Preparation of Bisoprolol Impurity A of High Quality

Aims: Research on the convenient method for obtaining (RS)-1-(4-Hydroxymethyl-phenoxy)-
3-isopropylaminopropan-2-ol, known as the Impurity A of Bisoprolol according to EP, of high quality.
Study Design: Impurity A may be formed as a by-product in the common processes used for
synthesis of bisoprolol fumarate. Impurity A may be also formed as a result of degradation (hydrolysis)
of Bisoprolol. This chemical compound is available as the reference standard, but the offered purity is
between 95% and 97%, what suggest that its purification to high quality is demanding. The most
common method used for purification of chemical standards is preparative chromatography, but it is
unattainable in many cases. There is continuous need for simple, convenient and repeatable
laboratory procedures.
Methodology: The synthesis of Bisoprolol Impurity A was performed starting from
p-hydroxybenzyl alcohol and subsequent reactions with epichlorohydrin and isopropylamine.
Purification process consisted particularly on obtaining and isolation of fumarate salt of Impurity A, its
crystallization and subsequent basification.
Results: The reference standard of Bisoprolol Impurity A of 95.5% purity was obtained with
convenient purification process. The structure of Impurity A was elucidated with IR, NMR and EA and
its purity was determined by HPLC technique.
Conclusion: The effective method of preparation of Impurity A of high quality is described in this
paper.