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The change in crystal structure that can be accomplished by salt formation can
lead to greatly improved properties. In many cases, substances containing free acid
or base groups have poor aqueous solubility. Saltification of these groups often
improves solubility, thus providing greater bioavailability. It is sometimes the case that a
salt provides increased chemical or physical stability compared to the parent drug
substance. Salts can also provide a means of purification and/or a way to improve the
handleability of a drug substance.
However, not all salts will perform equally well. For example, a crystalline,
bioavailable salt with few polymorphs is easier to purify, dry, mill, store, and
manufacture into a drug product than a hygroscopic, amorphous salt.
Delays in drug development due to improper salt selection can be costly to the
public health by delaying drug availability. Unfortunately, rational salt selection is not
always practiced. Often the first salt produced at laboratory scale is used for
development without further consideration. In other cases, rather than initiating an
orderly, sequenced investigation based on the material properties of the drug
substance, drug developers may re-use trial-and-error methods based on past
experience.
Even when rational selection processes are used, they can be flawed. For
example, it is common to estimate salt solubility by mixing solutions of drug and
counterion source until precipitation occurs, then choosing the salt based on a solubility
criterion. The true equilibrium solubility of a salt can only be determined in the presence
of excess solid salt, and the solubility will differ depending on the form of the excess
solid (amorphous, crystalline, polymorphic form).
SSCI uses a decision tree approach to salt selection. An example of this is shown in
Figure 1. Steps may be removed, added, or performed in a different order as required