Crystallographic evaluation of the conformation of quetiapine included in β-cyclodextrin

• Published in: International journal of pharmaceutics 2020-09, Vol.587, p.119625-119625, Article 119625
• Main Authors: Ogawa, Noriko, Nagase, Hiromasa, Matsumoto, Takashi, Kaga, Mayumi, Ishihara, Shintaro, Endo, Tomohiro, Yasunaga, Toshiya, Kawashima, Yoshiaki, Ueda, Haruhisa, Yamamoto, Hiromitsu
• Format: Article
• Language: English
• Subjects: Crystal structure; Crystallography; Cyclodextrin; Inclusion compounds; Theoretical calculation
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2020.119625

[Display omitted] •β-CD and quetiapine form an inclusion complex at a ratio of 2:1.•The crystal of quetiapine-β-CD belongs to the monoclinic space group P21.•Quetiapine is disordered inside the dimeric cavity of the β-CD complex.•The conformation, which was high in occupancy, was more stable in crystal energy. Single-crystal X-ray diffraction and theoretical calculations were conducted for insights into the β-cyclodextrin (β-CD)-quetiapine inclusion complex structure. β-CD and quetiapine form a host–guest inclusion complex at a ratio of 2:1 in which the β-CD molecules form head-to-head dimers with their secondary hydroxyl groups linked by multiple hydrogen bonds. Quetiapine is totally contained within the β-CD cavity and exhibits two kinds of disorder (parts 1 and 2) in opposite directions in the β-CD complex. To clarify the mobility of the guest molecule in the β-CD cavity, theoretical molecular conformational calculations, crystal optimization and crystal energy calculations were conducted using CONFLEX software. The results of theoretical molecular conformation calculations showed that the mobility of quetiapine is restricted because its tricyclic structure is covered by β-CD. The results of crystal energy calculations indicated that the conformation of disorder part 1, which has high occupancy, was more stable.