An estimated 50% of all drug molecules used in medicinal therapy are administered as salts. This fact indicates that the salification,
or salt formation, of a drug substance is a critical step in drug development (1, 2). A drug substance often has certain suboptimal
physicochemical or biopharmaceutical properties that can be overcome by pairing a basic or acidic drug molecule with a counterion
to create a salt version of the drug (3). The process is a simple way to modify the properties of a drug with ionizable functional
groups to overcome undesirable features of the parent drug (4). This fact underlines the importance of salt formation for
drugs that are designed, developed, and marketed after a rigorous research and development program (1).
Basic concepts in salt formation
Figure 1: Diagrammatic representation of salt formation.
|
Salts are formed when a compound that is ionized in solution forms a strong ionic interaction with an oppositely charged counterion,
leading to crystallization of the salt form (5). In the aqueous or organic phase, the drug and counterion are ionized according
to the dielectric constant of the liquid medium. The charged groups in the drug's structure and the counterion are attracted
by an intermolecular coulombic force. During favorable conditions, this force crystallizes the salt form (see Figure 1). All
acidic and basic compounds can participate in salt formation (4). However, the success and stability of salt formation depends
upon the relative strength of the acid or base or the acidity or basicity constants of the species involved (6).
Table Ia: Advantages of salt formation for drug properties.
|
The salt form is separated into individual entities (i.e., the ionized drug and the counterion) in liquid medium, and its
solubility depends upon the solvation energy in the solvent. The solvent must overcome the crystal lattice energy of the solid
salt and create space for the solute. Thus, the solubility of a salt depends on its polarity, lipophilicity, ionization potential,
and size. A salt's solubility also depends on the properties of solvent and solid such as the crystal packing and presence
of solvates (7).
The importance of salt formation
Table Ib: Disadvantages of salt formation for drug properties.
|
Salt forms of drugs have a large effect on the drugs' quality, safety, and performance. The properties of salt-forming species
(i.e., counterions) significantly affect the pharmaceutical properties of a drug (see Tables Ia and Ib) and can greatly benefit
chemists and formulators in various facets of drug discovery and development (6).
