Chapter 37 - Preparation of Water-Soluble Compounds Through Salt Formation

Abstract

Medicinal chemists in pharmaceutical companies involved in drug discovery normally prepare many compounds each year; however, the majority of these are usually found to be inactive in cell-based screens. Historically, salt formation was primarily used as a means to improve aqueous solubility (hydrophilicity) and crystallinity and it also has an effect on many other properties, including bioavailability, organoleptic properties (e.g. taste), melting point, dissolution rate, hygroscopicity, stability, processing, and powder characteristics. The solubility is determined experimentally as soon as sufficient substance of an active compound is available. Many experimental methods have been described and are in use. The true equilibrium solubility is the data that counts. This chapter briefly describes how salt selection and optimization studies normally evolve within major pharmaceutical companies. It is important to select drug candidates rapidly and to propose a suitable salt for development very early in the drug discovery program. The selection of the optimum solid state and salt form of a pharmacologically active substance is a multidisciplinary task that cannot be accomplished by the discovery chemist alone as it had been in past times. Too many factors now need to be taken into account, many requirements satisfied, limitations respected, and a considerable amount of experimental effort expended in order to convert the drug candidate into a producible, stable, therapeutically useful drug product. This task requires a highly interactive team representing the many disciplines involved: drug discovery, process development, physical pharmacy, biopharmacy, dosage form development, analytics, toxicology, pharmacokinetics, and regulatory affairs.