The acid–base chemistry of a drug substance plays a key role in the development of a new drug. The acid–base chemistry will:
Determine whether the drug is in ionic or non-ionic form
Affect its solubility and rate of dissolution in the gastrointestinal tract
Determine its permeability across biological membranes
Affect its bioavailability and access to the site of action
In addition, the acid-base chemistry can also be used to predict the extent of receptor binding and hypothesize the mode of action.
4-Anilino-3-quinolinecarbonitrile compounds show inhibitory activity against a range of enzymes which have been implicated in a number of diseases, and several of these compounds have found therapeutic application. One such drug is Bosutinib (SKI-606), a treatment for chronic myelogenous leukemia.
To investigate the acid-base chemistry of this compound a collaborative project was initiated with Sirius Scientific, employing a combination of potentiometric, UV spectrophotometric and NMR spectroscopic pH titrimetric methodology. These studies reveled Bosutinib:
Has three basic pKas (8.04 4.80 3.77) and one acidic pKa (11.27)
Two of these were well separated (ΔpKa > 3.0), whereas the other two overlapped to form a diprotic system
The acid-base chemistry of Bosutinib can be represented by the following scheme
Macroscopic protonation Scheme
Microscopic protonation Scheme
These studies have been published in the literature and greatly assisted in obtaining the marketing authorisation for Bositinib (Bosulif).
ACID-BASE CHEMISTRY OF 4-ANILINO-3-QUINOLINECARBONITRILE COMPOUNDS