Kinetics of co-crystal formation with caffeine and citric acid via liquid-assisted grinding analyzed using the distinct element method.

The kinetics of co-crystal formation of caffeine (CF) with citric acid (CTA) was evaluated. Ball milling of CF and CTA in molar ratios of 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, and 1:4 was performed by the liquid-assisted grinding (LAG) method. The samples were characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). Two types of co-crystals (co-crystal-1, a 1:1 CF-CTA co-crystal; and co-crystal-2, a new co-crystal form) were obtained. The kinetic characteristics of this new co-crystal formation were assessed by calculating the ball impact energy and force using the distinct element method (DEM) simulations. The results indicated that co-crystal-2 creation occurred under a condition in which the ball impact force exceeded a certain threshold value. Moreover, the total ball impact energy was positively correlated with co-crystal formation, exhibiting a higher ball impact force than the threshold value. The kinetics of co-crystal-2 formation was almost consistent with the Jander equation. Consequently, co-crystal-2 formation could be explained according to a three-dimensional diffusion mechanism.

Diffusion behavior in a liquid-liquid interfacial crystallization by molecular dynamics simulations.

Interfacial crystallization, such as surface crystallization in solution (solid-liquid) and liquid-liquid crystallization, gives us an asymmetric reaction field and is a technique for morphology control of crystals. In the liquid-liquid crystallization, the concentration distribution of solute ions and solvent molecules at the liquid-liquid interface directly relates to nucleation, crystal growth, and crystal morphology. Nonequilibrium molecular dynamics (MD) simulations have been performed at interfaces in NaCl solution/1-butanol and KCl solution/1-butanol system in order to clarify diffusion behavior of solute ions and solvent molecules. As simulation results, the hydrated solute ions were dehydrated with the diffusion of water from solution phase into 1-butanol phase. The different dehydration behaviors between NaCl and KCl solution can be also obtained from MD simulation results. Aggregated ions or clusters were formed by the dehydration near the solution/1-butanol interface. By comparison on the normalized number of total solute ions, the size and number of generated cluster in KCl solution/1-butanol interface are larger than those in the NaCl system. This originates in the difference hydration structures in the each solute ion.