Pharmaceutical Research

, Volume 27, Issue 4, pp 608–618

Understanding the Behavior of Amorphous Pharmaceutical Systems during Dissolution

Research Paper

Abstract

Purpose

To investigate the underlying physical processes taking place during dissolution of amorphous pharmaceuticals and correlate them to the observed solution concentration-time profiles. Felodipine and indomethacin were used as model hydrophobic compounds.

Methods

Concentration-time profiles were monitored during dissolution of the model amorphous compounds using in situ fiber-optic ultraviolet spectroscopy. Crystallization of the solid exposed to an aqueous environment was monitored using Raman spectroscopy and/or powder X-ray diffraction. Polarized light microscopy was used to provide qualitative information about crystallization processes.

Results

For felodipine, a small extent of supersaturation was generated via dissolution at 25°C but not at 37°C. The amorphous solid was found to crystallize rapidly at both temperatures upon exposure to the dissolution medium. Addition of low concentrations of polymers to the dissolution medium was found to delay crystallization of the amorphous solid, leading to the generation of supersaturated solutions. Amorphous indomethacin did not crystallize as readily in an aqueous environment; hence, dissolution resulted in supersaturated solutions. However, crystallization from these supersaturated solutions was rapid. Polymeric additives were able to retard crystallization from supersaturated solutions of both indomethacin and felodipine for up to 4 h.

Conclusions

The dissolution advantage of amorphous solids can be negated either by crystallization of the amorphous solid on contact with the dissolution medium or through rapid crystallization of the supersaturated solution. Polymeric additives can potentially retard both of these crystallization routes, leading to the generation of supersaturated solutions that can persist for biologically relevant timeframes.

KEY WORDS

amorphous dissolution felodipine indomethacin metastable polymer supersaturation 

Supplementary material

ESM 1

(AVI 3472 kb)

References

  1. 1.
    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50:47–60.CrossRefPubMedGoogle Scholar
  2. 2.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev. 1997;23:3–25.CrossRefGoogle Scholar
  3. 3.
    Ambike AA, Mahadik KR, Paradkar A. Spray-dried amorphous solid dispersions of simvastatin, a low Tg drug: in vitro and in vivo evaluations. Pharm Res. 2005;22:990–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Six K, Verreck G, Peeters J, Brewster M, Van den Mooter G. Increased physical stability and improved dissolution properties of itraconazole, a class II drug, by solid dispersions that combine fast- and slow-dissolving polymers. J Pharm Sci. 2004;93:124–31.CrossRefPubMedGoogle Scholar
  5. 5.
    Yamashita K, Nakate T, Okimoto K, Ohike A, Tokunaga Y, Ibuki R, et al. Establishment of new preparation method for solid dispersion formulation of tacrolimus. Int J Pharm. 2003;267:79–91.CrossRefPubMedGoogle Scholar
  6. 6.
    Kennedy M, Hu J, Gao P, Li L, Ali-Reynolds A, Chal B, et al. Enhanced bioavailability of a poorly soluble vr1 antagonist using an amorphous solid dispersion approach: a case study. Mol Pharm. 2008;5:981–93.CrossRefPubMedGoogle Scholar
  7. 7.
    Kim MS, Jin SJ, Kim JS, Park HJ, Song HS, Neubert RHH, et al. Preparation, characterization and in vivo evaluation of amorphous atorvastatin calcium nanoparticles using supercritical antisolvent (SAS) process. Eur J Pharm Biopharm. 2008;69:454–65.CrossRefPubMedGoogle Scholar
  8. 8.
    Law D, Schmitt EA, Marsh KC, Everitt EA, Wang WL, Fort JJ, et al. Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J Pharm Sci. 2004;93:563–70.CrossRefPubMedGoogle Scholar
  9. 9.
    Vaughn JM, McConville JT, Crisp MT, Johnston KP, Williams RO. Supersaturation produces high bioavailability of amorphous danazol particles formed by evaporative precipitation into aqueous solution and spray freezing into liquid technologies. Drug Dev Ind Pharm. 2006;32:559–67.CrossRefPubMedGoogle Scholar
  10. 10.
    Marsac PJ, Konno H, Taylor LS. A comparison of the physical stability of amorphous felodipine and nifedipine systems. Pharm Res. 2006;23:2306–16.CrossRefPubMedGoogle Scholar
  11. 11.
    Shamblin SL, Tang XL, Chang LQ, Hancock BC, Pikal MJ. Characterization of the time scales of molecular motion in pharmaceutically important glasses. J Phys Chem B. 1999;103:4113–21.CrossRefGoogle Scholar
  12. 12.
    Wu T, Yu L. Surface crystallization of indomethacin below T-g. Pharm Res. 2006;23:2350–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Delivery Rev. 2001;48:27–42.CrossRefGoogle Scholar
  14. 14.
    Zhou D, Zhang GGZ, Law D, Grant DJW, Schmitt EA. Thermodynamics, molecular mobility and crystallization kinetics of amorphous griseofulvin. Mol Pharm. 2008;5:927–36.CrossRefPubMedGoogle Scholar
  15. 15.
    Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17:397–404.CrossRefPubMedGoogle Scholar
  16. 16.
    Chikaraishi Y, Otsuka M, Matsuda Y. Dissolution phenomenon of the piretanide amorphous form involving phase change. Chem Pharm Bull. 1996;44:2111–5.Google Scholar
  17. 17.
    Fukuoka E, Makita M, Yamamura S. Glassy state of pharmaceuticals. 2. Bioinequivalence of glassy and crystalline indomethacin. Chem Pharm Bull. 1987;35:2943–8.PubMedGoogle Scholar
  18. 18.
    Savolainen M, Kogermann K, Heinz A, Aaltonen J, Peltonen L, Strachan C, et al. Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy. Eur J Pharm Biopharm. 2009;71:71–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Windbergs M, Jurna M, Offerhaus HL, Herek JL, Kleinebudde P, Strachan CJ. Chemical imaging of oral solid dosage forms and changes upon dissolution using coherent anti-stokes Raman scattering microscopy. Anal Chem. 2009;81:2085–91.CrossRefPubMedGoogle Scholar
  20. 20.
    Konno H, Taylor LS. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci. 2006;95:2692–705.CrossRefPubMedGoogle Scholar
  21. 21.
    Matsumoto T, Zografi G. Physical properties of solid molecular dispersions of indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinylacetate) in relation to indomethacin crystallization. Pharm Res. 1999;16:1722–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Van den Mooter G, Wuyts M, Blaton N, Busson R, Grobet P, Augustijns P, et al. Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur J Pharm Sci. 2001;12:261–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Weuts I, Kempen D, Decorte A, Verreck G, Peeters J, Brewster M, et al. Physical stability of the amorphous state of loperamide and two fragment molecules in solid dispersions with the polymers PVP-K30 and PVP-VA64. Eur J Pharm Sci. 2005;25:313–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Hoffman JD. Thermodynamic driving force in nucleation and growth processes. J Chem Phys. 1958;29:1192–3.CrossRefGoogle Scholar
  25. 25.
    Konno H, Handa T, Alonzo DE, Taylor LS. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur J Pharm Biopharm. 2008;70:493–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Taylor LS, Zografi G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res. 1997;14:1691–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Towler CS, Taylor LS. Spectroscopic characterization of intermolecular interactions in solution and their influence on crystallization outcome. Cryst Growth Des. 2007;7:633–8.CrossRefGoogle Scholar
  28. 28.
    Marsac PJ, Konno H, Rumondor ACF, Taylor LS. Recrystallization of nifedipine and felodipine from amorphous molecular level solid dispersions containing poly(vinylpyrrolidone) and sorbed water. Pharm Res. 2008;25:647–56.CrossRefPubMedGoogle Scholar
  29. 29.
    Sato T, Okada A, Sekiguchi K, Tsuda Y. Difference in physico-pharmaceutical properties between crystalline and noncrystalline 9, 3″-diacetylmidecamycin. Chem Pharm Bull. 1981;29:2675–82.Google Scholar
  30. 30.
    Zhu L, Wong L, Yu L. Surface-enhanced crystallization of amorphous nifedipine. Mol Pharm. 2008;5:921–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Ishida H, Wu TA, Yu LA. Sudden rise of crystal growth rate of nifedipine near T-g without and with polyvinylpyrrolidone. J Pharm Sci. 2007;96:1131–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Wu T, Sun Y, Li N, de Villiers MM, Yu L. Inhibiting surface crystallization of amorphous indomethacin by nanocoating. Langmuir. 2007;23:5148–53.CrossRefPubMedGoogle Scholar
  33. 33.
    Andronis V, Yoshioka M, Zografi G. Effects of sorbed water on the crystallization of indomethacin from the amorphous state. J Pharm Sci. 1997;86:346–51.CrossRefPubMedGoogle Scholar
  34. 34.
    Bhugra C, Pikal MJ. Role of thermodynamic, molecular, and kinetic factors in crystallization from the amorphous state. J Pharm Sci. 2008;97:1329–49.CrossRefPubMedGoogle Scholar
  35. 35.
    Lachman L, Lieberman HA, Kanig JL. The theory and practice of industrial pharmacy. Stipes Publishing LLC, 1986.Google Scholar
  36. 36.
    Mullin JW. Crystallization. 4th ed. Oxford: Elsevier Butterworth-Heinemann; 2001.Google Scholar
  37. 37.
    Garside J, Mersmann A, Nyvlt J. Measurement of Crystal Growth and Nucleation Rates. 2nd ed. Rugby: Institute of Chemical Engineers; 2002.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Industrial and Physical Pharmacy, School of PharmacyPurdue UniversityWest LafayetteUSA
  2. 2.Global Pharmaceutical R&DAbbott LaboratoriesAbbott ParkUSA
  3. 3.Global Pharmaceutical OperationAbbott LaboratoriesAbbottUSA

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