Form (III) of artemisinin: discovery and crystallographic characterization of a new high-pressure polymorph

Artemisinin (ART) is mainly used for the treatment of malaria and exhibits polymorphism with two known crystalline forms. In this study, the high-pressure behaviour of these two polymorphs was investigated to evaluate their compressibility and identify if any pressure-induced phase transitions occur with a view to assessing the impact of manufacturing pressure on the active pharmaceutical ingredient. Form (I), the orthorhombic polymorph, is found to be the most compressible of the three. Form (II), a triclinic phase, undergoes a phase transition to a new polymorph that is observed at different pressures depending on the pressure-transmitting medium (PTM) used. The transition to form (III) occurs at 0.75 GPa when compressed in petroleum ether, however, this transition is delayed to 2.02 GPa in silicone oil. This highlights the influence of the PTM on the stability of the crystal structure. The newly characterized form (III) shares structural similarities with form (II) but differs in symmetry where a pseudo-2₁ screw axis in form (II) becomes a formal 2₁ screw axis in form (III), resulting in a change from triclinic to monoclinic and a reduction of the asymmetric unit from Z' = 4 to Z' = 2. These findings contribute to a deeper understanding of pressure-induced polymorphism in ART and underscores the importance of external factors such as PTM in influencing solid-state transitions relevant to pharmaceutical processing and formulation.