Control of 11-Aza:4-X-SalA Cocrystal Polymorphs Using Heteroseeds That Switch On/Off Halogen Bonding

A family of: 1:1 cocrystals 11-Aza:4-X-SalA have been prepared from the potent anti-malarial compound 11-azaartemisinin with 4-halosalicylic acids. When X = 4-Cl, 4-Br and 4-I, two conformational polymorphs can be isolated in each case. Monoclinic type-I was found previously for parent 11-Aza:SalA (1) and 11-Aza:4-Br-SalA (3a) which have polar 2(1) stacks of molecular pairs with no short halogen bond contacts between stacks. Orthorhombic type-II is found for 4-Cl (3b) and 4-I (4b) from solution growth. This has a translational stack of molecular pairs involving a conformational change of the acid-lactam hetero-synthon and supramolecular association of stacks via halogen bonds. Notably, phase pure polymorph type-I can be formed for 4-Cl (3a) and 4-I (4a) by hetero-seeding with 11-Aza:SalA, whist conversely phase pure type-II for 4-Br (2b) can be formed using homo-seeding from liquid assisted grinding (LAG) product. This work demonstrates both the viability of engineering polymorphic cocrystal forms using hetero-seeds and the involvement of halogen bonds in helping to discriminate quite different polymorphic types.

Automated summary

This study demonstrates the formation of different types of cocrystals using different seeds, while also showing the role of halogen bonds in discriminating between different polymorphic types.