Abstract
Objective: Dimethyl sulfate has been highlighted as potential genotoxic and carcinogenic impurity. A sensitive Headspace gas chromatography (HS-GC) method with pre-column derivatization was developed and validated for the determination of dimethyl sulfate impurity in methoxsalen active pharmaceutical ingredient.Methods: HS-GC method on the column Agilent DB-5, 30m X 0.53 mm, film thickness 1.5 µm, with flame ionization detector (FID) was used. Derivatization reagent concentration, time of reaction and pH of the solution were optimized during method development. This analytical method was evaluated by performing method validation as per ICH guideline.Results: The proposed method was specific, linear, accurate, rugged and precise. The calibration curves showed good linearity over the concentration range of 0.5 μg/ml to 3.0 μg/ml and the correlation coefficient was 0.999. Method had very low limit of detection (LOD) and limit of quantification (LOQ) 2.0 μg/g and 5.0 μg/g respectively. Accuracy was observed within 98.1%–104.5%.Conclusion: The developed method was demonstrated to be accurate, robust and sensitive for the determination of dimethyl sulfate impurity in methoxsalen drug substance.
Highlights
Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant
Photochemotherapy (PUVA) is treatment involving the use of psoralen, like methoxsalen, an exogenous photosensitizer followed by ultraviolet A (UVA) irradiation [3,4,5]
DB-5, 30m X 0.53 mm, Film Thickness: 1.5 μm 40 °C 40 °C hold for 8.0 min, ramp-1 at 5 °C/min to 100 °C hold for 0 minute, ramp-2 at 20 °C/min to 250 °C hold for 5 minute, Flame Ionization Detector (FID) 280 °C 220 °C Nitrogen 5.0 psi 32.50 min 90 °C 110 °C 120 °C 16 psi 3.0 min 0.20 min 0.5 min 30.0 min 46.0 min Chemical and reagents
Summary
Methoxsalen is a naturally occurring photoactive substance found in the seeds of the Ammi majus (Umbelliferae) plant It belongs to a group of compounds known as psoralens or furocoumarins [1]. Dimethyl sulfate is probably carcinogenic to humans so IARC classified DMS in Group 2A It is a potent genotoxic chemical which can directly alkylate DNA both in vitro and in vivo [6,7,8]. Because of the known carcinogenicity and genotoxicity, the presence of residual dimethyl sulfate in methoxsalen drug substance must be controlled as per European Medicines Agency (EMA), International Conference on Harmonization [9] and Food and Drug Administration (FDA) guidelines [10, 11]. It is necessary to develop sensitive, accurate and robust analytical method
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