title: Characterization and monitoring of pseudo-polymorphs in manufacturing process by NIR.
abstract: Moisture-sensitive pseudo-polymorphs with different stabilities were characterized, and their polymorphisms were monitored in the process of tableting and film coating by near-infrared (NIR) spectroscopy. In this study, we proved that we could successfully maintain the crystal form ratio in the tablet by controlling the moisture profile during the manufacture to sufficiently stabilize the drug product. Mitemcinal fumarate is an erythromycin derivative with two pseudo-polymorphic forms, hydrate and anhydrate. We characterized them by X-ray powder diffraction and water sorption isotherm plot analysis. Stability test revealed that the hydrate form is more stable than the anhydrate form. We established a quantitative method by using NIR and monitored the hydrate form ratio in the tablet during the tableting and coating process. The manufacturing room was controlled to between 40 and 60% RH. Although the hydrate form ratio just after the onset of tableting decreased to below 40%, 60% was obtained at the end of the final process which sufficiently retains stability. Transition of the hydrate form ratio during the manufacturing process was reasonable; this indicates that our NIR method is suitable for monitoring. Thus, NIR is one of the most suitable tools for in-process testing of these humidity-sensitive APIs.
authors.affiliation: Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama Funabashi, Chiba 274-8510, Japan. kamadaknj@chugai-pharm.co.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Kamada
authors.forename: Shiho
authors.initials: S
authors.lastname: Yoshimura
authors.forename: Masami
authors.initials: M
authors.lastname: Murata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagai
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Ushio
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Terada
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004355:Drug Stability; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000737:chemistry; D006813:Humidity; D019265:Spectroscopy, Near-Infrared; D013607:Tablets; D014961:X-Ray Diffraction
chemical_list: D013607:Tablets; D004917:Erythromycin; C103741:mitemcinal