Ritonavir Form III: An unexpected discovery while searching for the late-appearing polymorph II from melts

19 September 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Here we present the rich polymorph of ritonavir achieved by melt crystallization, including two previously known polymorphs (I and II) and a new polymorph, denoted Form III. This new polymorph was unexpectedly discovered to crystallize from melts as a major phase as we tried to search for the kinetically hindered polymorph II. Form II was found at very high temperature (0.90-0.93 melting point). The addition of 30% or 50% PEG 1000 highly tunes the nucleation of RIT and makes Form II the only phase when crystallizing at 0.89-0.90 melting point. The ability to reveal rich polymorph of RIT, especially the kenitically hindered stable Form II, highlights the urgen need to involve melt crystallization as a regular method in polymorphism screening in early stage of drug development.


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