High Pressure Homogenization as a Novel Approach for the Preparation of Co-Crystals

The feasibility of producing pharmaceutical co-crystals by simultaneous high pressure homogenization (HPH) of solid API and co-former has been investigated using as model the co-crystal forming system represented by theophylline (TPL) and saccharin (SAC). First, thermodynamic aspects of this process have been clarified by investigating the ternary system TPL – SAC – water, particularly by constructing its phase diagram and by measuring representative points of its solubility in water at temperatures between 15 and 35 °C. In a second step, the co-crystal TPL:SAC has been produced through simultaneous homogenization of aqueous suspensions of the raw materials TPL and SAC, achieving at the same time a solvent-mediated transformation of the precursors toward the co-crystal TPL:SAC and a comminution of the product particles. After 2 h of processing, corresponding to ca. 34 passes across the homogenizer at a pressure drop of 600 bar, a narrow size distribution with a median x50of 4.1 μm has been obtained. Finally, the presented concept has been extended to the use of liquid carbon dioxide as operating fluid of the homogenization process. Also in this case, TPL and SAC have been converted successfully into a product consisting largely of the co-crystal TPL:SAC, while achieving at the same time a comminution of particles down to an average size of 5.8 μm. Liquid carbon dioxide is subject to residue-free evaporation upon pressure release, such that the micronized product particles can be directly recovered in form of a dry powder at the end of the process. The presented results open thus new possibilities for a quick and clean manufacturing of pharmaceutical co-crystals whose particle size distribution can be tightly tuned.