Systematic study into the salt formation of functionalised organic substrates

Abstract

There is currently a great amount of interest in the use of salts in the pharmaceutical industry because the physiochemical properties of the solid forms can be modified without altering the biochemical properties of the drug. Much effort has been expended in screening to select the best salt form and a number of empirical rules have been proposed such as the 'rule of three', which states that a successful salt formation generally requires a difference of three pKa units between the conjugate acid and the conjugate base. However, this rule does not always hold and the reasons are often unclear. The idea of this project is to perform a detailed systematic study of organic salt formation through a series of designed experiments, in order to obtain a broader and better understanding of the chemical descriptors, or factors that might be involved. A set of descriptors that describe molecular properties relevant to salt formation have been identified. For the initial experiments, a collection of salt forming acids has been assembled from the Cambridge Structural Database [1], and other sources, and their descriptor values calculated. These acids define a chemical space from which the compounds for the experiments can be chosen. The experiments aim to explore this chemical space whilst building statistical models that will allow an understanding of how the descriptors affect salt formation. Findings from the chemical space investigation coupled with experimental results from this study will be presented. This work is part of the Combechem E-science project at the University of Southampton.