Abstract
A sensitive static headspace gas chromatographic method was developed and validated for the determination of residual epichlorohydrin (ECH) in sevelamer hydrochloride (SVH) drug substance. This method utilized a Phenomenex Zebron ZB-WAX GC column, helium as carrier gas with flame ionization detection. The critical experimental parameters, such as, headspace vial incubation time and incubation temperature were studied and optimized. The method was validated as per United States Pharmacopoeia (USP) and International Conference on Harmonization (ICH) guidelines in terms of detection limit (DL), quantitation limit (QL), linearity, precision, accuracy, specificity and robustness. A linear range from 0.30 to 10 μg/mL was obtained with the coefficient of determination (r2) 0.999. The DL and QL of ECH were 0.09 μg/mL and 0.30 μg/mL, respectively. The recovery obtained for ECH was between 91.7 and 96.6%. Also, the specificity of the method was proved through gas chromatography mass spectrometry (GC-MS). This method was applied successfully to determine the content of residual ECH in SVH bulk drug.
Highlights
Sevelamer hydrochloride (SVH) drug substance is intended for oral administration in the treatment of hyperphosphatemia
The threshold of toxicological concern” (TTC) refers to a threshold exposure level to compounds that do not pose a significant risk for carcinogenicity / genotoxicity or other toxic effects; and an exposure level of 1.5 μg per day (TTC) for genotoxic impurity is considered to be associated with an acceptable risk for most pharmaceuticals [8, 9]
The detection limit (DL) and quantitation limit (QL) for ECH were determined by signal-to-noise ratio (S/N) method
Summary
Sevelamer hydrochloride (SVH) drug substance is intended for oral administration in the treatment of hyperphosphatemia. Considering the recommended dose of >2.4g SVH per day, ECH must be limited to less than 0.6 μg/g in the drug substance, necessitating the development of sensitive, accurate and robust analytical method. The published methods evaluated ECH, mostly on clean sample matrices, such as, water and air These methods [10,11,12,13,14] utilized derivatization procedures, adduct analysis, SPME fibers, mass and electrochemical detectors. The complexities and limitations of the existing methods and no method reported so far, for the determination of ECH in polymeric drug substance (SVH), prompted to develop a new method. The present investigation was, initiated with the objective to develop a simple and sensitive analytical method for the ECH estimation in SVH drug substance utilizing static headspace (HS) GC with FID. The proposed HS-GC method with FID has been validated using ICH and USP [18, 19] guidelines as references
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