TY - JOUR
T1 - Structure elucidation and formation mechanistic study of a methylene-bridged pregabalin dimeric degradant in pregabalin extended-release tablets
AU - Tian, Yun
AU - Lin, Jinsheng
AU - Chen, Feifei
AU - Wang, Shaolan
AU - Li, Dan
AU - Kuang, Zijian
AU - Zhu, Wenquan
AU - Li, Yue
AU - Zheng, Terry
AU - Cao, Wei
AU - Zhu, Bob
AU - Tsai, Eric
AU - Fu, Lei
AU - Li, Min
N1 - Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2020/2/15
Y1 - 2020/2/15
N2 - During the pharmaceutical development of pregabalin extended-release tablets, an unknown degradant at a relative retention time (RRT) of 11.7 was observed and its nominal amount exceeded the ICH identification threshold in an accelerated stability study. The aim of this study is to identify the structure and investigate the formation mechanism of this impurity for the purpose of developing a chemically stable pharmaceutical product. By utilizing multi-stage LC-MS analysis in conjunction with mechanism-based stress study, the structure of the RRT 11.7 impurity was rapidly identified as a dimeric degradant that is caused by dimerization of two pregabalin molecules with a methylene bridging the two pregabalin moieties. The structure of the dimer was confirmed by 1D and 2D NMR measurement. The formation pathway of the dimeric degradant was also inferred from the mechanism-based stress study, which implicated that the bridging methylene could originate from formaldehyde which might be the culprit that triggers the dimerization in the first place. The subsequent API-excipients compatibility study indicated that the degradant was indeed formed in the compatibility experiments between pregabalin API and two polymeric excipients (PEO and PVPP) that are known to contain residual formaldehyde, but only in the co-presence of another excipient, colloidal silicon dioxide (SiO2). The kinetic behavior of the degradant formation was also investigated and two kinetic models were utilized based on the Arrhenius and Eyring equations, respectively, to calculate the activation energy (Ea) as well as the enthalpy of activation (△H‡), entropy of activation (△S‡), and Gibbs free energy (△G‡) of the degradation reaction. The results of this study would be useful for the understanding of similar dimeric degradant formation in finished products of drug substances containing primary or secondary amine moieties.
AB - During the pharmaceutical development of pregabalin extended-release tablets, an unknown degradant at a relative retention time (RRT) of 11.7 was observed and its nominal amount exceeded the ICH identification threshold in an accelerated stability study. The aim of this study is to identify the structure and investigate the formation mechanism of this impurity for the purpose of developing a chemically stable pharmaceutical product. By utilizing multi-stage LC-MS analysis in conjunction with mechanism-based stress study, the structure of the RRT 11.7 impurity was rapidly identified as a dimeric degradant that is caused by dimerization of two pregabalin molecules with a methylene bridging the two pregabalin moieties. The structure of the dimer was confirmed by 1D and 2D NMR measurement. The formation pathway of the dimeric degradant was also inferred from the mechanism-based stress study, which implicated that the bridging methylene could originate from formaldehyde which might be the culprit that triggers the dimerization in the first place. The subsequent API-excipients compatibility study indicated that the degradant was indeed formed in the compatibility experiments between pregabalin API and two polymeric excipients (PEO and PVPP) that are known to contain residual formaldehyde, but only in the co-presence of another excipient, colloidal silicon dioxide (SiO2). The kinetic behavior of the degradant formation was also investigated and two kinetic models were utilized based on the Arrhenius and Eyring equations, respectively, to calculate the activation energy (Ea) as well as the enthalpy of activation (△H‡), entropy of activation (△S‡), and Gibbs free energy (△G‡) of the degradation reaction. The results of this study would be useful for the understanding of similar dimeric degradant formation in finished products of drug substances containing primary or secondary amine moieties.
KW - Compatibility study
KW - Dimerization
KW - Formaldehyde
KW - LC-MS
KW - Pregabalin extended-release tablets
KW - Stability study
UR - http://www.scopus.com/inward/record.url?scp=85076671573&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2019.118910
DO - 10.1016/j.ijpharm.2019.118910
M3 - Article
C2 - 31805310
AN - SCOPUS:85076671573
SN - 0378-5173
VL - 575
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
M1 - 118910
ER -