Classical Spiral Growth Mechanism of Azilsartan Form I Revealed by In Situ Atomic Force Microscopy

Abstract

The crystal growth mechanism of form I (AZ-I) of the antihypertensive drug azilsartan is revealed by in situ atomic force microscopy (AFM). On the dominant (100) face, AZ-I grows by a classical spiral growth mechanism. The growth spiral is asymmetric due to the different step kinetics in different crystallographic directions. The normal growth rate of the (100) face is inferred to be much lower than the step velocity within this face according to the step geometry, resulting in the plate-like crystal morphology. The dependence of step velocity on terrace width indicates that molecules incorporate into steps primarily by a surface diffusion mechanism involving molecular adsorption on terraces at first and then diffusion into steps. Within the (100) face, steps in different directions exhibit different step edge free energies and total minimal energies for step advancement. The step kinetics depends on the step length within a certain range. These findings provide a fundamental understanding of drug crystal growth at the microscale.