(15g) Crystallization Entropy: Constituents and Contributions to Crystal Form Stability

Polymorphism is a form of molecular self-assembly that is defined as the possibility of the solid-state having at least two different arrangements of the molecules to form distinct crystal forms. Crystal polymorphism heavily impacts the pharmaceutical industry as different polymorphs can have different properties that include the solubility, dissolution rate, and overall bioavailability of a drug. Current work in the field of polymorphism has focused on finding ways to predict different polymorphs using mostly computational methods. However, until recently, most models only used the lattice energy leading to the validity of their results to be constrained at 0 K. One approach to increase the range of validity is to consider the contributions from the free energy to the relative stability of the polymorphs. To estimate this contribution, we investigate the entropy of crystallization (ΔS_crys) via an all-atomistic molecular dynamics approach using mefenamic acid (MFA), a non-steroidal anti-inflammatory drug with three distinct conformational polymorphs, as our model system. In MFA, the experimental ΔS_crys for Form I shows positive deviations from the melt, which we attribute to the binding of the solute and solvent, as well as negative deviations from the melt that correlates to solvents that are highly polar halides. The experimental data has also shown that for Form II of MFA, the ΔS_crys is significantly more negative than that of Form I. Our initial hypothesis based on our experimental findings was that the differences were due to the different conformational entropies between the polymorphs. However, our computational results revealed that both forms showed equivalent conformational entropies indicating that the conformational entropy does not effect ΔS_crys.