Skip to main content
SpringerLink
Log in

Review: Use of Thermal, Diffraction, and Vibrational Analytical Methods to Determine Mechanisms of Solid Dispersion Stability

  • Review Article
  • Published:
Journal of Pharmaceutical Innovation Aims and scope Submit manuscript

Abstract

Formulations such as amorphous dispersions have been proposed to counter the ever present need to make drug products sufficiently soluble. However, a major concern with amorphous pharmaceuticals is physical instability, where the higher free-energy form will spontaneously revert to the more stable (and less soluble) crystalline form. Proposed mechanisms of amorphous pharmaceutical stabilization via solid dispersions are presented, as well as the analytical methods used to understand or monitor physical stability. This work focuses on differential scanning calorimetry, Raman and infrared spectroscopy, and powder X-ray diffraction, based on the general accessibility of these methods and abundant references in the pharmaceutical literature.

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

Similar content being viewed by others

References

  1. Ku MS. Use of the biopharmaceutical classification system in early drug development. AAPS J. 2008;10(1):208–12.

    Article  PubMed  CAS  Google Scholar 

  2. Kauzmann W. The nature of the glassy state and the behavior of liquids at low temperatures. Chem Rev. 1948;43(2):219–56.

    Article  CAS  Google Scholar 

  3. Kivelson D, et al. A thermodynamic theory of supercooled liquids. Physica A. 1995;219:27–38.

    Article  CAS  Google Scholar 

  4. Edigers MD, Angell CA, Nagel SR. Supercooled liquids and glasses. J Phys Chem. 1996;100:13200–12.

    Article  Google Scholar 

  5. Hancock B, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86(1):1–12.

    Article  PubMed  CAS  Google Scholar 

  6. Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Discov Rev. 2001;48:27–42.

    Article  CAS  Google Scholar 

  7. Hilden LR, Morris KR. Physics of amorphous solids. J Pharm Sci. 2004;93(1):3–12.

    Article  PubMed  CAS  Google Scholar 

  8. Bates S, et al. Analysis of amorphous and nanocrystalline solids from their X-ray diffraction patterns. Pharm Res. 2006;23(10):2333–49.

    Article  PubMed  CAS  Google Scholar 

  9. Matsumoto T, Zografi G. Physical properties of solid molecular dispersions of Indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl-acetate) in relation to indomethacin crystallization. Pharm Res. 1999;16(11):1722–8.

    Article  PubMed  CAS  Google Scholar 

  10. Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971;60:1281–302.

    Article  PubMed  CAS  Google Scholar 

  11. Mooter GVd, et al. Physical stabilisation of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur J Pharm Sci. 2001;12:261–9.

    Article  PubMed  Google Scholar 

  12. Sairam M, et al. Poly(methylmethacrylate)-poly(vinyl pyrrolidone) microspheres as drug delivery systems: indomethacin/cefadroxil loading and in vitro release study. J Appl Polym Sci. 2007;104:1860–5.

    Article  CAS  Google Scholar 

  13. Tantishaiyakul V, Kaewnopparat N, Ingkatawornwong S. Properties of solid dispersions of piroxicam in polyvinylpyrrolidone K-30. Int J Pharm. 1996;143:59–66.

    Article  CAS  Google Scholar 

  14. Lovrecich M, et al. Effect of ageing on the release of indomethacin from solid dispersions with Eudragits. Int J Pharm. 1996;131:247–55.

    Article  CAS  Google Scholar 

  15. Taylor LS, Zografi G. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersions. Pharm Res. 1997;14:1691–8.

    Article  PubMed  CAS  Google Scholar 

  16. Taylor LS, Zografi G. Sugar–polymer hydrogen bond interactions in lyophilized amorphous mixtures. J Pharm Sci. 1998;87(12):1615–21.

    Article  PubMed  CAS  Google Scholar 

  17. Lu Q, Zografi G. Phase behavior of binary and ternary amorphous mixtures containing indomethacin, citric acid, and PVP. Pharm Res. 1998;15(8):1202–6.

    Article  PubMed  CAS  Google Scholar 

  18. Shamblin SL, Taylor LS, Zografi G. Mixing behavior of colyophilized binary systems. J Pharm Sci. 1998;87(6):695–701.

    Article  Google Scholar 

  19. Khougaz K, Clas S-D. Crystallization inhibition in solid dispersions of MK-0591 and poly(vinylpyrrolidone) polymers. J Pharm Sci. 2000;89(10):1325–34.

    Article  PubMed  CAS  Google Scholar 

  20. Raghavan SL, et al. Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm. 2001;212:213–21.

    Article  PubMed  CAS  Google Scholar 

  21. Forster A, Hempenstall J, Rades T. Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymers. J Pharm Pharmacol. 2001;53(3):303–15.

    Article  PubMed  CAS  Google Scholar 

  22. Weuts I, et al. Phase behaviour analysis of solid dispersions of loperamide and two structurally related compounds with the polymers PVP-K30 and PVP-VA64. Eur J Pharm Sci. 2004;22:375–85.

    Article  PubMed  CAS  Google Scholar 

  23. Miyazaki T, et al. Ability of polyvinylpyrrolidone and polyacrylic acid to inhibit the crystallization of amorphous acetaminophen. J Pharm Sci. 2004;93(11):2710–7.

    Article  PubMed  CAS  Google Scholar 

  24. Fujii M, et al. Preparation, characterization, and tableting of a solid dispersion of indomethacin with crospovidone. Int J Pharm. 2005;293:145–53.

    Article  PubMed  CAS  Google Scholar 

  25. Weuts I, 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.

    Article  PubMed  CAS  Google Scholar 

  26. Konno H, Taylor LS. Influence of different polymers on the crystallization tendency of molecularly dispersed amorphous felodipine. J Pharm Sci. 2006;95(12):2692–705.

    Article  PubMed  CAS  Google Scholar 

  27. Patterson JE, et al. Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling. Int J Pharm. 2007;336:22–34.

    Article  PubMed  CAS  Google Scholar 

  28. Suknuntha K, et al. Molecular modeling simulation and experimental measurements to characterize chitosan and poly(vinyl pyrrolidone) blend interactions. J Polymer Sci Part B Polym Phys. 2008;46(12):1258–64.

    Article  CAS  Google Scholar 

  29. Shibata Y, et al. The preparation of a solid dispersion powder of indomethacin with crospovidone using a twin-screw extruder or kneader. Int J Pharm. 2009;365:53–60.

    Article  PubMed  CAS  Google Scholar 

  30. Kararli TT, Catalano T. Stabilization of misoprostol with hydroxypropyl methylcellulose (HPMC) against degradation by water. Pharm Res. 1990;7(11):1186–9.

    Article  PubMed  CAS  Google Scholar 

  31. Yoshioka M, Hancock BC, Zografi G. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J Pharm Sci. 1994;83(12):1700–5.

    Article  PubMed  CAS  Google Scholar 

  32. Bhugra C, Pikal MJ. Role of thermodynamic, molecular, and kinetic factors in crystallization from the amorphous state. J Pharm Sci. 2008;97(4):1329–49.

    Article  PubMed  CAS  Google Scholar 

  33. ICH. ICH harmonized tripartite guideline–specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances (ICH Q6A). Geneva: ICH; 1999.

    Google Scholar 

  34. Rumondor ACF, et al. Phase behavior of poly(vinylpyrrolidone) containing amorphous solid dispersions in the presence of moisture. Mol Pharm. 2009;6(5):1492–505.

    Article  PubMed  CAS  Google Scholar 

  35. Alexander L, Klug HP. Basic aspects of X-ray absorption. Anal Chem. 1948;20(10):1641–65.

    Article  Google Scholar 

  36. Zevin LS, Kimmel G, editors. Quantitative X-ray diffractometry. New York: Springer; 1995. 372.

    Google Scholar 

  37. Moore M, et al. The use of net analyte signal orthogonalization in the separation of multi-component diffraction patterns obtained from X-ray powder diffraction of intact compacts. J Pharm Biomed Anal. 2008;47:238–47.

    Article  PubMed  CAS  Google Scholar 

  38. Rumondor ACF, Taylor LS. Application of partial least-squares (PLS) modeling in quantifying drug crystallinity in amorphous solid dispersions. Int J Pharm. 2010;398:155–60.

    Article  PubMed  CAS  Google Scholar 

  39. Sarsfield BA, et al. Powder X-ray diffraction detection of crystalline phase in amorphous pharmaceuticals. In 2005 Denver X-ray Conference. Denver: International Centre for Data Diffraction; 2006.

    Google Scholar 

  40. Nunes C, Mahendrasingam A, Suryanarayanan R. Quantification of crystallinity in substantially amorphous materials by synchrotron X-ray powder diffraction. Pharm Res. 2005;22(11):1942–53.

    Article  PubMed  CAS  Google Scholar 

  41. Crowley KJ, Zografi G. Cryogenic grinding of indomethacin polymorphs and solvates: assessment of amorphous phase formation and amorphous phase physical stability. J Pharm Sci. 2002;91(2):492–507.

    Article  PubMed  CAS  Google Scholar 

  42. Yoshioka M, Hancock BC, Zografi G. Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates. J Pharm Sci. 1995;84:983–6.

    Article  PubMed  CAS  Google Scholar 

  43. Newman A, et al. Characterization of amorphous API: polymer mixtures using X-ray powder diffraction. J Pharm Sci. 2008;97(11):4840–56.

    Article  PubMed  CAS  Google Scholar 

  44. Pan Z, Julian T, Augsburger L. Quantitative measurement of indomethacin crystallinity in indomethacin-silical gel binary system using differential scanning calorimetry and X-ray powder diffractometry. AAPS PharmSciTech. 2006;7(1):E1–7.

    Article  Google Scholar 

  45. Hancock BC. Comments on “An approach to estimate the amorphous content of pharmaceutical powders using calorimetry with no calibration standards”. Int J Pharm. 1998;160:131–3.

    Article  CAS  Google Scholar 

  46. FDA. PAT: a framework for innovative manufacturing and quality assurance, guidance for industry. Washington, DC: US Food and Drug Administration; 2003.

    Google Scholar 

  47. Taylor LS, Langkilde FW. Evaluation of solid-state forms present in tablets by Raman spectroscopy. J Pharm Sci. 2000;89(10):1342–53.

    Article  PubMed  CAS  Google Scholar 

  48. Savolainen M, et al. Determination of amorphous content in the pharmaceutical process environment. J Pharm Pharmacol. 2007;59:161–70.

    Article  PubMed  CAS  Google Scholar 

  49. Hu Y, et al. Estimation of the transition temperature for an enantiotropic polymorphic system from the transformation kinetics monitored using Raman spectroscopy. J Pharm Biomed Anal. 2007;45:546–51.

    Article  PubMed  CAS  Google Scholar 

  50. Okumura T, Otsuka M. Evaluation of the microcrystallinity of a drug substance, indomethacin, in a pharmaceutical model tablet by chemometric FT-Raman spectroscopy. Pharm Res. 2005;22(8):1350–7.

    Article  PubMed  CAS  Google Scholar 

  51. Heinz A, et al. Quantifying ternary mixtures of different solid-state forms of indomethacin by Raman and near-infrared spectroscopy. Eur J Pharm Sci. 2007;32:182–92.

    Article  PubMed  CAS  Google Scholar 

  52. Konno H, Taylor LS. Ability of different polymers to inhibit the crystallization of amorphous felodipine in the presence of moisture. Pharm Res. 2008;25(4):969–78.

    Article  PubMed  CAS  Google Scholar 

  53. Rumondor ACF, Taylor LS. Effect of polymer hygroscopicity on the phase behavior of amorphous solid dispersions in the presence of moisture. Mol Pharm. 2010;7(2):477–90.

    Article  PubMed  CAS  Google Scholar 

  54. Short SM, Cogdill RP, Anderson CA. Determination of figures of merit for near-infrared and Raman spectrometry by net analyte signal analysis for a 4-component solid dosage system. AAPS PharmSciTech. 2007;8(4):109–19.

    Article  Google Scholar 

  55. Gendrin C, Roggo Y, Collet C. Pharmaceutical applications of vibrational chemical imaging and chemometrics: a review. J Pharm Biomed Anal. 2008;48:533–53.

    Article  PubMed  CAS  Google Scholar 

  56. Cogdill RP, Anderson CA, Drennen JK. Process analytical technology case study, part III: calibration monitoring and transfer. AAPS PharmSciTech. 2005; 6(2)(Article 39).

  57. Ma H, Anderson CA. Characterization of pharmaceutical powder blends by NIR chemical imaging. J Pharm Sci. 2008;97(8):3305–20.

    Article  PubMed  CAS  Google Scholar 

  58. Otsuka M, Kato F, Matsuda Y. Determination of indomethacin polymorphic contents by chemometric near-infrared spectroscopy and conventional powder X-ray diffractometry. Analyst. 2001;126:1578–82.

    Article  PubMed  CAS  Google Scholar 

  59. Seyer JJ, Luner PE. Determination of indomethacin crystallinity in the presence of excipients using diffuse reflectance near-infrared spectroscopy. Pharm Dev Tech. 2001;64(4):573–82.

    Article  Google Scholar 

  60. Otsuka M, et al. Comparative determination of polymorphs of indomethacin in powders and tablets by chemometrical near-infrared spectroscopy and X-ray powder diffraction. AAPS PharmSciTech. 2003;4(2):1–12.

    Article  Google Scholar 

  61. Otsuka M, Kato F, Matsuda Y. Comparative evaluation of the degree of indomethacin crystallinity by chemoinfometrical Fourier-transformed near-infrared spectroscopy and conventional powder X-ray diffractometry. PharmSciTech. 2000;2(1):1–8.

    Google Scholar 

  62. Reich G. Near-infrared spectroscopy and imaging: basic principles and pharmaceutical applications. Adv Drug Discov Rev. 2005;57:1109–43.

    Article  CAS  Google Scholar 

  63. Ellison CD, et al. Measuring the distribution of density and tabletting force in pharmaceutical tablets by chemical imaging. J Pharm Biomed Anal. 2008;48:1–7.

    Article  PubMed  CAS  Google Scholar 

  64. Furuyama N, et al. Evaluation of solid dispersions on a molecular level by the Raman mapping technique. Int J Pharm. 2008;361:12–8.

    Article  PubMed  CAS  Google Scholar 

  65. Qi S, et al. Characterisation of solid dispersions of paracetamol and EUDRAGIT E prepared by hot-melt extrusion using thermal, microthermal and spectroscopic analysis. Int J Pharm. 2008;354:158–67.

    Article  PubMed  CAS  Google Scholar 

  66. Wu T, et al. Inhibiting surface crystallization of amorphous indomethacin by nanocoating. Langmuir. 2007;23:5148–53.

    Article  PubMed  CAS  Google Scholar 

  67. Wu T, Yu L. Surface crystallization of indomethacin below Tg. Pharm Res. 2006;23(10):2350–5.

    Article  PubMed  CAS  Google Scholar 

  68. Aso Y, Yoshioka S, Kojima S. Molecular mobility-based estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly(vinylpyrrolidone) solid dispersions. J Pharm Sci. 2003;93(2):384–91.

    Article  Google Scholar 

  69. Tong P, Zografi G. Effects of water vapor absorption on the physical and chemical stability of amorphous sodium indomethacin. AAPS PharmSciTech. 2003;5(2):1–8.

    Article  Google Scholar 

  70. Andronis V, Zografi G. The molecular mobility of supercooled amorphous indomethacin as a function of temperature and relative humidity. Pharm Res. 1998;15(6):835–42.

    Article  PubMed  CAS  Google Scholar 

  71. DiMartino P, Palmieri GF, Martelli S. Molecular mobility of the paracetamol amorphous form. Chem Pharm Bull. 2000;48(8):1105–8.

    Article  CAS  Google Scholar 

  72. Mao C, et al. A calorimetric method to estimate molecular mobility of amorphous solids at relatively low temperatures. Pharm Res. 2006;23(10):2269–76.

    Article  PubMed  CAS  Google Scholar 

  73. Vyazovkin S, Dranca I. Physical stability and relaxation of amorphous indomethacin. J Phys Chem B. 2005;109:18637–44.

    Article  PubMed  CAS  Google Scholar 

  74. Gordon JM, et al. The composition dependence of glass transition properties. J Chem Phys. 1976;66(11):4971–6.

    Article  Google Scholar 

  75. Pinal R. Entropy of mixing and the glass transition of amorphous mixtures. Entropy. 2008;10:207–23.

    Article  CAS  Google Scholar 

  76. Xiang T-X, Anderson BD. Distribution and effect of water content on molecular mobility in poly(vinylpyrrolidone) glasses: a molecular dynamics simulation. Pharm Res. 2005;22(8):1205–14.

    Article  PubMed  CAS  Google Scholar 

  77. Bansal SS, Kaushal AM, Bansal AK. Co-relationship of physical stability of amorphous dispersions with enthalpy relaxation. Pharmazie. 2008;63:812–4.

    PubMed  CAS  Google Scholar 

  78. Rumondor ACF, et al. Evaluation of drug–polymer miscibility in amorphous solid dispersion systems. Pharm Res. 2009;26(11):2523–34.

    Article  PubMed  CAS  Google Scholar 

  79. Konno H, et al. Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine. Eur J Pharm Sci. 2008;70:493–9.

    CAS  Google Scholar 

  80. Alonzo DE, et al. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27(4):608–18.

    Article  PubMed  CAS  Google Scholar 

  81. Ali W, Williams AC, Rawlinson CF. Stoichiometrically governed molecular interactions in drug: poloxamer solid dispersions. Int J Pharm. 2010;391:162–8.

    Article  PubMed  CAS  Google Scholar 

  82. Takayama K, Nambu N, Nagai T. Dissolution kinetics for coprecipitates of indomethacin with polyvinylpyrrolidone. Chem Pharm Bull. 1980;28(11):3304–9.

    Article  CAS  Google Scholar 

  83. Chokshi RJ, et al. Stabilization of low glass transition temperature indomethacin formulations: impact of polymer-type and its concentration. J Pharm Sci. 2008;97(6):2286–98.

    Article  PubMed  CAS  Google Scholar 

  84. Liu H, et al. Effects of extrusion process parameters on the dissolution behavior of indomethacin in Eudragit EPO solid dispersions. Int J Pharm. 2010;383:161–9.

    Article  PubMed  CAS  Google Scholar 

  85. Forster A, Hempenstall J, Rades T. Investigation of drug/polymer interaction in glass solutions prepared by melt extrusion. Internet J Vib Spectro. 2001;5(2):1–6.

    Google Scholar 

  86. Taylor LS, Langkilde FW, Zografi G. Fourier transform Raman spectroscopic study of the interaction of water vapor with amorphous polymers. J Pharm Sci. 2001;90(7):888–901.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, 15282, USA

    Ryanne N. Palermo, Carl A. Anderson & James K. Drennen III

  2. Center for Pharmaceutical Technology, Duquesne University, Pittsburgh, PA, 15282, USA

    Carl A. Anderson & James K. Drennen III

Authors
  1. Ryanne N. Palermo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carl A. Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James K. Drennen III
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James K. Drennen III.

Additional information

Teaser

This is a review focusing on diffraction, thermal, and Raman and infrared methods used to characterize, monitor, and understand the physical stability of amorphous solid dispersions.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Palermo, R.N., Anderson, C.A. & Drennen, J.K. Review: Use of Thermal, Diffraction, and Vibrational Analytical Methods to Determine Mechanisms of Solid Dispersion Stability. J Pharm Innov 7, 2–12 (2012). https://doi.org/10.1007/s12247-012-9121-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12247-012-9121-2

Keywords

Search

Navigation