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Solubility Advantage of Amorphous Ketoprofen. Thermodynamic and Kinetic Aspects by Molecular Dynamics and Free Energy Approaches
journal contribution
posted on 2020-06-11, 19:13 authored by D. Gobbo, P. Ballone, S. Decherchi, A. CavalliThermodynamic
and kinetic aspects of crystalline (c-KTP) and amorphous
(a-KTP) ketoprofen dissolution in water have been investigated by
molecular dynamics simulation focusing on free energy properties.
Absolute free energies of all relevant species and phases have been
determined by thermodynamic integration on a novel path, first connecting
the harmonic to the anharmonic system Hamiltonian at low T and then extending the result to the temperature of interest. The
free energy required to transfer one ketoprofen molecule from the
crystal to the solution is in fair agreement with the experimental
value. The absolute free energy of the amorphous form is 19.58 kJ/mol
higher than for the crystal, greatly enhancing the ketoprofen concentration
in water, although as a metastable species in supersaturated solution.
The kinetics of the dissolution process has been analyzed by computing
the free energy profile along a reaction coordinate bringing one ketoprofen
molecule from the crystal or amorphous phase to the solvated state.
This computation confirms that, compared to the crystal form, the
dissolution rate is nearly 7 orders of magnitude faster for the amorphous
form, providing one further advantage to the latter in terms of bioavailability.
The problem of drug solubility, of great practical importance, is
used here as a test bed for a refined method to compute absolute free
energies, which could be of great interest in biophysics and drug
discovery in particular.