Salt Selection

Salt formation can enhance solubility and dissolution rate of basic and acidic drugs, therefore improving their bioavailability and absorption. As such, salt selection should be viewed as a part of the overall strategy in choosing the optimal form of the drug substance for development.

Strategy: Salt formation is frequently performed on weak acidic and weak basic drugs because it is a relatively simple chemical manipulation, which may alter the physicochemical, formulation, biopharmaceutical and therapeutic properties of the drug substance without modifying the basic chemical structure. Theoretically, every drug substance has acidic or basic properties that could be a possible nominee for salt formation. Consideration should include material that is crystalline, non-hydroscopic, a high single melting temperature and chemically stable in the solid form.

Methods: The determination of the drug substance’s pKa value(s) by calculated or experimental means is the two universal focal points in pharmaceutically acceptable counterion selection. The pKa of the acids used should be at least two pH units below that of the drug substance and the only ones considered in the test. Solubility studies are generally conducted with the concentration of the acid being 0.1M. An In-situ salt screen is conducted with calculated amounts of drug substances to know which counterion will provide higher or lower aqueous solubility. This process is used as a guide to aid in rank ordering the salts and identifying a counterion that will provide the highest solubility in water. Organic solvents or water/organic cosolvents systems are another procedure for isolation of possible salt formation utilizing different counterions, temperatures and conditions. All characterization of solid material obtained from the above experiments should be analyzed by means of XRPD (wet and dry solids), DSC, TGA, Polarized and Hot Stage Microscopy.

Result: Salts are generated to change the solid state and bulk properties of the drug substance to help ease the processing steps or formulation aspects. Salts are also a solution to increase the chemical or physical stability when compared to its parent form. The areas include a change in the solubility, change in the rate of dissolution which will aid in the bioavailability and also increase the options for final drug product route of administration. Salts that show evidence of beneficial properties over the parent compound can also be patented as new chemical entities to strengthen a new drug application (NDA).