Understanding Poor Milling Behavior of Voriconazole from Crystal Structure and Intermolecular Interactions

The study investigated the milling behavior of voriconazole (VRZ) subjected to particle size reduction using air jet mill at differential air pressures of 5, 6, 7, and 8 bar for five cycles at each pressure. The crystal structure of VRZ was probed for understanding the fracture behavior from crystal packing and intermolecular interactions using molecular modeling tools of attachment energy (E_att), density functional theory, and energy framework analysis. Upon milling for different cycles, VRZ showed that size reduction from (D₉₀) 20 to 9 μm and 100% particles could not be milled to sizes below 9 μm, with the increase in either the milling intensity or cycle. The milled samples retained the original crystal lattice as evident from consistent melting endotherm (T_m = 130.75 °C); heat of fusion (ΔH_f = 96.52 J/g) values; and the plate-shaped morphology. The powder X-ray diffraction pattern of milled samples consistently showed characteristic peaks of stable form B of VRZ. The crystallographic plane (001) was found to be the most prominent slip and the cleavage plane due to least E_att and weak noncovalent interactions (6.996 kJ/mol) between 3'H and 4'F functional groups of the neighboring planes. The predicted indentation hardness value of 228.67 MPa further indicated toward the plastic nature of VRZ crystals. Corroborating outcomes from the different molecular modeling tools for VRZ, cleavage along the plane (001) was determined to be energetically favorable, whereas cleavage of isotropic 2D molecular sheets was energetically unfavorable. As milling proceeds and crystal reduces in size, contact surface area and overall interaction energy decrease contributing to plastic behavior of the crystal. It was concluded that crystal plasticity and isotropic 2D molecular sheets along with the orientation of particles to the direction of stress and attrition energy during air jet milling are contributing factors for nonuniform size reduction of VRZ particles.