Salt Selection in Drug Development or Salt is good for you!

Suppose you have an exciting new drug which is potentially capable of alleviating much suffering.  Suppose also that it is a solid and it doesn’t dissolve in water.  In fact it will only dissolve in hydrocarbons.  How do you ensure that when orally taken, the drug will get into the bloodstream (water) and travel to the point of action? Salt selection is your answer.

The time honoured way of achieving this is to turn the drug into a salt which is usually more water soluble by a process known as salt selection.  50% of all drug molecules are in fact administered as salts.  Your drug candidate may be ‘basic’, in which case reaction with an acid will produce a salt.  Alternatively the drug might be acidic, so reaction with a base will also produce a salt.  Salts are comprised of charged molecules which are readily dissolved in water.  

Clearly, the original (non salt) drug will have disadvantageous properties. It is highly likely to be poorly biologically available.  It might be in a form that is difficult to process.  A salt version has the potential to improve the thermal or hydrolytic stability of the drug, to improve it’s permeability, efficacy or formulation.  In fact these properties are able to be fine tuned in a salt selection programme which gives the drug developer much more flexibility in designing the optimum new pharmaceutical.

Salt selection should be conducted before long-term toxicology studies are performed. That is, at the beginning of Phase I clinical trials. This will minimise the need to repeat work if the salt is introduced later in clinical development.  

The main objective in a salt selection study is to find the form best suited for development including good aqueous solubility, high crystallinity, low hygroscopicity (water absorbance) and optimal stability.  A programme of polymorph investigation is usually carried out in conjunction with the salt selection work.

For salt selection it is common to use acids (or bases) that are ‘generally regarded as safe’ from which a wide selection is available and in the initial stages automation is helpful.  Crystallinity is assessed using a variety of techniques including X-Ray Powder Diffraction.  

Rather than complicate the drug development process a salt selection programme is a viable extension because salts with superior properties can be patent protected. Moreover, salt selection is a key component of the development of a robust new drug and an essential stage to consider.

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