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Short-term storage stability of Triple IT solution

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Abstract
For the majority of children with acute lymphoblastic leukemia (ALL), treatment consists in part of a triple intrathecal (Triple IT) therapy, i.e. a combination of cytarabine (CB), methotrexate (MT) and methylprednisolone sodium succinate (MPSS) [1]. This combination product is prepared ex-tempore. However, no in-use shelf-life under defined storage conditions has yet been established. In this study, the short-term storage stability (up to 48 hours) was evaluated and included following study design variables: i) 3 packaging materials, i.e. PhaSeal® system, dark glass vial and dark glass vial + needles, ii) 4 storage conditions, i.e. light protected at 5 °C, 25 °C, 40 °C and photometric (UV and visible light) exposure at 25 °C, iii) batch reproducibility, i.e. 3 different batches. Calculation of the degradation kinetic parameters, obtained from HALO-HPLC-UV/DAD data, was performed using the Arrhenius equation to describe the temperature dependence. Moreover, identity of the major degradants was performed using ESI-MSn detection, and their specification relevance discussed. While CB is reasonably stable, MPSS did show hydrolysis as well as isomerisation (21- to 17-succinate ester). Moreover, MT was extremely light sensitive under the tested ICH conditions. The recommended storage condition for the ex-tempore prepared Triple IT solution is in a refrigerator (5 ± 3 °C) and protected from light. Primary packaging can be PhaSeal® syringes as well as glass vials. Under these conditions, no functionality-significant degradation is expected over a 24 hour storage period [2]. References: [1] A. Ruggiero, V. Conter, M. Milani, E. Biagi, I. Lazzareschi, P. Sparano, R. Riccardi. Intrathecal chemotherapy with antineoplastic agents in children. Paediatric drugs 3(4) (2001) 237-246. [2] M. D’Hondt, E. Vangheluwe, S. Van Dorpe, J. Boonen, T. Bauters, B. Pelfrene, J. Vandenbroucke, H. Robays, B. De Spiegeleer. Stability of ex-tempore prepared Triple intrathecal solution consisting of cytarabine, methotrexate and methylprednisolone sodium succinate. American Journal of Health-System Pharmacy, submitted for publication.
Keywords
methylprednisolone sodium succinate stability, cytarabine, methotrexate

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Chicago
D’Hondt, Matthias, Elien Vangheluwe, Nadia Lemeire, Tieneke Bauters, BRIGITTE PELFRENE, Johan Vandenbroucke, Hugo Robays, and Bart De Spiegeleer. 2011. “Short-term Storage Stability of Triple IT Solution.” In Abstract Book 15th Forum of Pharmaceutical Sciences.
APA
D’Hondt, Matthias, Vangheluwe, E., Lemeire, N., Bauters, T., PELFRENE, B., Vandenbroucke, J., Robays, H., et al. (2011). Short-term storage stability of Triple IT solution. Abstract book 15th forum of pharmaceutical sciences. Presented at the 15th Forum of Pharmaceutical Sciences.
Vancouver
1.
D’Hondt M, Vangheluwe E, Lemeire N, Bauters T, PELFRENE B, Vandenbroucke J, et al. Short-term storage stability of Triple IT solution. Abstract book 15th forum of pharmaceutical sciences. 2011.
MLA
D’Hondt, Matthias, Elien Vangheluwe, Nadia Lemeire, et al. “Short-term Storage Stability of Triple IT Solution.” Abstract Book 15th Forum of Pharmaceutical Sciences. 2011. Print.
@inproceedings{1223790,
  abstract     = {For the majority of children with acute lymphoblastic leukemia (ALL), treatment consists in part of a triple intrathecal (Triple IT) therapy, i.e. a combination of cytarabine (CB), methotrexate (MT) and methylprednisolone sodium succinate (MPSS) [1]. This combination product is prepared ex-tempore. However, no in-use shelf-life under defined storage conditions has yet been established. In this study, the short-term storage stability (up to 48 hours) was evaluated and included following study design variables: i) 3 packaging materials, i.e. PhaSeal{\textregistered} system, dark glass vial and dark glass vial + needles, ii) 4 storage conditions, i.e. light protected at 5 {\textdegree}C, 25 {\textdegree}C, 40 {\textdegree}C and photometric (UV and visible light) exposure at 25 {\textdegree}C, iii) batch reproducibility, i.e. 3 different batches. Calculation of the degradation kinetic parameters, obtained from HALO-HPLC-UV/DAD data, was performed using the Arrhenius equation to describe the temperature dependence. Moreover, identity of the major degradants was performed using ESI-MSn detection, and their specification relevance discussed. While CB is reasonably stable, MPSS did show hydrolysis as well as isomerisation (21- to 17-succinate ester). Moreover, MT was extremely light sensitive under the tested ICH conditions. The recommended storage condition for the ex-tempore prepared Triple IT solution is in a refrigerator (5 {\textpm} 3 {\textdegree}C) and protected from light. Primary packaging can be PhaSeal{\textregistered} syringes as well as glass vials. Under these conditions, no functionality-significant degradation is expected over a 24 hour storage period [2]. References:
[1]\unmatched{0009}A. Ruggiero, V. Conter, M. Milani, E. Biagi, I. Lazzareschi, P. Sparano, R. Riccardi. Intrathecal chemotherapy with antineoplastic agents in children. Paediatric drugs 3(4) (2001) 237-246.
[2]\unmatched{0009}M. D{\textquoteright}Hondt, E. Vangheluwe, S. Van Dorpe, J. Boonen, T. Bauters, B. Pelfrene, J. Vandenbroucke, H. Robays, B. De Spiegeleer. Stability of ex-tempore prepared Triple intrathecal solution consisting of cytarabine, methotrexate and methylprednisolone sodium succinate. American Journal of Health-System Pharmacy, submitted for publication.},
  author       = {D'Hondt, Matthias and Vangheluwe, Elien and Lemeire, Nadia and Bauters, Tieneke and PELFRENE, BRIGITTE and Vandenbroucke, Johan and Robays, Hugo and De Spiegeleer, Bart},
  booktitle    = {Abstract book 15th forum of pharmaceutical sciences},
  keyword      = {methylprednisolone sodium succinate stability,cytarabine,methotrexate},
  language     = {eng},
  location     = {Spa, Belgium},
  title        = {Short-term storage stability of Triple IT solution},
  year         = {2011},
}