Imipramine solubility-pH profiles: self-aggregation vs. common-ion effect

The pH-dependent solubility of imipramine, a tricyclic antidepressant, and its hydrochloride salt was investigated in phosphate buffers and chloride-containing aqueous media using the pH-ramp shake-flask method. It was reported that aggregation of imipramine in acidic media and its partial degradation in alkaline media complicate the determination of its solubility. This was further investigated with modified methods.

For imipramine solubility studies, the computer program pDISOL-X was used to design experiments, process data, and refine the equilibrium constants. Isolated solid precipitates under various conditions were characterized using thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and elemental analysis. The critical micelle concentration of imipramine hydrochloride was determined in 0.10 mol L^-1 NaH₂PO₄ and in 0.15 mol L^-1 NaCl by conductometric titrations.

A detailed analysis of imipramine pH-solubility profiles reveals complex equilibria in the aqueous phase, as well as various solid-phase transformations. Intrinsic solubility of imipramine, solubility products of imipramine hydrochloride and imipramine phosphate salts, and aggregation constants (trimer, heptamer, and cationic complex with phosphate ions) were determined. Solid state characterization results are in accordance with pDISOL-X analysis.

These findings, along with our previous solubility studies of desipramine and nortriptyline, suggest that even subtle structural variations can lead to significant differences in the aqueous media behaviour of tricyclic antidepressants. This type of information can be valuable in the early stages of drug discovery, in formulation optimization experiments, as well as in in vitro and in vivo studies.