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‐azatetracyclo10.3.1.0^4,13.0^8,13]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.