Molecular Dynamics Electric Field Crystallization Simulations of Paracetamol Produce a New Polymorph

Abstract

Using molecular dynamics simulations, we demonstrate the ability of high intensity, 1.5 V/nm, static electric fields to induce the formation of a new polymorph of paracetamol, one of the most important fever and pain suppressants in the world. In the newly produced polymorphic form, paracetamol molecules adopt a spatial orientation that maximizes the alignment between the electric dipole and the applied electric field vector. As the properties of crystalline materials are ultimately determined by the conformational and packing patterns of molecules in the solid state, it is predicted that electric fields have the potential to spur the creation of never before seen materials with potential novel properties such as increased drug efficacy in vivo. Paracetamol nanocrystal growth and dissolution dynamics are systematically investigated as a function of the applied electric field intensity and temperature. It is shown that the electric field suppresses the growth rate of supersaturated paracetamol nanocrystals, and can both increase and inhibit the dissolution rates of undersaturated paracetamol nanocrystals. This shows that molecular dynamics predicts that electric fields are a useful control variable for the manipulation of crystal size distributions and crystallization dynamics. Analysis of the crystal morphology under the presence of the electric field shows that paracetamol nanocrystals adopt an electric field intensity dependent morphology. Finally, the new polymorph is shown to be metastable in the absence of the electric field with increased aqueous solubility and hence potentially bioavailability relative to form I and II. The new form is stabilized at short times through a temperature quench, but requires longer application of the electric field to maintain the new polymorph during crystallization.