Varying degrees of homostructurality in a series of cocrystals of antimalarial drug 11-azaartemisinin with salicylic acids

The X-ray structures of three new 1:1 pharmaceutical cocrystals 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, C₁₅H₂₃NO₄) with bromo-substituted salicylic acids [namely, 5-bromo- (5-BrSalA, C₇H₅BrO₃), 4-bromo- (4-BrSalA, C₇H₅BrO₃) and 3,5-dibromosalicylic acid (3,5-Br₂SalA, C₇H₄Br₂O₃)] are reported. All the structures are related to the parent 11-Aza:SalA cocrystal (monoclinic P2₁) reported previously. The 5-BrSalA analogue is isostructural with the parent, with lattice expansion along the c axis. The 4-BrSalA and 3,5-Br₂SalA cocrystals retain the highly preserved 2₁ stacks of the molecular pairs, but these pack with a varying degree of slippage with respect to neighbouring stacks, altering the close contacts between them, and represent two potential alternative homostructural arrangements for the parent compound. Structure redeterminations of the bromosalicylic acids 5-BrSalA, 4-BrSalA and 3,5-Br₂SalA at 100 K show that the packing efficiency of the cocrystals need not be higher than the parent coformers, based on specific-volume calculations, attributable to the strong O-H...O=C hydrogen bonds of 2.54 Å in the cocrystals.