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

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.