Co-crystals are being intensively studied nowadays primarily due to the potential of improving pharmaceutical properties including the dissolution behavior for BCS class-II drug substances such as indomethacin (IMC).Recently,we discovered a new method using anti-solvent addition method to prepare indomethacin-saccharin (IMC-SAC) co-crystals [1] and proposed the criterion for pure IMC-SAC cocrystals formation [2].The aim of this study was to apply quality by design (QbD) concept to the anti-solvent cocrystallization process.Box-Benhnken experimental design was used to develop space design and determine the optimal process variables for producing high yield of pure cocrystals.The anti-solvent cocrystallization process of IMC-SAC was monitored using an in-line NIRS and spectra were correlated with off-line characterization data by HPLC,XRD and PSA.Non-invasive NIR measurement was successfully used for predicting the product attributes.And our results showed the applicability of design of experiments (DoE) for enhancing the yield of the pure cocrystal and reducing the cost of excess reagent.The knowledge of the relationship between process variables and product attributes will enable rational process design to obtain a desired outcome.