Sponsors may require a salt screen for a number of reasons, or a combination of these:
• Solubility
In general the aqueous solubility of a salt will be greater than the API because of the polar nature of charged species, salts retain their charge in aqueous solution. The current trend is for APIs to become more lipophilic and it is common to run into aqueous solubility issues with compounds that have been designed for potency by optimisation of lipophilic interactions. Exceptions to high aqueous solubility are salts made with high MW, lipophilic (and hence highly aqueous insoluble) acids such as naphthalene sulfonic acids. Such examples will dominate the properties of the salt produced. They may be useful, however, to generate crystallinity in otherwise reluctant examples.
•Stability
Common causes of drug substance instability are oxidation, hydrolysis and inter- or intra- molecular reactions of the API itself. Salt formation can have an influence on stability by reducing the nucleophilicity of basic centres to shut down the majority of these processes. Hygroscopicity, i.e. form instability to high humidity will vary amongst different salts.
• Crystallinity
It is reasonable to assume that salts will have greater crystallinity and higher melting point than the parent material. Sponsor may also be seeking the first crystalline forms of a compound that is amorphous as the free API. Crystalline forms are generally more stable, easier to handle and show greater reliability in formulation and pharmaceutical performance.
• Novelty
A novel salt form is patentable if it has some demonstrable advantage over the prior art and the inventor has a proven method of preparation, i.e. reduction to practice. It is therefore prudent to look for optimal solid forms that offer little scope for attack from competitors who may see an opportunity to exploit a flawed profile.
• Other processability
This can include issues in large scale synthesis such as slow filtration, and further downstream processes such as compressibility etc.
