Ritonavir Form III: A New Polymorph After 24 Years.

Polymorphism occurs widely in pharmaceutical solids, and must be thoroughly studied during product development. Twenty-four years after ritonavir (RTV) Form II materialized, we report a new polymorph, Form III, discovered via melt crystallization. Form III has a unique PXRD pattern, Raman spectrum, lower melting point and heat of fusion, compared to the known polymorphs, Form I and Form II. It is the least stable form, monotropically, among the three polymorphs. Form III differs from Form I and Form II in molecular conformation and hydrogen bonding motifs in crystal lattice. Nucleation from RTV supercooled liquid is slow, and selected Form III exclusively. The discovery of RTV Form III demonstrates the importance of crystal nucleation studies. Crystallization from supercooled liquids should be incorporated as part of polymorph screening workflow.