Generation of salt forms.
Salts can be prepared on a small scale using various methods. Forming salts from free acid or base is the most common method.
The free acid or base of the drug substance is combined with the counterion base or acid in specific molar ratios in a suitable
solvent system. The salt form is then isolated, and the solid precipitate is recrystallized. A less common method is to form
salts through salt exchange. In this method, a counterion salt is treated with a free acid or base in a specific molar concentration
in a suitable solvent. The solid is then isolated and recrystallized. The sulfate salt of methyl pyridinium-2-aldoxime was
prepared using silver sulfate as a counterion. The unwanted silver ions were removed as insoluble iodide salt, and the desired
sulfate salt was precipitated by adding antisolvent (36). A wide range of salts are generally prepared for each new substance.
Their properties are compared during a preformulation program that improves the chances of selecting the optimal salt form
(29). However, a balanced approach should be adopted because limited resources are available at this early stage of drug development.
Commonly used salts such as hydrochlorides and sodium have advantages over other salt-forming moieties. For example, they
have low molecular weight and low toxicity. However, other salt forms such as mesylate may sometimes offer advantages such
as higher solubility and bioavailability (37).
High-throughput synthesis has gained greater importance in the salt-selection process. This technique allows many counterions
and crystallization solvents to be evaluated using as little as 50 mg of drug substance. After the optimum drug-substance
form is selected at the microlevel, the synthesis of the compound can be scaled up to several hundred grams to test for other
stages of preformulation (27). In situ salt screening also offers a viable alternative to traditional salt screening (34). This method has a special relevance for
poorly soluble compounds because it can rapidly rank compounds based on their solubility, effectively screening out insoluble
compounds immediately (13). During in situ salt screening, a known concentration of drug is added to a concentrated counterion solution sufficient to obtain the pHmax (see Figure 2) for successful salt formation that may be subjected to solubility screening. Tong applied in situ salt screening to GW1818, an alpha 1A adrenergic receptor antagonist, and short-listed four salts—the phosphate, succinate,
mesylate, and hydrochloride—for further development. These salts were found to be crystalline with adequate solubility (comparable
with the authentic salts later prepared by the traditional method) and were selected for further evaluation (34).
Figure 2: The pH-solubility profile for a compound with a single, basic pKa value of 5. The four regions of pH-dependent solubility are: salt plateau, pHmax, ionized compound, and unionized compound.
In spite of the abundance of available counterions, few are used frequently. The preference for pharmaceutical counter-ions
is explained by studying the distribution of different counterions of medicinal compounds in USP 2006 (38) (see Table III). The table shows that salt forms of drugs (56.15%) are preferred over free forms (43.85%). Hydrochloride
and sodium remain the favorite counterions for the salt formation of medicinal compounds. However, the availability of many
pharmaceutically acceptable counterions makes the salt-selection process difficult and cumbersome.
Table III: Salt forms in USP 2006.
The generated salt forms are compared for the desired physico-chemical and biopharmaceutical properties, which guide the
final selection of an optimal salt form.