Pharmaceutical Research

, 36:175 | Cite as

Drug-Polymer Solubility Determination: A New Thermodynamic Model Free from Lattice Theory Assumptions

  • Luis Almeida e SousaEmail author
  • Kata J. Dömötör
  • Mafalda Paiva
  • Constança Cacela
Research Paper



Traditional methods for estimating drug-polymer solubility either require fast dissolution in the polymeric matrix, rapid re-crystallization kinetics from supersaturated states or derive from regular solution theories. In this work, we present a new method for determining drug solubility, purely based on thermodynamic considerations, that uses only experimental data from DSC for calculations.


The new thermodynamic model presented combines DSC analysis and application of Hess’s law to determine free energies of conversion of binary mixtures to amorphous solid dispersions, free energies of mixing as well as solubility as a function of temperature. The model drug indomethacin and polymers HPMCAS LF, PVP K29/32 and Eudragit EPO were used in these studies.


Free energies were calculated as a function of temperature, for different drug-polymer compositions and the results show that HPMCAS LF solid dispersion with high drug content are less thermodynamically favorable compared to other polymer systems. Solubility of indomethacin in HPMCAS LF, PVP K29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C.


The thermodynamic model presented has great advantages over traditional methods. It does not require estimation of any interaction parameters, it is almost assumption-free and uses only thermal data for calculations.


amorphous solid dispersions free energy mixing solubility curve thermodynamics 



Active pharmaceutical ingredient


Amorphous solid dispersions


Differential scanning calorimetry






Hypromellose acetate succinate




Physical mixture




Spray dried dispersion



The authors would like to thank Raquel Borda D’Água for the valuable help with some of the DSC work.


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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.R&D Analytical DevelopmentHovione Farmaciencia SALisbonPortugal
  2. 2.Budapest University of Technology and EconomicsBudapestHungary
  3. 3.Supported by Hovione Research Program ScholarshipLisbonPortugal

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