Sodium and potassium salts of bumetanide trihydrate: Impact of counterion on structure, aqueous solubility and dehydration kinetics

Abstract

A form of bumetanide potassium trihydrate that is structurally similar to bumetanide sodium trihydrate was identified. Structural analysis indicated however that the change from sodium to potassium salt resulted in meaningful changes in the packing arrangement and even greater changes on physicochemical properties. The potassium trihydrate salt was five times more soluble in water relative to the sodium trihydrate salt (27 mg mL⁻¹vs. 5.6 mg mL⁻¹). Both salts underwent complete dehydration to their corresponding anhydrate forms following exposure to low humidity or elevated temperature. Arrhenius plots for the dehydration between 20–30 °C yielded a lower activation barrier for the potassium trihydrate compared to the sodium trihydrate (14.9 kcal mol⁻¹vs. 19.9 kcal mol⁻¹), translating into a 15–20-fold difference in the rate of dehydration. Such a 5.0 kcal mol⁻¹ gap suggests that the H₂O molecules are more tightly bound in the sodium trihydrate compared to potassium trihydrate. These differences in solubility and rate of dehydration further illustrate that changes to chemical composition can have a meaningful and unpredictable impact on the physicochemical properties of closely related pharmaceutical salt forms.