Predicting the ritonavir crisis by revisiting the polymorph landscape with crystal structure prediction and form 4...

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Computational Chemistry

Background:

• Crystal polymorphism in pharmaceuticals, exemplified by ritonavir, poses significant risks.
• Advancements in theoretical crystal structure prediction (CSP) model potential polymorphs and their stability.
• The experimental data for ritonavir polymorphs, particularly form 4, remains incomplete.

Purpose of the Study:

• To evaluate if in silico modeling could have predicted the ritonavir form 2 disaster.
• To assess the potential of CSP to identify severe risks associated with new polymorphs.
• To experimentally determine the crystal structure of ritonavir form 4 and its stability.

Main Methods:

• Utilized crystal structure prediction (CSP) to forecast ritonavir polymorphs and stability.
• Employed three-dimensional electron diffraction for crystal structure determination of form 4.
• Combined in silico modeling with experimental powder X-ray diffraction.

Main Results:

• CSP accurately predicted the existence of a more stable, then-undiscovered form 2 of ritonavir at room temperature.
• The predicted form 2 presented severe risks due to its structural characteristics and low formulation solubility tolerance.
• The crystal structure of form 4 was determined, revealing a disordered motif and thermodynamic instability.

Conclusions:

• In silico CSP could have identified the severe risks of ritonavir form 2, potentially averting the crisis.
• Experimental determination of form 4 confirmed its instability, completing the experimental landscape.
• CSP is a valuable tool for risk assessment in pharmaceutical development, guiding proactive interventions.