@conference{
author = "Marković, Olivera S. and Pešić, Miloš P. and Shah, Ankita V. and Serajuddin, Abu T. M. and Avdeef, Alex and Verbić, Tatjana",
year = "2019",
abstract = "Optimal experimental design to measure the aqueous equilibrium solubility of an ionizable
substance requires a number of critical considerations. The aqueous medium to which the
substance is added usually contains a buffer to help control the pH.
The solution behavior of desipramine hydrochloride (DsHCl) in phosphate-buffered and
unbuffered solutions is evidently complicated and only tentatively understood. The computer
program pDISOL-X was used to design the structured pH-ramp shake flask experiments (pH RSF method), to process the data, and to refine the equilibrium constants. Specifically,
solubility was measured: a) using state-of-the-art experimental design, as recommended in a
recently published white paper on solubility [1], b) performing solubility titrations in two
directions, pH 11.6→1.3 as well as 1.3→11.6, c) using both DsHCl and Ds (free base), as
starting solids, d) performing titrations in chloride-containing media, without any phosphate, e)
performing the converse measurements (phosphate-containing, chloride-free media),
f) isolating solids at critical log S-pH points and performing solid state characterizations using
elemental, thermogravimetric, differential scanning calorimetric, and powder X-ray diffraction
analyses. Concentration was measured using HPLC with UV/VIS detection.
Under the assay conditions, only the phosphate free solutions showed some supersaturation
near pHmax 8.0. In phosphate-containing solutions, pHmax was indicated at higher pH (8.8–
9.6). Oils mixed with solids were observed to form in alkaline solutions (pH>11). Notably,
soluble drug-phosphate complexes appeared to form below pH 3.9 and above pHmax in
saturated phosphate‑containing saline solutions. This was indicated by the systematic pH
shift to higher values in the log S-pH curve in alkaline solution than expected from the
Henderson-Hasselbalch equation. For pH<3.9, saturated phosphate-containing saline
solutions exhibited elevated solubility, with drug-hydrochloride as the sole precipitate. Salt
solubility products, intrinsic solubility, and complexation constants, which rationalized the
data, were determined [2].",
publisher = "International Association of Physical Chemists",
journal = "8th IAPC Meeting Eighth World Conference on Physico-Chemical Methods in Drug Discovery & Fifth World Conference on ADMET and DMPK , Split, Croatia, September 9-11, 2019",
title = "Desipramine solubility studies: enhanced solubility due to drug-buffer aggregates",
pages = "17-17",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5941"
}