Solvent-mediated morphology selection of the active pharmaceutical ingredient isoniazid: Experimental and simulation studies.

This work combines the crystallization experiments and constant chemical potential molecular dynamics simulations to investigate the solvent-mediated crystal morphology selection of an anti-tuberculosis drug, isoniazid. Experiments show that the aspect ratio of isoniazid crystals decreases with the decrease in the relative solvent polarity. Simulations provide a rationale for the experimentally observations and reveal the solvents role in controlling growth of important surfaces that modulate the crystal morphology, a rough growth mechanism for the fast growing (1 1 0) surface and stepwise growth for the slow growing (0 0 2) surface are also discovered. • Experiments and constant chemical potential molecular dynamics simulations are combined to investigate the solvent effects on isoniazid crystal morphology. • Experiments show that the aspect ratio of isoniazid crystals grown from solution decreases with the decrease in the relative solvent polarity. • Simulations reveal a rough growth mechanism for the fast growing (1 1 0) surface and stepwise growth for the slow growing (0 0 2) surface. In solution crystallization, solvent has a profound effect on controlling crystal morphology. However, the role played by solvents in affecting crystal morphology remains elusive. Here, we accompany experiments with molecular dynamics simulations to investigate crystallization of an anti-tuberculosis drug, isoniazid, in different solvents. Experiments show that isoniazid grows as needle-like crystals in water, while in alcohols such as methanol, ethanol and isopropanol, it exhibits a rod-like crystal habit. The aspect ratio of isoniazid crystals decreases with the decrease in the relative solvent polarity. We modeled these experiments by performing molecular dynamics simulations of isoniazid crystallization in different solvents at constant chemical potential thus keeping the solution concentration constant. The simulation results reveal a rough growth mechanism for the fast growing (1 1 0) surface, and bulk transport of the solute from solution to the growing surface is the limiting-step. In accordance with experiments, the relative growth rate of this surface decreases from methanol, ethanol to isopropanol. On the other hand, the slow growing (0 0 2) surface appears to follow a stepwise growth mechanism, with a surface integration step chiefly controlling the growth. The relative growth rate of this surface increases from methanol to ethanol and isopropanol. [ABSTRACT FROM AUTHOR]