Most drug substances are produced synthetically in bulk in specific salt forms to promote solubility, stability, and bioavailability. The most common pharmaceutical counter ions used in the development of basic drugs include chloride (~50%) and sulfate (5-10%). It is important to accurately determine the concentration of these counter ions to establish the correct molecular mass of the drug, the stoichiometric relationship between the drug and counter ion, and the completeness of salt formation. In addition, it is also critical to determine the concentrations of unknown ionic impurities during the early stages of drug product development. Impurities can originate raw materials, intermediates, byproducts, degradation products, and contaminants in the synthetic pathway.
The International Conference on Harmonization (ICH) guidelines for impurities in pharmaceutical products proposes a qualification threshold of 0.1% if the maximum daily dose is ≤2 g/day and 0.05% if the maximum daily dose exceeds 2 g/day. However, higher or lower limits may be implemented based on scientific rationale with respect to safety considerations.
This blog post focuses on a high-throughput method for the analysis of impurities in aminoglycosides, which are a large and diverse class of antibiotics that are commonly used in the treatment of severe infections of the abdomen and urinary tract, bacteremia, and endocarditis. Ion chromatography (IC) with suppressed conductivity detection is well established and the most common technique for determining inorganic and organic ions in a wide range of matrices, including those of pharmaceutical origin.
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Application Note 190,Determination of Sulfate Counter Ion and Anionic Impurities in Aminoglycoside Drug Substances by Ion Chromatography with Suppressed Conductivity Detection (downloadable PDF) describes the linearity, detection limits, precisions, and recoveries in the successful determination of sulfate counter ions and impurities in aminoglycosides about 16 min. (The method uses the Thermo Scientific IonPac AS18 Hydroxide-Selective Anion-Exchange column.)
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