Cocrystals of the antimalarial drug 11-azaartemisinin with three alkenoic acids of 1:1 or 2:1 stoichiometry.

The stoichiometry, X-ray structures and stability of four pharmaceutical cocrystals previously identified from liquid-assisted grinding (LAG) of 11-azaartemisinin (11-Aza; systematic name: 1,5,9-trimethyl-14,15,16-trioxa-11-azatetracyclo[10.3.1.04,13.08,13]hexadecan-10-one) with trans-cinnamic (Cin), maleic (Mal) and fumaric (Fum) acids are herein reported. trans-Cinnamic acid, a mono acid, forms 1:1 cocrystal 11-Aza:Cin (1, C15H23NO4·C9H8O2). Maleic acid forms both 1:1 cocrystal 11-Aza:Mal (2, C15H23NO4·C4H4O4), in which one COOH group is involved in self-catenation, and 2:1 cocrystal 11-Aza2:Mal (3, 2C15H23NO4·C4H4O4). Its isomer, fumaric acid, only affords 2:1 cocrystal 11-Aza2:Fum (4). All cocrystal formation appears driven by acid-lactam R22(8) heterosynthons with short O-H...O=C hydrogen bonds [O...O = 2.56 (2) Å], augmented by weaker C=O...H-N contacts. Despite a better packing efficiency, cocrystal 3 is metastable with respect to 2, probably due to a higher conformational energy for the maleic acid molecule in its structure. In each case, the microcrystalline powders from LAG were useful in providing seeding for the single-crystal growth.