TY - JOUR
T1 - Unequal Behaviour between Hydrolysable Functions of Nirmatrelvir under Stress Conditions
T2 - Structural and Theoretical Approaches in Support of Preformulation Studies
AU - Secretan, Philippe Henri
AU - Annereau, Maxime
AU - Kini-Matondo, Willy
AU - Prost, Bastien
AU - Prudhomme, Jade
AU - Bournane, Lina
AU - Paul, Muriel
AU - Yagoubi, Najet
AU - Sadou-Yayé, Hassane
AU - Do, Bernard
N1 - Publisher Copyright:
© 2022 by the authors.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - Nirmatrelvir is an antiviral drug approved for the treatment of COVID-19. The available dosage form consists of tablets marketed under the brand name PAXLOVID®. Although knowledge of nirmatrelvir’s intrinsic stability may be useful for any potential development of other pharmaceutical forms, no data regarding this matter is available to date. Preliminary forced degradation studies have shown that the molecule is stable under oxidative and photolytic conditions, while hydrolytic conditions, both acidic and basic, have proven deleterious. Indeed, the molecule presents a priori several functions that can undergo hydrolysis, i.e., three amide moieties and a nitrile function. However, considering the degradation products formed under forced conditions and which were detected and identified by LC-UV-HRMSn, the hydrolysis process leading to their formation is selective since it involved only 2 of the 4 hydrolysable functions of the molecule. Ab initio studies based on density functional theory (DFT) have helped better understand these reactivity differences in aqueous media. Some hydrolyzable functions of nirmatrelvir differ from others in terms of electrostatic potential and Fukui functions, and this seems to correlate with the forced degradation outcomes.
AB - Nirmatrelvir is an antiviral drug approved for the treatment of COVID-19. The available dosage form consists of tablets marketed under the brand name PAXLOVID®. Although knowledge of nirmatrelvir’s intrinsic stability may be useful for any potential development of other pharmaceutical forms, no data regarding this matter is available to date. Preliminary forced degradation studies have shown that the molecule is stable under oxidative and photolytic conditions, while hydrolytic conditions, both acidic and basic, have proven deleterious. Indeed, the molecule presents a priori several functions that can undergo hydrolysis, i.e., three amide moieties and a nitrile function. However, considering the degradation products formed under forced conditions and which were detected and identified by LC-UV-HRMSn, the hydrolysis process leading to their formation is selective since it involved only 2 of the 4 hydrolysable functions of the molecule. Ab initio studies based on density functional theory (DFT) have helped better understand these reactivity differences in aqueous media. Some hydrolyzable functions of nirmatrelvir differ from others in terms of electrostatic potential and Fukui functions, and this seems to correlate with the forced degradation outcomes.
KW - ab initio calculations
KW - degradation products
KW - DFT
KW - mass spectrometry
KW - preformulation studies
KW - selective hydrolysis
UR - http://www.scopus.com/inward/record.url?scp=85137412864&partnerID=8YFLogxK
U2 - 10.3390/pharmaceutics14081720
DO - 10.3390/pharmaceutics14081720
M3 - Article
AN - SCOPUS:85137412864
SN - 1999-4923
VL - 14
JO - Pharmaceutics
JF - Pharmaceutics
IS - 8
M1 - 1720
ER -