28 February / March 2021
Leveraging Ion Chromatography- Mass Spectrometry for the Impurity Analysis of a Small Organic Acid
by Andrew D. Raya* , Bethany Jacksonb .
Chemical Development, Pharmaceutical Technology & Development, AstraZeneca, Operations, Macclesfield, UK *corresponding email address:
andrew.ray@astrazeneca.com
Abstract
Small organic acids are used throughout the pharmaceutical industry [1], but are challenging analytically when using conventional methods such as reverse-phase high performance liquid chromatography (HPLC) and gas chromatography (GC). Ion chromatography (IC) offers better analytical separation of these acids, but conductivity detection does not provide peak purity information. When coupled with mass spectrometry (MS), information about components contributing to each peak is obtained. IC-MS was used for the method development of 2-butynoic acid impurity analysis; where it was possible to analyse the impurities and confirm their peak purity. Quantitative performance of the method for sensitivity and linearity for a series of organic acids, spiked into 2-butynoic acid at levels representative of impurities, was evaluated [2].
Introduction
Organic acids are used as reagents in pharmaceutical synthetic processes or potentially formed as impurities. They need to be controlled throughout the synthesis and manufacturing routes to ensure a high-quality final product. Trace impurities present in starting or intermediate materials, if undetected, can directly impact the quality of the final product. Discovering discrepancies in the product quality at later stages makes it technically challenging and expensive to identify contaminants across different preceding stages of the production process. The purer the starting materials and intermediates, the easier it is to control and assure the quality of the final product. Accurate and reliable analytical detection of organic acid impurities is, therefore, an extremely important requirement for those who manufacture products for internal use. It is essential to have methods that can identify and quantify all possible impurities when investing in expensive supply of starting material or intermediates.
The widely used analytical methods, gas chromatography (GC) and high performance liquid chromatography (HPLC), when applied towards organic acid analyses face numerous challenges [3,4]:
• Small organic acids, many of which are highly polar molecules, are difficult to
a New Modalities Product Development, Pharmaceutical Technology & Development, AstraZeneca, Operations, Macclesfield, UK b
Figure 1. IC-MS configuration used for method development [2]. retain on reversed-phase LC columns.
• As they are often poor chromophores, using UV detection to analyse small organic acids can produce varying response factors and poor sensitivity such that this cannot be used for accurate quantitation, especially at lower levels.
• Performing measurements with detection at lower wavelengths also poses some restrictions on the type of solvents or additives used as eluent components, further limiting the scope of LC analyses.
• For samples to be analysed using GC, they often need to be derivatised, adding
an extra level of sample handling [5,6], and consequently making the protocol more time-consuming.
Ion chromatography (IC) with suppressed conductivity detection (sCD), on the other hand, is a promising method to analyse organic acids without derivatisation. When coupled with MS, it offers better sensitivity and higher resolution of potential analytes [7,8], enabling accurate quantitation of resolved peaks and improved quality assurance. Ion chromatography takes advantage of the fact that organic acids are readily charged through the addition of a basic additive to the eluent. The separation
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