pH-Dependent solubility profiles of imipramine and amitriptyline hydrochlorides

Abstract

Amphiphilic tricyclic bases are surface-active, sparingly-soluble drugs, which can exhibit complicated aqueous solution chemistry. New pH-Ramp Shake-Flask method was previously applied to desipramine hydrochloride solubility studies and described in the literature [1]. Solubility was measured using state-of-the-art experimental design, recommended in the white paper on equilibrium solubility measurements [2]. The aim of this study was to examine solubility-pH behavior of desipramine structural analogues: imipramine and amitriptyline hydrochlorides (Figure 1). Imipramine and amitriptyline are tricyclic antidepressants, which are used in the treatment of mental illnesses. pH-Ramp Shake-Flask method was applied. Appearance of aggregates (trimer, around pH 4 in imipramine case), which lead to slow sedimentation, and oil forms make solubility determination extremely challenging. Oils which are more soluble than crystalline forms are formed in alkaline solutions (above pH 7.8 in imipramine case). Sometimes in such cases, pH adjustment in that pH region can be unpredictable. Furthermore, oil sticks to electrode making pH measurement difficult, especially in amitryptiline case. Concentration was measured using HPLC with UV/Vis detection. Different techniques were used for solid phase characterization. Solid phase characterization is particularly important in complicated systems like this.