Screening and Characterization of Hydrate Forms of T-3256336, a Novel Inhibitor of Apoptosis (IAP) Protein Antagonist

Abstract

Different crystal packing of hydrates from anhydrate crystals leads to different physical properties, such as solubility and stability. Investigation of the potential of varied hydrate formation, and understanding the stability in an anhydrous/hydrate system, are crucial to prevent an undesired transition during the manufacturing process and storage. Only one anhydrous form of T-3256336, a novel inhibitor of apoptosis (IAP) protein antagonist, was discovered during synthesis, and no hydrate form has been identified. In this study, we conducted hydrate screening such as dynamic water vapor sorption/desorption (DVS), and the slurry experiment, and characterized the solid-state properties of anhydrous/hydrate forms to determine the most desirable crystalline form for development. New hydrate forms, both mono-hydrate and hemi-hydrate forms, were discovered as a result of this hydrate screening. The characterization of two new hydrate forms was conducted, and the anhydrous form was determined to be the most desirable development form of T-3256336 in terms of solid-state stability. In addition, the stability of the anhydrous form was investigated using the water content and temperature controlled slurry experiment to obtain the desirable crystal form in the crystallization process. The water content regions of the stable phase of the desired form, the anhydrous form, were identified for the cooling crystallization process. Key words inhibitor of apoptosis (IAP) protein; T-3256336; hydrate; water activityApproximately one-third of pharmaceutical solids have been reported to crystallize in the hydrate forms.1,2) The solidstate characterization of hydrate is essential for pharmaceutical development because the hydrate form has different physicochemical properties such as solubility and stability from its anhydrous form.3-5) Therefore, it is important to discover the possible hydrate forms in early drug development and understand the anhydrous/hydrate phase transformations to ensure undesired conversions do not occur during the development process. 6)There are several approaches for investigation of the anhydrous/hydrate phase transformation, such as dynamic water vapor sorption/desorption isotherm (DVS), storage under high humidity, and slurry experiments in water-content-controlled organic solvent mixtures.7-10) Cui and Yao explained that slurry experiments using water and organic solvent mixtures under water-content-controlled-conditions were rapid and reliable hydrate screening approaches.1) Some applications of slurry experiments with water and organic solvent mixtures to investigate the stability in the anhydrous/hydrate system of theophylline and ampicillin, carbamazepine were also reported.11-13) Water content is related to water activity, defined by the activity coefficient and mole fraction of water.Hydrate formation is represented by the following equilibrium (Eq. 1), previously described by Grant and Higuchi ) in a water and organic solvent mixture is a crucial factor for the hydrate formation. The stability o...