The chemomechanics of paracetamol polymorphs studied using density functional theory
Abstract
The mechanical properties of pharmaceutical crystal polymorphs are of great importance in tablet manufacturing, reducing the overall production cost. In this study, computational work was performed via density functional theory (DFT) calculations on three paracetamol crystal polymorphs: Forms I, II, and III. Form I is of monoclinic structure while forms II and III are orthorhombic. Linking types of chemical bonding to elastic properties, we discovered that for both forms II and III, the direction governed by the intermolecular hydrogen bond OH-O possesses the stiffest Young’s modulus and the lowest Poisson ratio. Meanwhile the least stiffness and largest Poisson ratio were found to be along the directions bonded by van der Waals (vdW). Lastly NH-O bond governed directions showed intermediate stiffness and Poisson ratios. For form I, no specific bond controls the axes directions; therefore, no similar chemomechanical trends can be elucidated. Moving to compressibility, there is a contradiction in literature regarding whether Form I or II is more compressible. This is due to their nearly equal bulk modulus values. Lastly, we compared the evaluation of the elastic properties of the three forms using two computational approaches: brute-force calculations and second-order elastic constants. Both agree well in terms of magnitudes and chemomechanical trends. Furthermore, the elastic constants approach revealed that Form III is mechanically unstable along certain crystallographic…
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