Disappearing Polymorphs Reappear in the Mill: The Case of Ritonavir

04 May 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.



Supplementary materials

Electronic Supplementary Information


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.