Pharmaceutical Research

, Volume 27, Issue 12, pp 2704–2714 | Cite as

Solubility Advantage of Amorphous Pharmaceuticals: II. Application of Quantitative Thermodynamic Relationships for Prediction of Solubility Enhancement in Structurally Diverse Insoluble Pharmaceuticals

  • Sharad B. Murdande
  • Michael J. Pikal
  • Ravi M. Shanker
  • Robin H. BognerEmail author
Research Paper



To quantitatively assess the solubility advantage of amorphous forms of nine insoluble drugs with a wide range of physico-chemical properties utilizing a previously reported thermodynamic approach.


Thermal properties of amorphous and crystalline forms of drugs were measured using modulated differential calorimetry. Equilibrium moisture sorption uptake by amorphous drugs was measured by a gravimetric moisture sorption analyzer, and ionization constants were determined from the pH-solubility profiles. Solubilities of crystalline and amorphous forms of drugs were measured in de-ionized water at 25°C. Polarized microscopy was used to provide qualitative information about the crystallization of amorphous drug in solution during solubility measurement.


For three out the nine compounds, the estimated solubility based on thermodynamic considerations was within two-fold of the experimental measurement. For one compound, estimated solubility enhancement was lower than experimental value, likely due to extensive ionization in solution and hence its sensitivity to error in pKa measurement. For the remaining five compounds, estimated solubility was about 4- to 53-fold higher than experimental results. In all cases where the theoretical solubility estimates were significantly higher, it was observed that the amorphous drug crystallized rapidly during the experimental determination of solubility, thus preventing an accurate experimental assessment of solubility advantage.


It has been demonstrated that the theoretical approach does provide an accurate estimate of the maximum solubility enhancement by an amorphous drug relative to its crystalline form for structurally diverse insoluble drugs when recrystallization during dissolution is minimal.


amorphous crystal dissolution re-crystallization solubility solubility enhancement solute activity in amorphous thermodynamics 


  1. 1.
    Murdande SB, Pikal MJ, Shanker RM, Bogner RH. Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis. J Pharm Sci. 2010;99:1254–64.PubMedGoogle Scholar
  2. 2.
    Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86:1–12.CrossRefPubMedGoogle Scholar
  3. 3.
    Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48:27–42.CrossRefPubMedGoogle Scholar
  4. 4.
    Craig DQ, Royall PG, Kett VL, Hopton ML. The relevance of the amorphous state to pharmaceutical dosage forms: glassy drugs and freeze dried systems. Int J Pharm. 1999;179:179–207.CrossRefPubMedGoogle Scholar
  5. 5.
    Kaushal AM, Gupta P, Bansal AK. Amorphous drug delivery systems: molecular aspects, design and performance. Crit Rev Ther Drug Carr Syst. 2004;21:133–93.CrossRefGoogle Scholar
  6. 6.
    Li DX, Oh Y-K, Lim S-J, Kim JO, Yang HJ, Sung JH, et al. Novel gelatin microcapsule with bioavailability enhancement of ibuprofen using spray-drying technique. Int J Pharm. 2008;355:277–84.CrossRefPubMedGoogle Scholar
  7. 7.
    Kim J-S, Kim M-S, Park HJ, Jin S-J, Lee S, Hwang S-J. Physicochemical properties and oral bioavailability of amorphous atorvastatin hemi-calcium using spray-drying and SAS process. Int J Pharm. 2008;359:211–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today. 2007;12:1068–75.CrossRefPubMedGoogle Scholar
  9. 9.
    Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17:397–404.CrossRefPubMedGoogle Scholar
  10. 10.
    Chawla G, Gupta P, Thilagavathi R, Chakraborti AK, Bansal AK. Characterization of solid-state forms of celecoxib. Eur J Pharm Sci. 2003;20:305–17.CrossRefPubMedGoogle Scholar
  11. 11.
    Bansal SS, Kaushal AM, Bansal AK. Molecular and thermodynamic aspects of solubility advantage from solid dispersions. Mol Pharmaceutics. 2007;4:794–802.CrossRefGoogle Scholar
  12. 12.
    Ran Y, Neera J, Yalkowsky SH. Solubility and partitioning of aqueous solubility of organic compounds by the General Solubility Equation (GSE). J Chem Inf Comput Sci. 1980;41:1208–17.Google Scholar
  13. 13.
    Yalkowski SH, Valvani SC. Solubility and partitioning I: solubility of nonelectrolytes in water. J Pharm Sci. 1980;69:912–22.CrossRefGoogle Scholar
  14. 14.
    Neera J, Yalkowsky SH. Estimation of the aqueous solubility I: application to organic nonelectrolytes. J Pharm Sci. 2001;90:234–52.CrossRefGoogle Scholar
  15. 15.
    Yalkowsky SH. Estimation of the aqueous solubility of complex organic compounds. Chemosphere. 1993;26:1239–61.CrossRefGoogle Scholar
  16. 16.
    Yalkowsky SH. Solubility and partitioning V: dependence of solubility on melting point. J Pharm Sci. 1981;70:971–3.CrossRefPubMedGoogle Scholar
  17. 17.
    Amidon GL, Williams NA. A solubility equation for non-electrolytes in water. Int J Pharm. 1982;11:249–56.CrossRefGoogle Scholar
  18. 18.
  19. 19.
    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 Deliv Rev. 1997;23:3–25.CrossRefGoogle Scholar
  20. 20.
    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 Deliv Rev. 2001;46:3–26.CrossRefPubMedGoogle Scholar
  21. 21.
    Manderschid M, Eichinger T. Determination of pKa values by liquid chromatography. J Chromatogr Sci. 2003;41:323–6.Google Scholar
  22. 22.
    Murdande SB, Pikal M, Shanker R, Bogner R. Aqueous solubility of crystalline and amorphous drugs: challenges in measurement. Pharm Dev Technol. (2010). doi: 10.3109/10837451003774377.
  23. 23.
    Johari GP, Shanker RM. Calorimetric relaxation and the glass-liquid temperature range of acetaminophen-nifedipine alloys. J Pharm Sci. 2007;9999:n/a .Google Scholar
  24. 24.
    Tombari E, Presto S, Johari G, Shanker R. Molecular mobility, thermodynamics and stability of Griseofulvin’s ultraviscous and glassy states from dynamic heat capacity. Pharm Res. 2008;25:902–12.CrossRefPubMedGoogle Scholar
  25. 25.
    Wan H, Holmen AG, Wang Y, Lindberg W, Englund M, Nagard MB, et al. High-throughput screening of pKa values of pharmaceuticals by pressure-assisted capillary electrophoresis and mass spectrometry. Rapid Commun Mass Spectrom. 2003;17:2639–48.CrossRefPubMedGoogle Scholar
  26. 26.
    Gerakis AM, Koupparis MA, Efstathiou CE. Micellar acid–base potentiometric titrations of weak acidic and/or insoluble drugs. J Pharm Biomed Anal. 1993;11:33–41.CrossRefPubMedGoogle Scholar
  27. 27.
    Chiang P-C, Foster KA, Whittle MC, Su C-C, Pretzer DK. Medium throughput pKa determinations of drugs and chemicals by reverse phase HPLC with an organic gradient. J Liq Chromatogr Relat Technol. 2006;29:2291–301.CrossRefGoogle Scholar
  28. 28.
    Wiczling P, Kawczak P, Nasal A, Kaliszan R. Simultaneous determination of pKa and lipophilicity by gradient RP HPLC. Anal Chem. 2006;78:239–49.CrossRefPubMedGoogle Scholar
  29. 29.
    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
  30. 30.
    Greco K, Bogner RH. Crystallization of amorphous indomethacin during dissolution: Effect of processing and annealing. Mol Pharm (2010). doi: 10.1021/mp1000197.
  31. 31.
    Zhou D, Zhang GGZ, Law D, Grant DJW, Schmitt EA. Physical stability of amorphous pharmaceuticals: Importance of configurational thermodynamic quantities and molecular mobility. J Pharm Sci. 2002;91:1863–72.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sharad B. Murdande
    • 1
    • 3
  • Michael J. Pikal
    • 1
    • 2
  • Ravi M. Shanker
    • 3
  • Robin H. Bogner
    • 1
    • 2
    Email author
  1. 1.Department of Pharmaceutical SciencesUniversity of ConnecticutStorrsUSA
  2. 2.Institute of Material ScienceUniversity of ConnecticutStorrsUSA
  3. 3.Pfizer Global R&DGroton LabsGrotonUSA

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