Published Mar 10, 2026

In the world of drug development, PROTACs (Proteolysis Targeting Chimeras) are notoriously difficult to crystallize. Their high molecular weight, inherent flexibility, and complex surface area often leave traditional screening methods coming up empty. However, recent research combined with industry expertise proves that the right screening strategy can fundamentally change the equation.

The Benchmark: An 11-Month Journey to a Single Crystal

A recent JACS paper—"Crystallizing the Uncrystallizable: Insights from Extensive Screening of PROTACs" (Screen et al., 2025)—provides a sobering look at these challenges. A collaborative team from Durham University, AstraZeneca, the University of Southampton, and Newcastle University conducted an exhaustive study on a PROTAC molecule designated "AZ1."

The scale of the effort was immense:

• Over 1,800 crystallization experiments were performed.

• Only two crystal structures were ultimately solved.

• One specific crystal required 11 months to grow.

• The study revealed that AZ1's packing is governed by weak dispersive forces, explaining its exceptionally stubborn crystallization behavior.

Technical Insight: Dissolution vs. Amorphous Stability

The JACS study also noted a 4-fold difference in apparent dissolution behavior between two amorphous forms of AZ1 prepared by different methods, despite them having nearly identical $T_g$ (glass transition temperature) values.

At Crystal Pharmatech, we observe that such discrepancies often reflect differential recrystallization kinetics during the dissolution process rather than fundamentally distinct amorphous-state properties. Resolving this distinction typically requires precise equilibrium solubility measurements to ensure the long-term stability of the formulation.

The Crystal Pharmatech Advantage: Overcoming the Odds

Recognizing these inherent hurdles, Crystal Pharmatech has developed proprietary technologies and tiered workflows designed specifically for complex modalities like PROTACs.

Proven Success Rates

Across more than 15 client PROTAC programs (with molecular weights ranging from 700 to 1,100 Da), our platform has delivered:

• An overall crystallization success rate above 80%.

• A 100% success rate for molecules under 1,000 Da.

This track record is built on property-guided experimental design and deep solid-state expertise that generic, high-throughput "scattergun" approaches simply cannot replicate.

Comprehensive Characterization Toolkit

Once crystals are obtained, we utilize the same high-end structural tools highlighted in the JACS study to ensure full optimization:

• Single Crystal XRD (SC-XRD)

• Synchrotron X-ray Crystallography

• MicroED (Electron Diffraction)

Case Studies: Turning Theory into Crystalline Reality

Our specialized protocols have consistently moved projects from amorphous starting materials into stable, developable crystalline forms:

• Weak Acid PROTAC: Starting with an amorphous material, we identified a stable      crystalline free acid through rigorous polymorph screening and successfully scaled the process with improved crystallinity.

• Weak Base PROTAC: Salt screening yielded 12 crystalline hits, ultimately leading to a maleate salt with superior solubility and solid-state stability compared to the parent molecule.

Conclusion

PROTAC solid-form development demands more than just standard screening; it requires a specialized, property-driven approach. If your pipeline is facing crystallization bottlenecks, we welcome the opportunity to discuss how our platform can accelerate your path to the clinic.

Reference:

Screen et al., "Crystallizing the Uncrystallizable: Insights from Extensive Screening of PROTACs," J. Am. Chem. Soc. 2025, 147, 28056–28072.