Salt Selection in Drug Development

The selection of an appropriate salt form for a potential drug candidate is an opportunity to modulate its characteristics to improve bioavailability, stability, manufacturability, and patient compliance.
Mar 02, 2008

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).