Strategy for the Prediction and Selection of Drug Substance Salt Forms

Through consideration of the ionic equilibria of acids and bases, one may readily calculate the formation constant of a salt species solely on the basis of knowledge of the pKA value of the acid and the pKB value of the base.
Oct 01, 2007

Any drug substance can be classified as either an acid or base because the drug substance possesses the ability to react with other, stronger acids or bases. As such, the drug substance also would possess the ability to exist as an ionic species when dissolved in suitable fluid media. Often, the state of ionization of a substance will profoundly affect its degree of aqueous solubility, as shown by the high solubility of sodium benzoate compared with the low solubility of benzoic acid. The utility of salt forms as active pharmaceutical ingredients is well known and represents one of the ways to increase the degree of solubility of an otherwise intractable substance (1–3) and bioavailability (4).

Historically, the process of selecting the most appropriate salt form of a drug substance has been approached in an empirical manner, where one prepares a large number of salts of the substance and then evaluates their qualities. Those products that exhibit acceptable degrees of aqueous solubility and dissolution rate, appropriate crystal form of low hygroscopicity, high melting point, good mechanical properties, and acceptable chemical stability become the chosen candidates for further development. This approach reached its epitome with the use of high-throughput screening methods, where substances are dispensed in 96-well plates and automated methods are used to set up the formation of multiple series of salts (5). Practically, the only restriction placed in these studies is that the salt-forming counterion must be one of the pharmaceutically acceptable species identified in compilations (1–3, 6).

Numerous attempts have been made to instill an intelligent design into the salt-selection process. Gould used a decision analysis process to develop a rational process of salt selection for basic drugs, where the course of the work was guided by the pivotal issues of melting point, solubility, and hydrophobicity (7). Morris et al. described a general method that was used to guide the salt selection of a drug candidate through consideration of hygroscopicity, physical stability, aqueous solubility, and chemical stability (8). The theoretical basis and application of in situ salt screening has been applied to monobasic and monoacidic substances (9) and extended to cover multibasic drugs in multiprotic acids (10). Procedures for salt selection and optimization have been reviewed, as have strategies for salt selection and optimization of salt forms (11–13). More recently, the use of a grid-based molecular modeling method for salt screening has been described (14).

Over time, it has become very clear that the ability to prepare and isolate a salt form of a drug substance in its solid state, and the stability of that salt form with respect to disproportionation when dissolved in an aqueous solution, is fundamentally determined by the relative acidity or basicity of the drug substance and its salt-forming counterion. Valuable insight into the salt-formation process can be gleaned from an evaluation of the chemical equilibria associated with weak acids, bases, and their salts. Manipulation of equilibrium expressions yields useful relations that can be used to predict the ability of a salt form to exist, and such predictions can be used to focus a salt-selection process.

Ionic equilibria of acidic and basic substances

There are many definitions for acids and bases, but the 1923 definitions of J.N. Brønsted and T.M. Lowry are the most useful for discussions of ionic equilibria in aqueous systems. According to the Brønsted–Lowry model, an acid is a substance capable of donating a proton to another substance, such as water:

The acidic substance (HA) that originally donated the proton becomes the conjugate base (A ) of that substance because the conjugate base could conceivably accept a proton from an even stronger acid than the original substance. The thermodynamic equilibrium constant expression for Equation 1 would be: