Ritonavir Form III: A New Polymorph After 24 Years

Area of Science:

• Pharmaceutical Science
• Solid-State Chemistry
• Crystallization Engineering

Background:

• Polymorphism is prevalent in pharmaceutical solids and requires thorough investigation during drug product development.
• Ritonavir (RTV) is an established antiviral medication with known polymorphic forms.

Purpose of the Study:

• To report the discovery and characterization of a new ritonavir (RTV) polymorph, designated Form III.
• To investigate the crystallization behavior of RTV from supercooled liquids.

Main Methods:

• Melt crystallization was employed to induce the formation of new RTV polymorphs.
• Powder X-ray Diffraction (PXRD) and Raman spectroscopy were used for characterization.
• Thermal analysis (melting point, heat of fusion) was performed.

Main Results:

• A novel RTV polymorph, Form III, was successfully synthesized via melt crystallization.
• Form III exhibits distinct PXRD patterns and Raman spectra compared to Forms I and II.
• Form III is the least thermodynamically stable form, exhibiting monotropic behavior.
• Unique molecular conformations and hydrogen bonding motifs characterize Form III.
• Nucleation from RTV supercooled liquid is slow, selectively yielding Form III.

Conclusions:

• The discovery of RTV Form III underscores the significance of crystal nucleation studies in polymorph screening.
• Crystallization from supercooled liquids is a valuable technique that should be integrated into polymorph screening workflows.
• Understanding and controlling polymorphism is critical for ensuring the efficacy and safety of pharmaceutical products.