Alternative methods to assess the impurity profile of a monographed API using acarbose as an example

Abstract

Even though the impurity analysis of the Ph. Eur. is considered well-studied, its methodology should be reviewed periodically to ensure that it is working properly, and all impurities are captured by the section „Related substances” of the monograph. Within this study, the biotechnological produced antidiabetic drug acarbose was chosen to demonstrate some of the advantages as well as the shortcomings arising from the current related substances test of acarbose. Due to its weak chromophore, acarbose is studied by UV detection at 210 nm after being separated on aminopropyl-silyl stationary phases. Thus, the use of alternative detection techniques, such as charge aerosol detection (CAD) and a volatile mobile phase can be beneficial here. Since a simple method transfer to a mobile phase usable with the CAD was not possible, more stable stationary phases were tested. For the rapid determination of the sum of impurities, a method was developed using a pentafluorophenyl column and a mobile phase of 0.1% TFA in water. Maltose and maltotriose were further identified as additional impurities of the API. Furthermore, a method was developed and validated by means of an Amide-HILIC phase, that adequately separated acarbose and all of its impurities. However, the sensitivity of this method needs to be further improved. Additionally, a method was also developed and validated, taking into account the temperature stability of graphite columns. Thus, the separation was carried out at temperatures of about 90 °C to solve the problem of anomerization of acarbose and some of its impurities. In comparison with the other developed methods, the elution order was changed and has to be confirmed, but all components were separated and detected at a sufficient LOQ of 0.10%.