(136d) Can Lattice Dynamics with Anisotropic and Isotropic Thermal Expansion Accurately Estimate Thermodynamic Properties of Crystals Pharmaceutics Compared to Molecular Dynamics?
AIChE Annual Meeting
2017
2017 Annual Meeting
Pharmaceutical Discovery, Development and Manufacturing Forum
Computational Solid State Pharmaceutics
Monday, October 30, 2017 - 1:33pm to 1:54pm
We have implemented three lattice dynamic methods to determine what level of thermal expansion is required to compute the thermodynamic properties of small organic polymorphs in varying size and torsional degrees of freedom. The fastest method is the harmonic approximation (HA), which neglects thermal expansion but includes the entropy of harmonic vibrations, giving at least a crude estimate for polymorphic free energy differences. We also examine the quasiharmonic approximations, including both isotropic and anisotropic expansion, using new methodology to make the anisotropic expansion computationally feasible. Finally, we compare the relative free energies versus temperature curves generated with MD to compare all lattice dynamic models to.
For small and rigid molecules (1,4-Diiodobenzene and resorcinol), where the entropic difference between polymorphs is constant, we found that isotropic QHA was sufficient in determining polymorph free energy differences within error of MD out to 300K. However, for more flexible molecules (chlorpropamide and tolbutamide) anisotropic-QHA is required to correct for failures with an isotropic model. We hypothesize that failures between our anisotropic thermal expansion model and MD is due to anharmonic motions, especially in the case of disordered crystals.