Do Polymorphic Compounds Make Good Cocrystallizing Agents? A Structural Case Study that Demonstrates the Importance of Synthon Flexibility

The ability of four polymorphic compounds, iso nicotinamide ( 1 ), 2-amino-3-nitropyridine ( 2 ), 4-chlorobenzamide ( 3 ), and maleic hydrazide ( 4 ), to form molecular cocrystals has been examined in a systematic structural study. Compounds 1 − 3 participate in a wide variety of binary and ternary (in the case of 1 ) cocrystals with aromatic or aliphatic compounds substituted with a multitude of functional groups. However, despite considerable efforts, it has not been possible to form any cocrystals with 4 . The reason for this may be due to the fact that even though there are three known polymorphs of 4, they all contain the same hydrogen-bonding synthons. In contrast, the polymorphs of 1 − 3 display considerable synthon flexibility, e.g., different hydrogen bond interactions are present in polymorphs of the same compound. Because 1 − 3 can form robust synthons in a variety of ways, whereas 4 always engages in the same primary hydrogen bond interactions, it may explain why the former compounds are readily able to accommodate other molecules within the same lattice whereas there are no known cocrystals of 4 .