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

Olivera S. Marković; Miloš P. Pešić; Alex  Avdeef; Abu T. M. Serajuddin; Tatjana Verbić

doi:10.5599/admet.3128

Authors

Olivera S. Marković 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 https://orcid.org/0000-0001-5830-1445
Miloš P. Pešić University of Belgrade – Faculty of Chemistry, Studentski trg 12-16, 11000 Belgrade, Republic of Serbia https://orcid.org/0000-0002-1982-040X
Alex Avdeef in-ADME Research, New York, NY 10128, USA https://orcid.org/0000-0002-3139-5442
Abu T. M. Serajuddin St. John's University, College of Pharmacy and Health Sciences, 8000 Utopia Parkway, Queens, NY 11439, USA https://orcid.org/0000-0002-2596-715X
Tatjana Verbić University of Belgrade – Faculty of Chemistry, Studentski trg 12-16, 11000 Belgrade, Republic of Serbia https://orcid.org/0000-0002-6348-1644

DOI:

https://doi.org/10.5599/admet.3128

Keywords:

pH-ramp shake-flask method, solubility product, phosphate salt, chloride salt, critical micellar concentration, pH and buffer effect

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.

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