title: Pharmaceutical solid-state kinetic stability investigation by using moisture-modified Arrhenius equation and JMP statistical software.
abstract: An accelerated stress approach utilizing the moisture-modified Arrhenius equation and JMP statistical software was utilized to quantitatively assess the solid state stability of an investigational oncology drug MLNA under the influence of temperature (1/T) and humidity (%RH). Physical stability of MLNA under stress conditions was evaluated by using XRPD, DSC, TGA, and DVS, while chemical stability was evaluated by using HPLC. The major chemical degradation product was identified as a hydrolysis product of MLNA drug substance, and was subsequently subjected to an investigation of kinetics based on the isoconversion concept. A mathematical model (ln k=-11,991×(1/T)+0.0298×(%RH)+29.8823) based on the initial linear kinetics observed for the formation of this degradant at all seven stress conditions was built by using the moisture-modified Arrhenius equation and JMP statistical software. Comparison of the predicted versus experimental lnk values gave a mean deviation value of 5.8%, an R(2) value of 0.94, a p-value of 0.0038, and a coefficient of variation of the root mean square error CV(RMSE) of 7.9%. These statistics all indicated a good fit to the model for the stress data of MLNA. Both temperature and humidity were shown to have a statistically significant impact on stability by using effect leverage plots (p-value<0.05 for both 1/T and %RH). Inclusion of a term representing the interaction of relative humidity and temperature (%RH×1/T) was shown not to be justified by using Analysis of Covariance (ANCOVA), which supported the use of the moisture-corrected Arrhenius equation modeling theory. The model was found to be of value to aid setting of specifications and retest period, and storage condition selection. A model was also generated using only four conditions, as an example from a resource saving perspective, which was found to provide a good fit to the entire set of data.
authors: Analytical Development Laboratories, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, United States. Electronic address: mingkun.fu@takeda.com.
authors: Mingkun
authors: M
authors: Fu
authors: Analytical Development Laboratories, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, United States.
authors: Michael
authors: M
authors: Perlman
authors: Analytical Development Laboratories, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, United States.
authors: Qing
authors: Q
authors: Lu
authors: Analytical Development Laboratories, Takeda Pharmaceuticals International Co., 35 Landsdowne Street, Cambridge, MA 02139, United States.
authors: Csanad
authors: C
authors: Varga
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods; D004349:Drug Packaging / Q000379:methods; D004355:Drug Stability; D004356:Drug Storage / Q000379:methods; D006813:Humidity; D006868:Hydrolysis; D007700:Kinetics; D008956:Models, Chemical; D012984:Software; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature
keywords: JMP; Model; Moisture-modified Arrhenius; Solid state; Stability