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

Abstract

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[10.3.1.0 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 , C 15 H 23 NO 4 ·C 9 H 8 O 2 ). Maleic acid forms both 1:1 cocrystal 11-Aza:Mal ( 2 , C 15 H 23 NO 4 ·C 4 H 4 O 4 ), in which one COOH group is involved in self-catenation, and 2:1 cocrystal 11-Aza 2 :Mal ( 3 , 2C 15 H 23 NO 4 ·C 4 H 4 O 4 ). Its isomer, fumaric acid, only affords 2:1 cocrystal 11-Aza 2 :Fum ( 4 ). All cocrystal formation appears driven by acid–lactam R 2 2 (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.