Physical and chemical stability of a generic etoposide formulation as an alternative to etoposide phosphate

Hassane Sadou Yayé 1 Lamia Hassani Philippe-Henri Secrétan 2 Martine Babiard Haroun Aouati Agnès Bellanger 3 Patrick Tilleul Najet Yagoubi 4 Bernard Do 4 Ivo Rietveld 5
1 Service de biochimie hormonale, métabolique et génétique
2 Groupe matériaux et santé
3 Néonatalogie
4 IFR 141, EA 401, UFR de Pharmacie
5 SMS - Sciences et Méthodes Séparatives
Abstract : The generic Mylan® etoposide (ETP) has been investigated as an alternative for Etopophos®, in part due to a global shortage of the latter. The generic alternative is different both in its formulation and in its very limited stability (6 h at 25 ◦ C against 4 days for Etopophos® ) once reconstituted in ready-to-use chloride or glucose solutions. Its intrinsic stability has been thoroughly studied under various conditions. Two degradation products resulting from hydrolysis were characterized by LC-HR-MSn and supported by density functional theory calculations of the frontier molecular orbitals energies, molecular electrostatic potential mapping, and Mulliken charge analysis. Chemical degradation increases with temperature and can be fitted to a zero order kinetic model with a half-life of 119 days and a kinetic constant of 0.0028 mM day−1 . Precipitation was only observed in solutions at 5 ◦ C and −20 ◦ C indicating that at these tempera- tures the reconstituted solutions are thermodynamically metastable. In conclusion, ETP at concentrations of 0.68 and 1 mM prepared and stored at 25 ◦ C under good manufacturing practices remained unchanged over a period of 21 days irrespective of the nature of the solvents or the type of container.
Keywords : Etoposide Etoposide phosphate Physico-chemical stability Supersaturation Solubility Degradation products Computational prediction
Type de document :
Article dans une revue
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02356006
Contributeur : Ivo Rietveld <>
Soumis le : vendredi 8 novembre 2019 - 15:14:19
Dernière modification le : dimanche 10 novembre 2019 - 01:30:13

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COMUE-NORMANDIE | UNIROUEN | LABO-SMS | UNIV-PARIS7 | UNIV-PARIS-SACLAY | USPC

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Hassane Sadou Yayé, Lamia Hassani, Philippe-Henri Secrétan, Martine Babiard, Haroun Aouati, et al.. Physical and chemical stability of a generic etoposide formulation as an alternative to etoposide phosphate. Journal of Pharmaceutical and Biomedical Analysis, Elsevier, 2019, 178, pp.112896. ⟨10.1016/j.jpba.2019.112896⟩. ⟨hal-02356006⟩

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