Spontaneous solid-state co-crystallization of caffeine and urea

The co-crystallization 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 co-crystal was shown to form spontaneously over several weeks under low energy mixing of the solids at room temperature and low relative humidity (<30%). Pre-milling the two coformers separately accelerated the process and the co-crystal formation could be detected within three 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 co-crystal within hours of storage at room temperature and 30 % relative humidity. The scanning electron microscopy images of the milled sample indicated the role of inter-particle surface contact in the spontaneous solidstate reaction. Multivariate data analysis was used to find the optimum cooling crystallization conditions for obtaining co-crystals suitable for single crystal X-ray analysis.