(32g) API Excipient Co-Crystal Screen to Optimize Robustness of An Oral Solution Drug Product

Purpose: When designing a liquid formulation, it is important to understand the solubility of the lowest energy (least soluble) API form to prevent undesired precipitation. During manufacturing and storage, observation of a new API form composed of formulation excipients, made it necessary to improvise screening approaches to enable definition of the thermodynamically stable form within the drug product.

 Methods: Extensive polymorph screening of the ingoing API found no additional crystalline anhydrous forms. Multiple crystalline salts were found through salt screening.  Components of this formulation (API, sodium benzoate, phosphoric acid) demonstrate an ionic equilibrium in the target pH range. Slow evaporation and binary diffusion of solutions of different combinations of components of oral formulation were conducted at room temperature and 5°C to find stable API forms. Single crystals isolated from this sample set were solved. Slurries of the stable form as a function of pH and temperature in aqueous and binary solvents were also conducted.

 Results: Formulation robustness scr eening identified the stable solid form as a function of formulation composition, pH and temperature.  Multiple stable forms were identified within the drug product design space, including salts and excipient co- crystals.

 Conclusion: An understanding of the stable API Form as a function of the drug product design space enabled the definition of the low energy form within the drug product. It also enabled drug product design to mitigate the risk of precipitation during clinical supplies manufacture within a short time frame.