Ritonavir: an extraordinary example of conformational polymorphism.

Area of Science:

• Solid-state chemistry
• Crystallography
• Pharmaceutical science

Background:

• Norvir (ritonavir) semi-solid capsule supply was jeopardized by a new, less soluble crystal form.
• Understanding ritonavir's solid-state properties is critical for pharmaceutical manufacturing and drug efficacy.

Purpose of the Study:

• To characterize the two polymorphs of ritonavir.
• To elucidate the structures and hydrogen bonding networks of each crystal form.
• To investigate the cause of the sudden appearance of a less soluble polymorph.

Main Methods:

• Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy
• Near Infrared (NIR) Spectroscopy
• Powder X-ray Diffraction (PXRD)
• Single crystal X-ray diffraction
• Development of a sensitive seed detection test

Main Results:

• Detailed characterization and structure determination of ritonavir polymorphs.
• Identification of an unusual conformation in form II, leading to a robust hydrogen bonding network.
• Investigation into the heterogeneous nucleation mechanism of form II.

Conclusions:

• Ritonavir displays conformational polymorphism with two distinct crystal lattices possessing differing solubilities.
• Form II, with a "cis" conformation, represents a more stable packing but is difficult to nucleate.
• The sudden emergence of form II was attributed to a combination of high supersaturation and heterogeneous nucleation, likely by a degradation product.