Spontaneous Solid-State Cocrystallization of Caffeine and Urea

The cocrystallization of caffeine and urea was monitored and analyzed using infrared spectroscopy, Raman microscopy, scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction. The caffeine-urea cocrystal was shown to form spontaneously over several weeks under low energy mixing of the solids at room temperature and low relative humidity (30%). Premilling the two coformers separately accelerated the process, and the cocrystal formation could be detected within 3 days. When caffeine and urea were milled together, the physical mixture that was confirmed by X-ray powder diffraction immediately after milling transformed to the cocrystal within hours of storage at room temperature and 30% relative humidity. The scanning electron microscopy images of the milled sample indicated the role of interparticle surface contact in the spontaneous solid-state reaction. Multivariate data analysis was used to find the optimum cooling crystallization conditions for obtaining cocrystals suitable for single crystal X-ray analysis.