Form III of artemisinin: discovery and crystallographic characterisation 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 (API). Form I, the orthorhombic polymorph, was 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 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 highlighting the influence of the pressure-transmitting medium on the stability of the crystal structure. The newly characterised, Form III, shares structural similarities with Form II but differs in symmetry where a pseudo-2₁ screw axis in Form II become a formal 2₁ screw axis in Form III, resulting in a change from triclinic to monoclinic crystal system 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 pressure transmitting medium in influencing solid-state transitions relevant to pharmaceutical processing and formulation.