Luis Almeida E Sousa1, Kata J Dömötör2,3, Mafalda Paiva4, Constança Cacela4. 1. R&D Analytical Development, Hovione Farmaciencia SA, Estrada do Paço do Lumiar, Campus do Lumiar, Edifício R, 1649-038, Lisbon, Portugal. lasousa@hovione.com. 2. Budapest University of Technology and Economics, Budapest, Hungary. 3. Supported by Hovione Research Program Scholarship, Lisbon, Portugal. 4. R&D Analytical Development, Hovione Farmaciencia SA, Estrada do Paço do Lumiar, Campus do Lumiar, Edifício R, 1649-038, Lisbon, Portugal.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS: 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, PVPK29/32 and Eudragit EPO were used in these studies. RESULTS: 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, PVPK29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C. CONCLUSIONS: 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.
Authors: Hywel D Williams; Natalie L Trevaskis; Susan A Charman; Ravi M Shanker; William N Charman; Colin W Pouton; Christopher J H Porter Journal: Pharmacol Rev Date: 2013-01 Impact factor: 25.468