Development and Validation of a Sensitive GC-MS Method for the Determination of Alkylating Agent, 4-Chloro-1-butanol, in Active Pharmaceutical Ingredients

Abstract

The analysis of genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs) is a challenging task. The target detection limit (DL) in an API is typically around 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis. 4-Chloro-1-butanol, an alkylating agent, is one of the GTIs. It is generated when tetrahydrofuran and hydrochloric acid are used during the synthesis of the APIs. In this study, a sensitive and robust gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the identification of 4-chloro-1-butanol in APIs. In the GC-MS method, 3-chloro-1-butanol was employed as an internal standard to ensure accuracy and precision. Linearity was observed over the range 0. Key words 4-chloro-1-butanol; GC-MS; genotoxic impurity; active pharmaceutical ingredient; trace analysisThe analysis of genotoxic impurities (GTIs) in trace amounts is of increasing interest to pharmaceutical industries owing to its potential application in the detection of human carcinogenesis and in regulatory aspects. The assessment of GTIs during clinical development is a major liability.1-5) Since GTIs are expected to be present in active pharmaceutical ingredients (APIs), a method for the sensitive and selective analysis of GTIs is required. The allowable limits of GTIs in new commercial drugs are regulated by government agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), [6][7][8][9] although the toxicological assessment of GTIs is not addressed sufficiently in the International Conference on Harmonisation (ICH) guidelines. The present ICH Q3A and Q3B guidelines only describe the limits of conventional impurities and related substances, where typical levels are above 0.05%. Therefore, the ICH has been discussing about GTIs as part of the ICH M7 guideline. The allowable limits of GTIs are decided by the U.S. FDA and the EMA depending on the duration and the daily dose of exposure during the clinical development. A toxicological threshold of 1.5 µg/d is suggested. Typically, the target detection limit (DL) in an API is 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis.4-Chloro-1-butanol, an alkylating agent, is one of the GTIs, which is generated when tetrahydrofuran (THF) and hydrochloric acid (HCl) are used during the synthesis of APIs. The interaction of THF with HCl leads to the generation of 4-chloro-1-butanol (Fig. 1). THF and HCl are frequently used in the synthesis of APIs. Hence, it is necessary to confirm the fate of 4-chloro-1-butanol, to develop the process control for APIs and ensure their quality. The quantitation limit (QL), as per the analytical method, should be at low ppm levels, considering the protocols (the daily dose and the duration of exposure) of the clinical studies.As part of the analytical method, conventional analytical instrumentations such as the HPLC with UV detection (for nonvolatile GTIs) or the GC with flame ioniza...

A Primer for Pharmaceutical Process Development Chemists and Analysts in Relation to Impurities Perceived to Be Mutagenic or “Genotoxic”

“…Failure to Apply a Class-Specific Limit. Harigaya et al 113 published details of a highly sensitive assay for 4-chlorobutanol (4-CB; CAS no. 928-51-8) in drug substances on the assumption that the compound is mutagenic (with no confirmatory evidence).…”

Quantitative mass spectrometry methods for pharmaceutical analysis

“…A more frequently used separation technique in pharmaceutical analysis is GC. Although GC-MS is limited to the measurement of volatile or semi-volatile compounds, it is regularly used in environmental studies and to a lesser extent in bioanalysis and impurity profiling [80][81][82][83]. Because pharmaceuticals are in general polar, non-volatile molecules, derivatization reactions are required to make them suitable for GC analysis.…”

Sensitive Quantitation of Residual Phenylhydrazine in Antipyrine by LC-ICP-MS with Iodo Derivatization

“…[14][15][16][17][18][19][20] However, in some cases, these techniques might not be applicable because of the properties (ionization efficiency, polarity, solubility, and purity, etc.) of the GTIs and/or APIs.…”