, 285.degree. C). LA-2 boronate had a retention time of 4 min and LA-1 boronate of 5 min, and the resolution of these peaks was almost complete. Linear relationship between peak height ratio and weight ratio of LA-1 to LA-2 was observed. By this method, urinary excretion of LA-1 and LA-2 was examined after single oral administration of LA.cntdot.HCl (100 mg/body) to 3 healthy volunteers. Urine was collected for 24 h after administration. To the urine sample was added prochlorperazine maleate as an internal standard, and extracted with ethyl acetate before and after treatment with .beta.-glucuronidase. The percentage of the dose (50 mg as each racemic mixture) excreted as LA-1, its phenolic glucuronide, LA-2 and its phenolic glucuronide were in the range of 1.2-2.4, 11.2-24.6, 0.6-1.3 and 4.7-11.2, respectively.