Non-clinical toxicological considerations for pharmaceutical salt selection

Introduction: Over half of all active pharmaceutical ingredients currently approved for use in the USA are pharmaceutical salts. The safety assessment of a pharmaceutical salt provides additional challenges in addition to those encountered when assessing the safety of the free acid or base form of a new chemical entity (NCE). The addition of a counter ion may have an impact on pharmacokinetics, toxicity, impurity profile and potential route of administration. Areas covered: In this review, the toxicologic profiles of commonly used counter ions and strategies for supporting the development of novel or alternate pharmaceutical salt forms are summarized. Furthermore, the article highlights the major concerns that may be encountered by the non-clinical toxicologist when considering a novel pharmaceutical salt. Expert opinion: Given the large numbers of pharmaceutical salts approved for use in the USA, relatively little non-clinical toxicologic data are available for commonly used counter ions. This information gap leaves the non-clinical toxicologist with limited resources to assess the impact of a counter ion on the toxicologic program for an NCE. The data summarized in this review provide a starting point toward a more detailed understanding of counter ion-related effects on the toxicity of pharmaceutical salts.