Disappearing Polymorphs Reappear in the Mill: The Case of Ritonavir

Organic compounds can crystallise in different forms known as polymorphs. Some polymorphs have disappeared from the physical world, never to be recrystallised again under the same conditions. The most infamous of these cases is that of the HIV drug ritonavir: once its reluctant stable form II was unwillingly nucleated for the first time, its desired but metastable form I could never be produced again with the same manufacturing process. The disappearance of metastable polymorphs remains a mysterious phenomenon, and the lack of control over it can be frustrating and costly for drug development. Here we show that Ritonavir’s extraordinary disappearing polymorph can be consistently produced by ball-mill grinding. Our work shows that not only crystal size, but also crystal shape and molecular conformation dictate polymorph stability switches in the mill. Through population balance modelling simulations, we also demonstrate how the size and shape of crystals at the steady state are determined by crystal breakage, dissolution and growth kinetics in the mill, which in turn can be controlled by the milling conditions. This work highlights the huge potential of mechanochemistry in polymorph discovery, and the manufacturing and control of complex flexible drug compounds such as Ritonavir.