(W1130-12-71) A Preclinical Solution Formulation Development with the Fundamental Understanding of Salt Solubility

Purpose: The properties of an ionizable drug molecule can be improved by salt formation. The solubility of a pharmaceutical salt is a critical attribute which directly relates to formulation development and in vivo performance. It is commonly accepted that the solubility of a salt is governed by its solubility product (K_sp), which is the product of the concentrations of the ionized drug and the counterion when the ionized drug species is saturated in the solution. There are different approaches to experimentally determine the salt solubility or the K_sp, for example, starting with either the salt form or the free form in the solid phase, and starting with pure water or acid/base solution in the liquid phase. Unfortunately, there is no standard method for salt solubility measurement and the misuse of the method may lead to inaccurate results. This study evaluated multiple approaches in measuring the solubility of a drug candidate. An aqueous solution formulation at physiological pH was successfully developed for toxicology studies. The solution formulation took advantage of the high aqueous solubility, i.e. above 100 mg/mL at pH 5, of the drug candidate in the salt form, which was underestimated using conventional method.

Methods: Solubility of the salt was measured by four approaches: (1) starting with a salt in water, (2) starting with a salt in acid, (3) starting with a free base in acid, and (4) starting with a stock solution. The amount of salt/free base and the concentration of the acid and stock solution were pre-determined. The suspensions were stirred for at least 3 days to allow form transformation in the solid phase. The suspensions were then filtered, and the drug concentrations were measured by HPLC. The K_sp value was calculated based on the measured drug concentration and the calculated counterion concentration.

Results: The equilibrium salt solubility measured by the conventional method that “starts with a salt in water” was lower than that measured by other methods. This method relies on de-ionizating the ionized drug species to provide proton and hence further promote drug dissolution. However, since the unionized drug species is also generated during the de-ionizating process, the unionized drug precipitates once the intrinsic solubility is reached. The transformation from salt to its unionized species in solid phase is also referred as salt disproportionation. In the case where the salt is stable against disproportionation, reaching to the equilibrium is a slow process.  The pH_max may not reach within the experimental timeframe. Therefore, the salt solubility determined by this method can be underestimated. A method for salt solubility measurement that “starts with a stock solution” as described in Figure 1 was developed. This method is the most time and cost effective among all tested methods. It does not require synthesis of the authentic salt with a close monitoring of the pH and drug concentration during the measurement. The salt is formed in situ and saturation of the ionized drug is observed visually.

Conclusion: During the solution formulation development for a drug candidate, multiple methods were compared in the salt solubility measurement. The conventional method was found to underestimate the salt solubility. In contrast, an in situ salt method was developed which was more reliable and saves time and resources. Based on the in situ salt solubility data, a solution formulation can be developed accordingly for preclinical studies, by using the counterion of the chosen salt without exotic excipients.  In this manner, the advantage of the high solubility of the pharmaceutical salts is taken in the early stage of drug development.  Meanwhile, the knowledge from the in situ salt solubility measurement can be the starting point of the authentic salt evaluation.  Even in the case that the free base is chosen due to other reasons such as stability, hygroscopicity, or complexity in manufacture, the advantages of the high solubility in salt are taken.

Figure 1. Salt solubility determination start with a stock solution