Purification of Structurally Similar Compounds by the Formation of Impurity Co-Former Complexes in Solution

Abstract

The purification of structurally similar compounds was investigated using selective impurity complex formation in solution followed by crystallization of the target compound. Two systems of structurally similar compounds, benzamide/benzoic acid (BAM/BA) and cinnamamide/cinnamic acid (CAM/CA), were chosen. Three reported co-formers that form co-crystals with both BA and CA were selected: isonicotinamide (INA), 2-amino-4,6-dimethylpyrimidine (DMP), and dimethylglyoxime (DMG). The addition of DMG to the BAM/BA system demonstrated the largest improvement of BAM purity. The amount of BA did not decrease with increasing amount of DMG added. For the CAM/CA system, adding DMP resulted in the largest CAM purity increase. Phase solubility diagrams were measured to calculate binding constants for 1:1 complexes. These binding constants were used as indications of the complexation level in the solution. For the CAM/CA system, the more complex formed in solution, the purer the CAM. This result was not seen in the BAM/BA system. The results indicate that, for difficult to purify compounds where the structurally similar impurities substitute in the crystal lattice, the use of additives which have the potential to complex with the impurity in solution can result in an increase in crystal purity. However, the correlation between the level of complexation and the purification result needs further verification.