@conference{
author = "Verbić, Tatjana and Avdeef, Alex and Tam, Kin Y. and Marković, Olivera S. and Pešić, Miloš P. and Topalović, Igor A. and Veljković, Dušan Ž. and Kathawala, Mufaddal and Serajuddin, Abu T. M.",
year = "2023",
abstract = "Since the introduction of combinatorial chemistry and high-throughput screening in drug
discovery in the early 1990s, the solubility of new chemical entities (NCE) decreased drastically
while their lipophilicities increased greatly. Characterizing physicochemical properties of low soluble molecules can be especially challenging, since such molecules can undergo
complicated reactions in aqueous solution, such as forming precipitates or complexes with
buffer species or undergoing self-aggregation (dimer, trimer, etc.)1,2 or micelle formations.
Most drugs are ionizable. Foremost to the rational interpretation of solution behavior of
ionizable drugs in a physiologically-relevant pH domain requires an accurate aqueous pKa,
determined by a suitable method. In a pH-dependent measurement of a property (e.g.
solubility-, lipophilicity-, permeability-pH), when the apparent pKa value is different from the
true aqueous pKa value, it may be an early clue that nonideal solution behavior may be taking
place. In pharmaceutical research, it may seem cost-effective to use calculated pKa instead of
measured values, but paradoxically, such preference can lead to inaccurate rationalization of
the pH-dependent behavior of the drug molecule. For simple molecules, calculated values can
be useful, but for today’s new drugs or for molecules prone to complicated solution behavior,
the use of calculated pKas can substantially wrench the interpretation of solution properties.
Clofazimine (CFZ), although discovered about 66 years ago, and used therapeutically for nearly
40 years, exhibits some of the properties of relatively recent drug molecules by being
extremely water insoluble and having variable pKa values reported. We have recently
combined potentiometric titrations and UV/Vis spectrophotometry in methanol-water
cosolvent media, accompanied by DFT calculations, to assess the hypothesis of CFZ free base
dimerization. We reasoned that a soluble dimer might form from drug-drug adhesion along
the hydrophobic molecular surface. With lessened exposure of the hydrophobic surface to
water, the dimer would be more water soluble than the monomeric free base. In saturated
solutions, the apparent solubility in alkaline pH would be elevated due to the presence of the
dimer. The effect of that would be a lower pKa and reverse pKa cosolvent dependence – the
behaviour we have noticed in CFZ aqueous solutions. These findings are of paramount
importance for understanding of CFZ speciation and the future progress in developing its
improved formulations which is the subject of our ongoing studies.",
publisher = "International Association of Physical Chemists",
journal = "10th IAPC Meeting: Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6, 2023",
title = "Revealing the story of an orphan drug: clofazimine speciation and solubilization as a function of pH",
pages = "15-15",
url = "https://hdl.handle.net/21.15107/rcub_cherry_5993"
}
