The utility of sulfonate salts in drug development.

The issue of controlling genotoxic impurities in novel active pharmaceutical ingredients (APIs) is a significant challenge. Much of the current regulatory concern, has been focused on the formation and control of genotoxic sulfonate esters. This is linked with the withdrawal of Viracept (Nefinavir mesilate) from European markets in mid-2007, over concerns about elevated levels of ethyl methanesulfonate (EMS). This issue has resulted in calls from European regulators to assess risk mitigation strategies for all marketed products employing a sulfonic acid counter-ion to ensure that the sulfonate esters that could be potentially formed are controlled to threshold of toxicological concern (TTC)-based limits. This has even led to calls to avoid sulfonic acids as salt counter-ions. However, sulfonic acid salts possess a range of properties that are useful to both synthetic and formulation chemists. Whilst sulfonate salts are not a universal panacea to some of the problems of salt formation they do offer significant advantages as alternatives to other salt forming moieties under certain circumstances. This review thus sets out to define some of the advantages provided through utilization of sulfonic acids, explaining the importance of their retention as part of a thorough salt selection process.

Analysis of potential genotoxic impurities in pharmaceuticals by two-dimensional gas chromatography with Deans switching and independent column temperature control using a low-thermal-mass oven module.

The analysis of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs) is a challenging task. The target limit of detection for a PGI in an API is typically 1 ppm (1 microg/g API). This is about 500 times lower than for classical impurity analysis. Consequently, analytical methods for trace analysis, mostly in combination with MS detection, need to be applied for the qualitative and quantitative determination of these impurities. A two-dimensional capillary GC method is presented that can be used for the determination of some target PGIs. A concentrated solution of the API sample is directly introduced in the GC-MS system, using an apolar column for first-dimension separation. The fraction (heart-cut) containing the PGIs is transferred to a second capillary column, installed in a low-thermal-mass oven (LTM). The LTM focuses the heart-cut(s) and allows independent temperature-programmed analysis with a polar second-dimension column. The API, solvent, and derivatization agents are not introduced in the second column or in the MS detector, avoiding contamination, column degradation, and target analyte peak detection/integration issues. The performance of this set-up is illustrated by the analysis of some Michael-reactive acceptor PGIs and haloalcohols in carbamazepine as test matrix. Excellent reproducibility (<10% RSD) at the low parts per million level and low detection limits (<1 ppm) were obtained.

Development and validation of an automated static headspace gas chromatography-mass spectrometry (SHS-GC-MS) method for monitoring the formation of ethyl methane sulfonate from ethanol and methane sulfonic acid.

An automated sample preparation and analysis procedure was developed to monitor the formation of ethyl methane sulfonate from reaction mixtures containing ethanol and methane sulfonic acid. The system is based on a liquid handling robot combined with a static headspace module. The formed ethyl methane sulfonate is analysed after derivatisation with pentafluorothiophenol using static headspace-gas chromatography-mass spectrometry (SHS-GC-MS). Using the automated reaction-derivatisation-headspace GC-MS system, the formation of ethyl methane sulfonate can be monitored in different reaction mixtures under different reaction conditions, including temperature, water content and pH. Excellent linearity, repeatability and robustness were obtained, allowing the system to be used in kinetic studies.