Quality by design development of brivanib alaninate tablets: degradant and moisture control strategy.
A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent compound, BMS-540215. The shelf-life of the tablets is determined by the rate of the hydrolysis reaction. Hydrolysis kinetics in the tablets was studied to understand its dependence on temperature and humidity. The BMS-540215 amount versus time profile was simulated using a kinetic model for the formation of BMS-540215 as function of relative humidity in the environment and a sorption-desorptiom moisture transfer model for the relative humidity inside the package. The combined model was used to study the effect of initial tablet water content on the rate of degradation and to identify a limit for initial tablet water content that results in acceptable level of the degradant at the end of shelf-life. A strategy was established for the moisture and degradant control in the tablet based on the understanding of its stability behavior and mathematical models. The control strategy includes a specification limit on the tablet water content and manufacturing process controls that achieve this limit at the time of tablet release testing.
Drug product Science and Technology, Bristol-Myers Squibb Research and Development, New Brunswick, NJ, USA. Electronic address: sherif.badawy@bms.com.
Sherif I F
SI
Badawy
Drug product Science and Technology, Bristol-Myers Squibb Research and Development, New Brunswick, NJ, USA.
Judy
J
Lin
Drug product Science and Technology, Bristol-Myers Squibb Research and Development, New Brunswick, NJ, USA.
Madhushree
M
Gokhale
Drug product Science and Technology, Bristol-Myers Squibb Research and Development, New Brunswick, NJ, USA.
Sachin
S
Desai
Drug product Science and Technology, Bristol-Myers Squibb Research and Development, New Brunswick, NJ, USA.
Vishwas V
VV
Nesarikar
Drug product Science and Technology, Bristol-Myers Squibb Research and Development, New Brunswick, NJ, USA.
Keirnan R
KR
LaMarche
Drug product Science and Technology, Bristol-Myers Squibb Research and Development, New Brunswick, NJ, USA.
Ganeshkumar A
GA
Subramanian
Drug product Science and Technology, Bristol-Myers Squibb Research and Development, New Brunswick, NJ, USA.
Ajit S
AS
Narang
D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000592:standards; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000592:standards; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D004355:Drug Stability; D006813:Humidity; D006868:Hydrolysis; D007700:Kinetics; D008956:Models, Chemical; D011355:Prodrugs / Q000737:chemistry* / Q000592:standards; D011786:Quality Control; D012995:Solubility; D013607:Tablets; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D014227:Triazines / Q000737:chemistry* / Q000592:standards; D014867:Water / Q000737:chemistry* / Q000592:standards
D020533:Angiogenesis Inhibitors; D011355:Prodrugs; D013607:Tablets; D014227:Triazines; D014867:Water; C509922:brivanib; D000409:Alanine
BMS-540215; Brivanib alaninate; Control strategy; Hydrolysis; Quality by design; Sorption–desorption moisture transfer; Stability