Takeuchi Shoko, Kojima Takashi, Hashimoto Kentaro, Saito Bunnai, Sumi Hiroyuki, Ishikawa Tomoyasu, Ikeda Yukihiro
Analytical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited.
Chem Pharm Bull (Tokyo). 2015;63(11):858-65. doi: 10.1248/cpb.c15-00262.
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.
水合物与无水晶体的不同晶体堆积导致不同的物理性质，如溶解度和稳定性。研究不同水合物形成的可能性，并了解无水/水合物体系中的稳定性，对于防止制造过程和储存期间出现不期望的转变至关重要。在合成过程中仅发现了一种新型凋亡抑制蛋白（IAP）拮抗剂T-3256336的无水形式，尚未鉴定出水合物形式。在本研究中，我们进行了水合物筛选，如动态水蒸气吸附/解吸（DVS）和淤浆实验，并对无水/水合物形式的固态性质进行了表征，以确定最适合开发的晶型。通过这种水合物筛选发现了新的水合物形式，即一水合物和半水合物形式。对两种新水合物形式进行了表征，并就固态稳定性而言，确定无水形式是T-3256336最适合开发的形式。此外，使用含水量和温度控制的淤浆实验研究了无水形式的稳定性，以在结晶过程中获得所需的晶型。确定了冷却结晶过程中所需形式（无水形式）稳定相的含水量区域。
