Preparation of Analytical Standard of Bisoprolol Impurity A

Aims: Research of the convenient method for obtaining (RS)-1-(4-Hydroxymethyl-phenoxy)-
3-isopropylaminopropan-2-ol, known as the Impurity A of Bisoprolol, of high purity as close as 100%.

Study Design: Impurity A may be formed as a by-product in the processes used for commercial synthesis of bisoprolol fumarate. Impurity A may be also formed as a result of degradation (hydrolysis) of active substance. This compound is available as the reference standard, but the offered purity is between 95% and 97%, what suggest that its purification to the pharmaceutical quality is demanding. The most common method of purification of chemical standards for pharmacy is preparative chromatography and is commonly used for obtaining the reference standards of high purity, but it is unattainable in many cases, so there is a need for simple, convenient and repeatable laboratory procedures elaboration.

Place of Study: ICN Polfa Rzeszów S.A., Poland, Synthesis Laboratory.

Methodology: The synthesis of Bisoprolol Impurity A was performed starting from
p-hydroxybenzyl alcohol and subsequent reactions with epichlorohydrin and isopropylamine, whereas purification process consisted particularly of obtaining and isolation of fumarate salt of Impurity A, its crystallization and basification.

Results: The analytical standard of Bisoprolol Impurity A of a purity of 95.5% was obtained with convenient chemical process without need of any advanced methodology. The structure was elucidated with IR, NMR and EA methods and the purity was determined by HPLC technique.

Conclusion: The method of obtaining the analytical standard of Impurity A of purity as close as 100% is described in this paper.