High-throughput polymorph screening of active pharmaceutical ingredients

Importance of the Topic

Polymorphism in active pharmaceutical ingredients (APIs) strongly influences their solubility, bioavailability and stability. Early identification of all possible crystalline forms is critical for safe and effective drug development, regulatory compliance and patent protection. Automated high-throughput screening accelerates this exploration while conserving precious material.

Objectives and Study Overview

This study aimed to evaluate an automated platform for systematic polymorph screening of an API under four crystallization methods (slurry, evaporation, cooling, anti-solvent precipitation). A library of 384 unique solvent combinations was designed to maximize chemical diversity. Key goals were rapid discovery of new forms, efficient data management and minimal compound consumption.

Methodology and Used Instrumentation

• Big Kahuna system with universal crystallization assembly for parallel processing of 96-well plates
• Powdernium solid dispenser for precise addition of API powder
• Single-tip liquid dispenser and positive-displacement pipette for solvent handling
• Library Studio and Automation Studio (LEA software suite) for solvent library design and instrument control
• PolyView and Spectra Studio for data storage, search and multivariate analysis
• Analytical techniques:

• Birefringence imaging (Zeiss AxioVert 200M microscope)
• Powder X-ray diffraction (Bruker D8 Discover with GADDS)
• Raman spectroscopy (Horiba spectrometer)
• HPLC for solubility and degradation screening

Main Results and Discussion

Statistical clustering of PXRD and Raman patterns identified wells containing known forms, amorphous material or potential new polymorphs. Four wells in the slurry experiment, three in evaporation and one in cooling were flagged by both techniques. Scale-up (50 mg API) and additional characterization (DSC, TGA, DVS) confirmed a series of new solvates and one metastable free-base form. The automated workflow ensured reproducibility and rapid data acquisition.

Benefits and Practical Applications

• Screening of 384 conditions in under five days by a single operator
• Total API consumption below one gram
• Integrated data capture, analysis and reporting in a common database
• Enhanced risk mitigation through early identification of polymorphic diversity
• Reduced manual handling and higher throughput compared to traditional methods

Future Trends and Potential Uses

Integration of machine-learning models for predictive crystallization and real-time experimental design optimization will further accelerate polymorph discovery. Miniaturization of assays and in situ process analytical technology (PAT) tools will enable even faster, more resource-efficient screens. Expansion to cocrystal, salt and solvate libraries and continuous flow crystallization could broaden applicability.

Conclusion

The Big Kahuna system configured for preformulation offers a robust end-to-end solution for high-throughput polymorph screening. By combining automated dispensing, diverse crystallization methods and advanced analytics, it enables rapid, material-efficient exploration of API solid-state landscapes.

Reference

Unchained Labs Application Note: High-Throughput Polymorph Screening of Active Pharmaceutical Ingredients (2019)