Abstract
Bosentan monohydrate (4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl]benzene-1-sulfonamide monohydrate) is a dual endothelin receptor antagonist (ERA) applied in the treatment of pulmonary arterial hypertension. To achieve effective process control of the bosentan monohydrate synthesis, it was necessary to develop a selective and not highly time-consuming method for ultra-high performance liquid chromatography (UHPLC). The method is characterized by adequate sensitivity, reproducibility and selectivity for the determination of bosentan monohydrate and related compounds from all synthetic stages. The UHPLC separation was carried out by reversed phase chromatography on the Acquity BEH C18 column (100 mm × 2.1 mm, 1.7 µm) with a mobile phase composed of solvent A (0.1 %, v/v, acetic acid in water) and solvent B (methanol), in the gradient mode at the flow rate of 0.4 mL min−1. Limits of detection and quantification for the compounds were ≤0.1 µg mL−1 and 0.3 µg mL−1, respectively. The linearity for all related compounds was investigated as in the range for the active pharmaceutical ingredient (API) and as in the range for the in-process control. The developed method was validated according to the current guidelines, proving the suitability of the method for its intended purpose.
Highlights
Bosentan monohydrate, 4-tert-butyl-N-[6-(2-hydroxyethoxy)5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl] benzene-1-sulfonamide, is a selective mixed endothelin A and B receptor antagonist used in the treatment of pulmonary hypertension
The 220 nm wavelength was selected for further method development of related substances determination in bosentan monohydrate while the 270 nm wavelength was selected for the assay determination method
Temperature above 30 °C caused an increase in the resolution between BO-1 and BO-2, but at the same time decreased the resolution between impurity D and bosentan
Summary
4-tert-butyl-N-[6-(2-hydroxyethoxy)5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl] benzene-1-sulfonamide, is a selective mixed endothelin A and B receptor antagonist used in the treatment of pulmonary hypertension. Elevated endothelin concentrations are strongly correlated with the disease severity [2]. Bosentan decreases both pulmonary and systemic vascular resistance resulting in an increased cardiac output without increasing the heart rate. It is indicated for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III. Some improvements have been shown in patients with PAH WHO functional class II [3]. The drug is indicated to reduce a number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease [3,4,5]
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