Skip to main content
SpringerLink
Log in

Theoretical Prediction of a Phase Diagram for Solid Dispersions

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To predict the temperature-composition phase diagram of solid dispersions (SDs) through theoretical approaches using cinnarizine-Soluplus® SD as a model system and evaluate the predicted results.

Methods

A complete phase diagram of cinnarizine-Soluplus® SD, including the solubility curve, miscibility curve and glass transition temperature curve, was constructed on the basis of the solid–liquid equilibrium (SLE) equation, Florry-Huggins (F-H) theory and Fox equation. Cinnarizine-Soluplus® SDs with different drug loadings were prepared by hot melt extrusion. The extrudates and corresponding physical mixtures were analyzed to check the predicted results.

Results

The experimental data revealed a solubility of 7.9 wt% at 110°C and a miscibility level of 65 wt% at room temperature, which were both consistent with predicted values.

Conclusions

The predicted phase diagram agrees well with the experimental results for the non-polar components which mainly interact through dispersion forces, thus facilitating the formulation design of SDs.

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
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  1. Alam MA, Ali R, Al-Jenoobi FI, Al-Mohizea AM. Solid dispersions: a strategy for poorly aqueous soluble drugs and technology updates. Expert Opin Drug Deliv. 2012;9(11):1419–40.

    Article  CAS  PubMed  Google Scholar 

  2. Qian F, Huang J, Hussain MA. Drug–polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci. 2010;99(7):2941–7.

    CAS  PubMed  Google Scholar 

  3. Zhao Y, Inbar P, Chokshi HP, Malick AW, Choi DS. Prediction of the thermal phase diagram of amorphous solid dispersions by Flory–Huggins theory. J Pharm Sci. 2011;100(8):3196–207.

    Article  CAS  PubMed  Google Scholar 

  4. Tao J, Sun Y, Zhang GG, Yu L. Solubility of small-molecule crystals in polymers: d-mannitol in PVP, indomethacin in PVP/VA, and nifedipine in PVP/VA. Pharm Res. 2009;26(4):855–64.

    Article  CAS  PubMed  Google Scholar 

  5. Karavas E, Georgarakis M, Docoslis A, Bikiaris D. Combining SEM, TEM, and micro-Raman techniques to differentiate between the amorphous molecular level dispersions and nanodispersions of a poorly water-soluble drug within a polymer matrix. Int J Pharm. 2007;340(1):76–83.

    Article  CAS  PubMed  Google Scholar 

  6. A.M. Kaushal, P. Gupta, and A.K. Bansal. Amorphous drug delivery systems: molecular aspects, design, and performance. Critical Reviews™ in Ther Drug Carrier Syst. 2004;21(3).

  7. Greco S, Authelin J-R, Leveder C, Segalini A. A practical method to predict physical stability of amorphous solid dispersions. Pharm Res. 2012;29(10):2792–805.

    Article  CAS  PubMed  Google Scholar 

  8. Linand D, Huang Y. A thermal analysis method to predict the complete phase diagram of drug–polymer solid dispersions. Int J Pharm. 2010;399(1):109–15.

    Google Scholar 

  9. Sun Y, Tao J, Zhang GG, Yu L. Solubilities of crystalline drugs in polymers: an improved analytical method and comparison of solubilities of indomethacin and nifedipine in PVP, PVP/VA, and PVAc. J Pharm Sci. 2010;99(9):4023–31.

    CAS  PubMed  Google Scholar 

  10. Mahieu A, Willart J-F, Dudognon E, Danède F, Descamps M. A new protocol to determine the solubility of drugs into polymer matrixes. Mol Pharm. 2013;10(2):560–6.

    Article  CAS  PubMed  Google Scholar 

  11. Marsac PJ, Shamblin SL, Taylor LS. Theoretical and practical approaches for prediction of drug–polymer miscibility and solubility. Pharm Res. 2006;23(10):2417–26.

    Article  CAS  PubMed  Google Scholar 

  12. Marsac PJ, Li T, Taylor LS. Estimation of drug–polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters. Pharm Res. 2009;26(1):139–51.

    Article  CAS  PubMed  Google Scholar 

  13. Bellantone RA, Patel P, Sandhu H, Choi DS, Singhal D, Chokshi H, et al. A method to predict the equilibrium solubility of drugs in solid polymers near room temperature using thermal analysis. J Pharm Sci. 2012;101(12):4549–58.

    Article  CAS  PubMed  Google Scholar 

  14. M. Rubinsteinand R.H. Colby. Polymer physics, OUP Oxford; 2003.

  15. S.Z. Cheng. Phase transitions in polymers: the role of metastable states: the role of metastable states, Elsevier; 2008.

  16. Kalogerasand IM, Brostow W. Glass transition temperatures in binary polymer blends. J Polym Sci B. 2009;47(1):80–95.

    Article  Google Scholar 

  17. Jayachandra Babu R, Brostow W, Kalogeras IM, Sathigari S. Glass transitions in binary drug + polymer systems. Mater Lett. 2009;63(30):2666–8.

    Article  CAS  Google Scholar 

  18. Kalogeras IM. A novel approach for analyzing glass-transition temperature vs. composition patterns: application to pharmaceutical compound + polymer systems. Eur J Pharm Sci. 2011;42(5):470–83.

    Article  CAS  PubMed  Google Scholar 

  19. A. Chan, K. Coppens, M. Hall, V. He, P. Jog, P. Larsen, B. Koblinksi, M. Read, D. Rothe, and S. Somasi. Solubility parameters as a tool to predict API morphology in hot melt extruded (HME) formulations containing ethycellulose, hypromellose, and polyethylene oxide, 2006 Am Assoc Pharm Sci Annu Meet Expo, San Antonio, TX, Vol. 29,2006.

  20. Djuris J, Nikolakakis I, Ibric S, Djuric Z, Kachrimanis K. Preparation of carbamazepine–Soluplus® solid dispersions by hot-melt extrusion, and prediction of drug–polymer miscibility by thermodynamic model fitting. Eur J Pharm Biopharm. 2013;84(1):228–37.

    Article  CAS  PubMed  Google Scholar 

  21. Frankand TC, Gupta S. Quickly screen solvents for organic solids. Chem Eng Prog. 1999;95(12):41–61.

    Google Scholar 

  22. Van Eerdenbrugh B, Vermant J, Martens JA, Froyen L, Van Humbeeck J, Augustijns P, et al. A screening study of surface stabilization during the production of drug nanocrystals. J Pharm Sci. 2009;98(6):2091–103.

    Article  PubMed  Google Scholar 

  23. Forster A, Hempenstall J, Tucker I, Rades T. Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis. Int J Pharm. 2001;226(1):147–61.

    Article  CAS  PubMed  Google Scholar 

  24. Fox T. Influence of diluent and of copolymer composition on the glass temperature of a polymer system. Bull Am Phys Soc. 1956;1(123):22060–6218.

    Google Scholar 

  25. Gramaglia D, Conway BR, Kett VL, Malcolm RK, Batchelor HK. High speed DSC (hyper-DSC) as a tool to measure the solubility of a drug within a solid or semi-solid matrix. Int J Pharm. 2005;301(1):1–5.

    Article  CAS  PubMed  Google Scholar 

  26. Ogata H, Aoyagi N, Kaniwa N, Ejima A, Sekine N, Kitamura M, et al. Gastric acidity dependent bioavailability of cinnarizine from two commercial capsules in healthy volunteers. Int J Pharm. 1986;29(2):113–20.

    Article  CAS  Google Scholar 

  27. Tian Y, Booth J, Meehan E, Jones DS, Li S, Andrews GP. Construction of drug–polymer thermodynamic phase diagrams using Flory–Huggins interaction theory: identifying the relevance of temperature and drug weight fraction to phase separation within solid dispersions. Mol Pharm. 2012;10(1):236–48.

    Article  PubMed  Google Scholar 

  28. Rimand PB, Runt JP. Melting point depression in crystalline/compatible polymer blends. Macromolecules. 1984;17(8):1520–6.

    Article  Google Scholar 

  29. Nair R, Nyamweya N, Gönen S, Martınez-Miranda L, Hoag S. Influence of various drugs on the glass transition temperature of poly (vinylpyrrolidone): a thermodynamic and spectroscopic investigation. Int J Pharm. 2001;225(1):83–96.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016, Liaoning Province, People’s Republic of China

    Bin Tian, Xiaoyan Wang, Yuanyuan Zhang, Keru Zhang, Yu Zhang & Xing Tang

Authors
  1. Bin Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoyan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuanyuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keru Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xing Tang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tian, B., Wang, X., Zhang, Y. et al. Theoretical Prediction of a Phase Diagram for Solid Dispersions. Pharm Res 32, 840–851 (2015). https://doi.org/10.1007/s11095-014-1500-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-014-1500-6

KEY WORDS

Search

Navigation