L-649,923 — The selection of an appropriate salt form and preparation of a stable oral formulation

Abstract

L-649,923 is an orally active leukotriene D 4 antagonist and the salt of a γ-hydroxy acid. It was formulated as a physically and chemically stable compressed tablet dosage form. Because the free acid was inherently unstable, the physical and chemical properties of the sodium, calcium, ethylenediamine and benzathine salts were evaluated and the calcium salt selected as the most pharmaceutically acceptable form of the drug for formulation development. The principal route of degradation was through an intramolecular esterification to yield the γ-lactone. Degradation could be monitored by following the appearance of the γ-lactone with an HPLC assay. A mechanism of degradation was proposed resembling acid-catalyzed solution esterificatiom occuring in the sorbed moisture. This postulate was used as a predictive model. Formation of γ-lactone was minimized in a direct compression tablet formulation by reducing the amount of free acid in the drug substance, avoiding an aqueous granulating process, using excipients with low water content and adding sodium carbonate as an alkalizing agent.