Enantiomeric resolution of albuterol sulfate by preferential crystallization

Albuterol is a β2-adrenoceptor agonist prescribed for the treatment of bronchial asthma; it exists as a racemate and its bronchodilator activity resides in the (R)-isomer or levalbuterol. The aim of this study was to determine a methodology that would separate the enantiomers of albuterol by preferential crystallization after a conglomerate is identified within its derivatives. We found that albuterol sulfate behaves as a conglomerate showing the characteristic αx-value = 2 (mole fraction solubility ratio of racemate vs enantiomer), the V-shaped ternary phase diagram and the preferential crystallization by seeding with the pure enantiomer. On the basis of these characteristics, we separated the enantiomers by entrainment, and crystallizing out a saturated methanolic solution of albuterol sulfate at 15 °C.

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(1R)-2-tert-Butylamino-1-(4-hydroxy-3-hydroxy-methyl) phenyl ethanolC26H44N2O10SEe = 99.8%[α]D20=-36.5 (c 1, MeOH)Source of chirality: preferential crystallization