Skip to main content
SpringerLink
Log in

Amorphization Alone Does Not Account for the Enhancement of Solubility of Drug Co-ground with Silicate: The Case of Indomethacin

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The solubility advantage of indomethacin amorphized by co-grinding with Neusilin US2 in various media was investigated. Physical mixtures of γ-indomethacin and Neusilin US2 (in the ratios 1:1, 1:4 and 1:5) were amorphized at room temperature employing 75% RH in a porcelain jar mill using zirconia balls. The crystallinity of the samples was determined using ATR-FTIR and PXRD. The solubility and dissolution profiles of co-ground powders and crystalline counterparts were evaluated in 0.1 N HCl, water and phosphate buffer (pH 6.8) in a USP type II dissolution apparatus at 250 rpm and 37 °C. Very high concentrations of dissolved indomethacin as compared to the solubility of γ-indomethacin (~500 times in water and ~ 3.7 times in phosphate buffer) were attained. However, the presence of other polymorphs detected by PXRD and a change in the pH of the medium made interpretation of the results difficult. In 0.1 N HCl the solubility (i.e., the peak in a concentration versus time plot) of the amorphized drug in a 1:5 ratio with Neusilin increased to 109 times the solubility of crystalline γ-indomethacin alone. An increase in amount of drug and Neusilin in the same ratio added to the dissolution medium also increased peak and plateau dissolution concentrations. The presence of silicic acid and ions (Mg2+ and Al3+) in the dissolution media were found to cause the increase in the plateau concentration of indomethacin. Amorphization alone does not account for all of the dissolution enhancement; acidity, ions, and silicic acid are major contributors to dissolution enhancement.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. B. C. Hancock, and G. Zografi. Characteristics and significance of the amorphous state in pharmaceutical systems. J. Pharm. Sci. 861:1–12 (1997).

    Article  CAS  Google Scholar 

  2. W. L. Chiou, and S. Riegelman. Pharmaceutical applications of solid dispersion systems. J. Pharm. Sci. 609:1281–1302 (1971).

    Article  CAS  Google Scholar 

  3. B. C. Hancock, and M. Parks. What is the true solubility advantage for amorphous pharmaceuticals? Pharma. Res. 174:397–404 (2000).

    Article  CAS  Google Scholar 

  4. M. Kinoshita, K. Baba, A. Nagayasu, K. Yamabe, T. Shimooka, Y. I. Takeichi, M. Azuma, H. Houchi, and K. Minakuchi. Improvement of solubility and oral bioavailability of a poorly water-soluble drug, TAS-301, by its melt-adsorption on a porous calcium silicate. J. Pharm. Sci. 912:362–370 (2002).

    Article  CAS  Google Scholar 

  5. T. Watanabe, S. Hasegawa, N. Wakiyama, A. Kusai, and M. Senna. Prediction of apparent equilibrium solubility of indomethacin compounded with silica by 13C solid state NMR. Int. J. Pharm. 2481–2:123–129 (2002).

    Article  CAS  Google Scholar 

  6. T. Watanabe, S. Hasegawa, N. Wakiyama, A. Kusai, and M. Senna. Comparison between polyvinylpyrrolidone and silica nanoparticles as carriers for indomethacin in a solid state dispersion. Int. J. Pharm. 2501:283–286 (2003).

    Article  CAS  Google Scholar 

  7. D. Law, E. A. Schmitt, K. C. Marsh, E. A. Everitt, W. Wang, J. J. Fort, S. L. Krill, and Y. Qiu. Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J. Pharm. Sci. 933:563–570 (2004).

    Article  CAS  Google Scholar 

  8. T. Watanabe, N. Wakiyama, F. Usui, M. Ikeda, T. Isobe, and M. Senna. Stability of amorphous indomethacin compounded with silica. Int. J. Pharm. 2261–2:81–91 (2001).

    Article  CAS  Google Scholar 

  9. P. Tong, and G. Zografi. A study of amorphous molecular dispersions of indomethacin and its sodium salt. J. Pharm. Sci. 9012:1991–2004 (2001).

    Article  CAS  Google Scholar 

  10. A. E. H. Gassim, P. G. Takla, and K. C. James. Polymorphism and possible intramolecular bonding in benperidol. Int. J. Pharm. 341–2:23–28 (1986).

    Article  CAS  Google Scholar 

  11. E. Nuernberg, and A. Hopp. Pharmaceutical studies of paracetamol. 2. Differential thermal analytical studies. Pharm. Ind. 451:85–87 (1983).

    CAS  Google Scholar 

  12. K. Y. Yang, R. Glemza, and C. I. Jarowski. Effects of amorphous silicon dioxides on drug dissolution. J. Pharm. Sci. 685:560–565 (1979).

    Article  CAS  Google Scholar 

  13. P. Tong, and G. Zografi. Solid-state characteristics of amorphous sodium indomethacin relative to its free acid. Pharma Res. 168:1186–1192 (1999).

    Article  CAS  Google Scholar 

  14. E. Yonemochi, S. Kitahara, S. Maeda, S. Yamamura, T. Oguchi, and K. Yamamoto. Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying. Eur. J. Pharm. Sci. 74:331–338 (1999).

    Article  CAS  Google Scholar 

  15. H. Takeuchi, S. Nagira, H. Yamamoto, and Y. Kawashima. Solid dispersion particles of amorphous indomethacin with fine porous silica particles by using spray-drying method. Int. J. Pharm. 2931–2:155–164 (2005).

    Article  CAS  Google Scholar 

  16. M. Ohta, and G. Buckton. A study of the differences between two amorphous spray-dried samples of cefditoren pivoxil which exhibited different physical stabilities. Int. J. Pharm. 2891–2:31–38 (2005).

    Article  CAS  Google Scholar 

  17. D. J. Van Drooge, W. L. J. Hinrichs, H. W. Frijlink, G. S. Zijlstra, and B. H. J. Dickhoff. A process for preparing formulations of lipophilic active substances by spray freeze drying. 2005-EP55805, 2006051067, 20051108 (2006).

  18. V. V. Boldyrev, T. P. Shakhtshneider, L. P. Burleva, and V. A. Severtsev. Preparation of the disperse systems of sulfathiazole–poly(vinylpyrrolidone) by mechanical activation. Drug Dev. Ind. Pharm. 206:1103–1114 (1994).

    Article  CAS  Google Scholar 

  19. F. Forni, G. Coppi, V. Iannuccelli, M. A. Vandelli, and M. T. Bernabei. Solid state transitions and CAP availability in surface solid dispersions of chloramphenicol stearate polymorphs. Drug Dev. Ind. Pharm. 145:633–647 (1988).

    Article  CAS  Google Scholar 

  20. E. Yonemochi, M. Matsumura, T. Oguchi, K. Yamamoto, and Y. Nakai. Interactions of medicinals and porous powder. VI. Stability of aspirin in controlled pore glass solid dispersions. Chem. Pharm. Bull. 394:1027–1031 (1991).

    CAS  Google Scholar 

  21. M. K. Gupta, A. Vanwert, and R. H. Bogner. Formation of physically stable amorphous drugs by milling with neusilin. J. Pharm. Sci. 923:536–551 (2003).

    Article  CAS  Google Scholar 

  22. T. Konno, K. Kinuno, and K. Kataoka. Physical and chemical changes of medicinals in mixtures with adsorbents in the solid state. I. Effect of vapor pressure of the medicinals on changes in crystalline properties. Chem. Pharm. Bull. 341:301–307 (1986).

    CAS  Google Scholar 

  23. K. H. Kim, M. J. Frank, and N. L. Henderson. Application of differential scanning calorimetry to the study of solid drug dispersions. J. Pharm. Sci. 743:283–289 (1985).

    Article  CAS  Google Scholar 

  24. L. Wang, F.-D. Cui, and H. Sunada. Preparation and evaluation of solid dispersions of nitrendipine prepared with fine silica particles using the melt-mixing method. Chem. Pharm. Bull. 541:37–43 (2006).

    Article  Google Scholar 

  25. H. Takeuchi, S. Nagira, H. Yamamoto, and Y. Kawashima. Solid dispersion particles of tolbutamide prepared with fine silica particles by the spray-drying method. Powder Technol. 1413:187–195 (2004).

    Article  CAS  Google Scholar 

  26. A. M. El-Sayed, A. S. Ali, and A. A. Assi. Enhancing the pharmacological effect of phenytoin using porous silica as carrier. STP Pharma 34:319–324 (1993).

    CAS  Google Scholar 

  27. A. E. Aboutaleb, A. A. Abdel-Rahman, M. O. Ahmed, and U. S. A. Uwaida. Enhancement of dissolution rate of meclozine HCl by co-grinding and loading onto certain adsorbents. Bull. Pharm. Sci. Assiut Univ. 251:7–14 (2002).

    CAS  Google Scholar 

  28. D. Bahl, and R. H. Bogner. Amorphization of indomethacin by co-grinding with Neusilin US2: amorphization kinetics, physical stability and mechanism. Pharm. Res. 2310:2317–2325 (2006).

    Article  CAS  Google Scholar 

  29. M. O’Brien, J. McCauley, and E. Cohen. Indomethacin. In H. G. Brittain (ed.), Analytical Profiles of Drug Substances, 13:Academic, London, UK, 1984, pp. 211–238.

    Google Scholar 

  30. R. K. Iler. The Chemistry of Silica: Solubility, Polymerization, Colloid and Surface Properties and Biochemistry, Wiley, New York, 1979, p 892.

    Google Scholar 

  31. M. Mosharraf, and C. Nystrom. The effect of dry mixing on the apparent solubility of hydrophobic, sparingly soluble drugs. Eur. J. Pharm. Sci. 92:145–156 (1999).

    Article  CAS  Google Scholar 

  32. M. Kinoshita, K. Baba, A. Nagayasu, K. Yamabe, M. Azuma, H. Houchi, and K. Minakuchi. Highly stabilized amorphous 3-bis(4-methoxyphenyl)methylene-2-indolinone (TAS-301) in melt-adsorbed products with silicate compounds. Drug Dev. Ind. Pharm. 295:523–529 (2003).

    Article  CAS  Google Scholar 

  33. Z. Wang, L. S. Burrell, and W. J. Lambert. Solubility of E2050 at various pH: a case in which apparent solubility is affected by the amount of excess solid. J. Pharm. Sci. 916:1445–1455 (2002).

    Article  CAS  Google Scholar 

  34. K. Kawakami, K. Miyoshi, and Y. Ida. Impact of the amount of excess solids on apparent solubility. Pharm. Res. 229:1537–1543 (2005).

    Article  CAS  Google Scholar 

  35. E. M. Phillips, and P. R. Byron. Surfactant promoted crystal growth of micronized methylprednisolone in trichloromonofluoromethane. Int. J. Pharm. 1101:9–19 (1994).

    Article  CAS  Google Scholar 

  36. M. Mosharraf, and C. Nystrom. Apparent solubility of drugs in partially crystalline systems. Drug Dev. Ind. Pharm. 296:603–622 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The financial support from the Dane O. Kildsig Center for Pharmaceutical Processing Research and from Fuji Chemicals is gratefully acknowledged. Dr. Isabelle Lagadic (Department of Chemistry) and Mr. Gary Lavigne (Institute of Material Sciences) at the University of Connecticut kindly assisted with X-ray diffractometer and FTIR instrument, respectively. Mr. Sharad Murdande performed the HPLC analysis.

Author information

Authors and Affiliations

  1. School of Pharmacy, University of Connecticut, Storrs, Connecticut, 06269, USA

    Deepak Bahl & Robin H. Bogner

  2. Institute of Material Science, University of Connecticut, Storrs, Connecticut, 06269, USA

    Robin H. Bogner

Authors
  1. Deepak Bahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robin H. Bogner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robin H. Bogner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bahl, D., Bogner, R.H. Amorphization Alone Does Not Account for the Enhancement of Solubility of Drug Co-ground with Silicate: The Case of Indomethacin. AAPS PharmSciTech 9, 146–153 (2008). https://doi.org/10.1208/s12249-007-9013-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-007-9013-9

Key words

Search

Navigation