Preparation of Amorphous Adefovir dipivoxil using Reverse Phase Column Chromatography and Solid Dispersion Method

역상컬럼 및 고체분산체를 이용한 무정형 아데포비어디피복실의 제조

  • Received : 2010.07.20
  • Accepted : 2010.08.17
  • Published : 2010.08.31

Abstract

Adefovir dipivoxil which was originally developed by Gilead Sciences has been used as treatments of HIV and HBV, especially a therapeutics for HBeAg positive and negative chronic patients. We developed highly efficient purification method using reverse phase column chromatography for mass production and a stable amorphous Adefovir dipivoxil using solid dispersion method. Reverse phase column chromatography led to highly pure product, more than 99.7% by HPLC and can be used for mass production compared with normal column chromatography. Solid dispersion method containing watersoluble polymer and Isomalt showed improved stability of amorphous Adefovir dipivoxil against heat and moisture.

Keywords

References

  1. Eugene, S., Ching-Lung, L., Stefanos, H., Peter, N., Norah, T. and Massimo, C. : Adefovir dipivoxil therapy for lamivudineresistan hepatitis B in pre- and post-liver transplantation patients. Hepatology 38(6), 1419 (2003).
  2. Mukherjee, P. : Adefovir dipivoxil for hepatitis be antigenpositive chronic hepatitis B. N Engl. J. Med. 348, 2468 (2001).
  3. Roula, Q., Keri, A. and David, J. : Adefovir dipivoxil: A new antiviral agent for the treatment of hepatitis B virus infection. Clinical Therapeutics 25, 12 (2003). https://doi.org/10.1016/S0149-2918(03)80252-7
  4. McClellan, M. B. : New drug for heptitis B. JAMA 288, 2112 (2002). https://doi.org/10.1001/jama.288.17.2112
  5. John, E., Starrett, R., Tortolani, J. R. and Michael, J. H. : Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9-[2-(phosphonomethoxy) ethyl]adenine (PMEA). J. Med. Chem. 37(12), 1857 (1994). https://doi.org/10.1021/jm00038a015
  6. Wan, G. and Hu, Z. : Preparation method of amorphous adefovir dipivoxil. US1621408.
  7. Cameron, L., Mcphail, W., Ray, G. and Blazecka, D. : Salt form and cocrystals of adefovir dipivoxil and process for preparation thereof. US0247749.
  8. Dahl, T. C. and Yuan, L. J. : Pharmaceutical formulations. US6635278.
  9. Arimili, M., Kell, B., Lee, T. K., Manes, V., Munger, J. and Prisbe, J. M. : Nucleotide analog compositions. US 6451340.
  10. Yuan, L. C., Terrence, C. and Reza, O. : Effect of carbonate salts on the kinetics of acid-catalyzed dimerization of adefovir dipivoxil. Pharm. Res. 17, 9 (2000).
  11. Takeuchi, H., Nagira, S., Yamamoto, H. and Kawashima, Y. : Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method. International J. Pharmaceutics. 293, 1 (2005). https://doi.org/10.1016/j.ijpharm.2004.10.028
  12. Shibata, Y., Fujii, M., Kokudai, M., Noda, S., Okada, H. and Kondoh, M. W. : Effect of charateristics of compounds on maintenance of an amorphous state in solid dispersion with crospovidone. J. Pharmaceutical Sciences 96, 6 (2007).
  13. Shibata, Y., Fujii, M., Kokudai, M., Noda, S., Okada, H., Kondoh, M. and Watanabe, Y. : Stability of amorphous indomethacin in a solid dispersion using crospovidone prepared by a twin-screw kneader of extruder and application of aqueous film-coating to solid dispersion tablets. J. Drug Delivery Science and Technology 19, 3 (2009). https://doi.org/10.1016/S1773-2247(09)50001-9
  14. Wang, G., Lu, X., Liu, Q., Tang, Y. and Yang, L. : A new form of adefovir dipivoxil and its composition. WO04/043972.
  15. Starrett, J. : Prodrug of phosphate. US5663159.
  16. Xiaozhong, F., Saihong, J., Chuan, L., Jian, X., Yushe, Y. and Ruyun, J. : Design and synthesis of novel bis(L-amino acid) ester prodrugs of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) with improved anti-HBV activity. Bioorganic & Medicinal Chemistry Letters 17(2), 465 (2007). https://doi.org/10.1016/j.bmcl.2006.10.021
  17. Arimili, M., Lee, T. K., Manes, L., Munger, J. and John, D. : Process of preparing adefovir dipivoxil. EP1256584.
  18. Lee, C. H. and Lim, C. B. : Studies on optimization techniques in solid dispersion system. J. Korean Pharmaceutical Sciences 17, 4 (1987).
  19. Rumondor, A., Ivanisevic, I., Bates, S., Alonzo, D. and Taylor, L. : Evaluation of drug-polymer miscibility in amorphous solid dispersion systems. Pharmaceutical Research 26, 11 (2009).
  20. Sanvordeker, R. : Stabilization of 16-oxygeneated prostanoic acid derivates. US4301146.
  21. Patel, R. and Patel, M. : Preparation, characterization, and dissolution of a solid dispersion of simvastatin with polyethylene glycol 4000 and polyvinylpyrrolidone K30. J. Dispersion Science and Technology 29, 2 (2008).