The anti-solvent approach has been demonstrated as one potential industrial method to produce pharmaceutical co-crystal powders with high purity. In this study, we combined the anti-solvent method with cooling to maximize the yield of the solution-based co-crystallization between indomethacin (IMC) and saccharin (SAC). The cooling start time was the key process parameter; other parameters were fixed based on results of preliminary work. Highly pure IMC-SAC co-crystal powders were produced via the combined method, regardless of the cooling start Lime, and the yield was substantially enhanced. However, some material properties, such as crystallinity and particle size, were affected by the cooling start time; i.e., whether cooling was started before nucleation (pre-nucleation cooling) or after nucleation (post-nucleation cooling). When pre-nucleation cooling was applied, a greater degree of supersaturation led to nucleation of alpha-IMC and IMC-SAC together. The metastable alpha-IMC eventually transitioned to stable IMC-SAC co-crystal particles, followed by crystal growth. When post-nucleation cooling was applied, the transient alpha-IMC was not detected during the entire process. (C) 2014 Elsevier B.V. All rights reserved.