ADMET and DMPK, Vol. 14 , 2026.
Original scientific paper
https://doi.org/10.5599/admet.3128
Imipramine solubility-pH profiles: self-aggregation vs. common-ion effect
Olivera S. Marković
orcid.org/0000-0001-5830-1445
; University of Belgrade – Institute of Chemistry, Technology and Metallurgy – National Institute of the Republic of Serbia, Department of Chemistry, Njegoševa 12, 11000 Belgrade, Republic of Serbia
Miloš P. Pešić
; University of Belgrade – Faculty of Chemistry, Studentski trg 12-16, 11000 Belgrade, Republic of Serbia
Alex Avdeef
; in-ADME Research, New York, NY 10128, USA
Abu T. M. Serajuddin
; St. John's University, College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY 11439, USA
Tatjana Verbić
orcid.org/0000-0002-6348-1644
; University of Belgrade – Faculty of Chemistry, Studentski trg 12-16, 11000 Belgrade, Republic of Serbia
*
* Corresponding author.
Abstract
Background and Purpose: The pH-dependent solubility of imipramine (Imp), a tricyclic antidepressant, was investigated in phosphate buffers and chloride-containing aqueous media using the pH-Ramp shake-flask method. It was reported that aggregation of Imp in acidic media and its partial degradation in alkaline media complicate the determination of its solubility. This was further investigated with modified methods. Experimental Approach: For Imp 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 (CMC) of ImpHCl was determined in 0.10 M NaH2PO4 and in 0.15 M NaCl by conductometric titrations. Key Results: Detailed analysis of Imp pH-solubility profiles reveal complex equilibria in the aqueous phase and various solid-phase transformations as well. Intrinsic solubility of Imp, solubility products of Imp hydrochloride and Imp 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. Conclusion: 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 behavior 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.
Keywords
pH-ramp shake-flask method; solubility product; phosphate salt; chloride salt; critical micellar concentration; pH and buffer effect
Hrčak ID:
345189
URI
Publication date:
31.12.2025.
Visits: 202 *