Formation of Hemihydrate Crystal form Overcomes Milling Issue Induced by Exposed Functional Groups on Cleavage Plane for a Y5 Receptor Antagonist of Neuropeptide Y |
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| Affiliation: | 1. Laboratory for Medicinal Chemistry Research, Shionogi & Co., Ltd., Osaka, 561-0825, Japan;2. Sustainability Management Department, Shionogi & Co., Ltd., Osaka, 541-0045, Japan;3. Intellectual Property Department, Shionogi & Co., Ltd., Osaka, 541-0045, Japan;4. Analysis and Evaluation Laboratory, Shionogi & Co., Ltd., Osaka, 561-0825, Japan;1. Department of Biomolecular Sciences, University of Urbino, Via S. Chiara 27, 61029, Urbino PU, Italy;2. Loccioni, Angeli di Rosora AN, Italy;1. Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA;2. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;3. Department of Gynecology & Obstetrics, Johns Hopkins University, Baltimore, MD, USA;4. Center for Biomedical Engineering, University of Texas Medical Branch, Galveston, TX, USA;5. Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, USA;6. Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA;7. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA;8. Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;1. Division of Drugs, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-9501, Japan;2. CMC Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan;3. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba 260-8675, Japan;4. Research Group V, Analytical & Quality Evaluation Research Laboratories, Daiichi Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan;5. Analytical Research Laboratories, Pharmaceutical Science & Technology Function Unit, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan;6. Core Technology Research Department, X-ray Research Laboratory, Rigaku Corp., 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan;7. Shionogi & Co., Ltd., 2-1-3 Kuise Terajima, Amagasaki, Hyogo 660-0813, Japan;8. Analytical Research & Development Laboratories, Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka, 554-0022, Japan;9. Takeda Pharmaceutical Co., Ltd., 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan;10. Research Center for Functional Materials, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan;1. Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China;2. Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China;3. Department of Resources Science of Traditional Chinese Medicines, China Pharmaceutical University, Nanjing, 211198, China;4. Nanjing Medical University, Nanjing, 210009, China;5. The Joint Laboratory of Chinese Pharmaceutical University and Taian City Centrol Hospitol, Taian City Central Hospitol, Taian, 271000, China;6. Pharmacy Department, Taian City Central Hospitol, Taian, 271000, China;7. Taian City institute of Digestive Disease, Taian City Central Hospitol, Taian, 271000, China;1. Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University, Im Neuenheimer Feld 329, 69120 Heidelberg, Germany;2. School of Pharmacy, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland;3. Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, P.O. Box 56, Helsinki, 00014, Finland |
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| Abstract: | This study aimed to investigate the crystal forms of an originally designed Y5 receptor antagonist of neuropeptide Y. Polymorphic screening was performed via solvent evaporation and slurry conversion using various solvents. The obtained crystal forms α, β, and γ were characterized by X-ray powder diffraction analysis. Thermal analysis determined that forms α, β, and γ were hemihydrate, metastable and stable forms, respectively; the hemihydrate and the stable forms were candidates. To arrange the particle size, forms α and γ were subjected to jet milling. However, form γ could not be milled because of powder stiction to the apparatus, whereas form α could be. To investigate this mechanism, single-crystal X-ray diffraction analysis was performed. The crystal structure of form γ was characterized by two-dimensional hydrogen bonding between neighboring molecules. This revealed that the functional groups forming hydrogen bonds were exposed on the cleavage plane of form γ. The three-dimensional hydrogen-bonding network with water stabilized the hemihydrate form, α. These results indicate that the hydrogen bondable groups exposed on the cleavage plane of form γ should result in stiction of the powder and adherence to the apparatus. It was concluded that crystal conversion is a method to overcome the milling issue. |
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