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Comparison of Molecular Mobility in the Glassy State Between Amorphous Indomethacin and Salicin Based on Spin-Lattice Relaxation Times

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Abstract

Purpose.

The purpose of the current study was to evaluate the molecular mobility of amorphous indomethacin and salicin in the relaxed glassy state based on spin-lattice relaxation times (T1c) and to clarify the effects of molecular mobility on their physical stability.

Methods.

Pulverized glassy amorphous indomethacin and salicin samples were completely relaxed, and the T1c values were investigated using solid-state 13C-nuclear magnetic resonance (NMR) at temperatures below the glass transition temperature (Tg). All NMR spectra were obtained using the T1c measurement method combined with variable-amplitude cross-polarization, the Torchia method, and total sideband suppression method.

Results.

The T1c value of amorphous indomethacin indicated that 73% of carbons were in a state of monodispersive relaxation, suggesting that the amorphous state was relatively homogeneous and restricted, particularly in backbone carbons. On the other hand, 92% of carbons of amorphous salicin exhibited both fast and slow biphasic relaxation. Individual structures of the salicin molecules behaved heterogeneously, and thus the entire molecule showed relatively fast local as well as slow mobility.

Conclusions.

At temperatures below Tg, amorphous salicin had relatively greater molecular mobility than amorphous indomethacin. This difference in the molecular mobility of the two compounds is correlated with their crystallization behavior. Solid-state 13C NMR provides valuable information on the physical stability of amorphous pharmaceuticals.

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References

  1. 1. L. Yu. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv. Drug Deliv. Rev. 48:27–42 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. 2. M. Yoshioka, B. C. Hancock, and G. Zografi. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J. Pharm. Sci. 83:1700–1705 (1994).

    CAS  PubMed  Google Scholar 

  3. 3. D. Zhou, G. G. Z. Zhang, D. Law, D. J. W. Grant, and E. A. Schmitt. Physical stability of amorphous pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility. J. Pharm. Sci. 91:1863–1872 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. 4. J. Liu, D. R. Rigsbee, C. Stotz, and M. J. Pikal. Dynamics of pharmaceutical amorphous solids: the study of enthalpy relaxation by isothermal microcalorimetry. J. Pharm. Sci. 91:1853–1862 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. 5. I. Weuts, D. Kempen, K. Six, J. Peeters, G. Verreck, M. Brewster, and G. V. Mooter. Evaluation of different calorimetric methods to determine the glass transition temperature and molecular mobility below Tg for amorphous drugs. Int. J. Pharm. 259:17–25 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. 6. S. L. Shamblin, B. C. Hancock, Y. Dupuis, and M. J. Pikal. Interpretation of relaxation time constants for amorphous pharmaceutical systems. J. Pharm. Sci. 89:417–427 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. 7. B. C. Hancock and S. L. Shamblin. Molecular mobility of amorphous pharmaceuticals determined using differential scanning calorimetry. Thermochim. Acta 380:95–107 (2001).

    CAS  Google Scholar 

  8. 8. H. Sillescu. Heterogeneity at the glass transition: a review. J. Non-Cryst. Solids 243:81–108 (1999).

    CAS  Google Scholar 

  9. 9. P. D. Martino, G. F. Palmieri, and S. Martelli. Molecular mobility of the paracetamol amorphous form. Chem. Pharm. Bull. 48:1105–1108 (2000).

    PubMed  Google Scholar 

  10. 10. B. C. Hancock, S. L. Shamblin, and G. Zografi. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm. Res. 12:799–806 (1995).

    CAS  PubMed  Google Scholar 

  11. 11. Y. Aso, S. Yoshioka, and S. Kojima. Explanation of the crystallization rate of amorphous nifedipine and phenobarbital from their molecular mobility as measured by 13C nuclear magnetic resonance relaxation time and the relaxation time obtained from the heating rate dependence of the glass transition temperature. J. Pharm. Sci. 90:798–806 (2001).

    CAS  PubMed  Google Scholar 

  12. 12. M. D. Ediger, C. A. Angell, and S. R. Nagel. Supercooled liquids and glasses. J. Phys. Chem. 100:13200–13212 (1996).

    CAS  Google Scholar 

  13. 13. V. Andronis and G. Zografi. Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J. Non-Cryst. Solids 271:236–248 (2000).

    CAS  Google Scholar 

  14. 14. K. J. Crowley and G. Zografi. The use of thermal methods for predicting glass-former fragility. Thermochim. Acta 380:79–93 (2001).

    CAS  Google Scholar 

  15. 15. V. Andronis and G. Zografi. Molecular mobility of supercooled amorphous indomethacin, determined by dynamic mechanical analysis. Pharm. Res. 14:410–414 (1997).

    CAS  PubMed  Google Scholar 

  16. 16. Y. Aso, S. Yoshioka, and S. Kojima. Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by their enthalpy relaxation and 1H NMR relaxation times. J. Pharm. Sci. 89:408–416 (2000).

    CAS  PubMed  Google Scholar 

  17. 17. E. Fukuoka, M. Makita, and S. Yamamura. Some physicochemical properties of glassy indomethacin. Chem. Pharm. Bull. 34:4314–4321 (1986).

    CAS  PubMed  Google Scholar 

  18. 18. E. Fukuoka, M. Makita, and S. Yamamura. Glassy state of pharmaceuticals. III. Thermal properties and stability of glassy pharmaceuticals and their binary glass systems. Chem. Pharm. Bull. 37:1047–1050 (1989).

    CAS  Google Scholar 

  19. 19. A. Koga, E. Yonemochi, M. Machida, Y. Aso, H. Ushio, and K. Terada. Microscopic molecular mobility of amorphous AG-041R measured by solid-state 13C NMR. Int. J. Pharm. 275:73–83 (2004).

    CAS  PubMed  Google Scholar 

  20. 20. D. A. Torchia. The measurement of proton-enhanced carbon-13 T1 values by a method which suppresses artifacts. J. Magn. Reson. 30:613–616 (1978).

    CAS  Google Scholar 

  21. 21. W. T. Dixon. Spinning-sideband-free NMR spectra. J. Magn. Reson. 44:220–223 (1981).

    CAS  Google Scholar 

  22. 22. R. I. Shrager. Quadratic programming for nonlinear regression. Commun. ACM 15:41–45 (1972).

    Google Scholar 

  23. 23. A. N. Garroway, W. B. Moniz, and H. A. Resing. High resolution 13C nuclear magnetic resonance in cured epoxy polymers. 13C N.M.R. in Polymers. Chem. Pharm. Bull. 13:63–74 (1979).

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutics, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan

    Katsuhiko Masuda, Etsuo Yonemochi & Katsuhide Terada

  2. Discovery Technology Laboratory II, Mitsubishi Pharma Corporation, Aoba-ku, Yokohama, Kanagawa, Japan

    Katsuhiko Masuda

  3. Yokohama Laboratory, Mitsubishi Chemical Group Science and Technology Research Center, Inc., Aoba-ku, Yokohama, Kanagawa, Japan

    Sachio Tabata

  4. Yokkaichi Laboratory, Mitsubishi Chemical Group Science and Technology Research Center, Inc., Toho-cho, Yokkaichi, Mie, Japan

    Yasuyuki Sakata

  5. Pharmaceutical Technology Coordination Department, Mitsubishi Pharma Corporation, Hasaki Kashima, Ibaraki, Japan

    Tetsuo Hayase

Authors
  1. Katsuhiko Masuda
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  2. Sachio Tabata
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  3. Yasuyuki Sakata
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  4. Tetsuo Hayase
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  5. Etsuo Yonemochi
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  6. Katsuhide Terada
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Correspondence to Katsuhiko Masuda.

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Masuda, K., Tabata, S., Sakata, Y. et al. Comparison of Molecular Mobility in the Glassy State Between Amorphous Indomethacin and Salicin Based on Spin-Lattice Relaxation Times. Pharm Res 22, 797–805 (2005). https://doi.org/10.1007/s11095-005-2597-4

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  • DOI: https://doi.org/10.1007/s11095-005-2597-4

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