Disappearing Polymorphs Reappear in the Mill: The Case of Ritonavir [dataset]

Organic compounds can crystallise in different forms known as polymorphs. Discovery and control of polymorphism is of key importance to the pharmaceutical industry since polymorphs can have significantly different physical properties impacting, therefore, their utilisation in drug delivery. Certain polymorphs have been reported to ‘disappear’ from the physical world leading to polymorphs. These unwanted polymorph conversions (initially prevented by the slow nucleation kinetics of the stable forms) are driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir: once its reluctant form was unwillingly nucleated for the first time, its desired form could not be produced again with the same manufacturing process. Here we show that Ritonavir’s extraordinary disappearing polymorph as well as its reluctant form can be consistently produced by ball-milling under different environmental conditions. We demonstrate that the significant difference in stability between its polymorphs can be changed and reversed in the mill -a process we show (with the aid of computer simulations) is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful changes in the milling conditions since they dictate the kinetics of crystal breakage, dissolution, and growth processes that eventually lead to steady-state crystal sizes and shapes in the mill. This work highlights the huge potential of mechanochemistry in polymorph discovery of forms initially hard to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as Ritonavir.