Salt formation investigations of drug substances: Why should it be considered?

The ability to produce a salt of a drug substance with counter ions relies on the new chemical entity, NCE, or API containing functionalities which allow proton transfer to take place. Alternatively, cocrystal formation utilises hydrogen bonding and Van der Waals interactions between suitable moieties in the drug substance and a conformer.

The primary driver for exploring salt or cocrystal formations of a drug substance is to modify the physicochemical characteristics, in particular solubility to enhance the oral bioavailability. This is often conducted during the discovery or investigational phases for an API. In addition, this can also provide IP to further protect the NCE for the discoverer.

Here, we will focus on salt formation of drug substances, but the obtained benefits can equally be applied to cocrystal investigations.

For proton transfer to take place between the drug substance and the counter ion, the pKa’s or ionisation values need to be suitable. You might think that the hydrochloride salt of an NCE containing basic functionality, or sodium salt of an API containing an acidic group is all that is required to improve the solubility of the compound in question. Although proton transfer will take place in solution, the isolation of a suitable crystalline solid might not be possible or afford a solid which presents different challenges.

Let us consider Amlodipine. This is available as the besylate, mesylate and maleate salt versions. These salt versions improve the solubility or bioavailability of the drug substance but can be considered interchangeable in terms of efficacy. The discoverer launched the besylate version as the drug product but by patenting a selection of salt versions, the discoverer was able to protect the API from competitors exploiting different salt versions. For amlodipine, seven salt versions were disclosed as isolatable solids which presents the challenge of which one do you select as the drug substance for development as the drug product.

This is not always the situation. A NCE might contain a suitable salt forming moiety, but unless the scope of the salt formation investigation is sufficiently broad in terms of counter ions this might not afford an isolatable solid which is suitable to develop as drug substance and then drug product. This is a consequence of the salt not generating a suitable crystal lattice as a solid. There might only be one or two counter ions of those generally regarded as safe, GRAS, for pharmaceutical applications that produces solids with suitable attributes for the drug substance.

Over the years, many NCEs and compounds have been assessed for salt formation. It is unwise to think that it is possible to predict which counter ion will produce a solid salt version which has all the attributes for further development and in silico tools, at this time, should be used as guides.

MorphCryst Consulting can support salt formation investigations of your NCE or compound from providing proposals and managing programmes to data review and appropriate recommendations for further development.