Improving solubility by crystallographic disorder: Enabling Peposertib first-in-human trials

Area of Science:

• Pharmaceutical Sciences
• Solid-State Chemistry
• Drug Development

Background:

• Peposertib, a DNA-dependent protein kinase inhibitor for advanced solid tumors, presents low solubility due to multi-parameter optimization.
• The active pharmaceutical ingredient (API) is classified as Biopharmaceutical Classification System (BCS) Class II and Developability Classification System (DCS) Class IIb.
• Accelerated clinical development required an innovative approach to overcome solubility challenges.

Purpose of the Study:

• To discover and characterize novel solid-state forms of peposertib.
• To investigate the impact of crystallographic disorder on the in vitro performance and stability of peposertib.
• To develop a scalable manufacturing process for a disordered solid-state form to facilitate early clinical trials.

Main Methods:

• Polymorphic screening to identify different solid-state forms.
• Crystallographic analysis to characterize the disordered structure (A2D) and stable form (A2).
• Microstrain analysis and thermal analysis for material characterization and quality control.
• Process development for robust manufacturing at scale.

Main Results:

• A crystallographically disordered solid-state form (A2D) was discovered with significantly enhanced in vitro performance compared to the stable form (A2).
• The disorder along a crystallographic axis reduced lattice energy, leading to higher solubility while maintaining high chemical and physical stability.
• A robust manufacturing process was developed, addressing variability in the degree of disorder and enabling scale-up.
• Microstrain and thermal analyses provided reliable methods for characterizing the disordered material.

Conclusions:

• The discovered crystallographically disordered form (A2D) of peposertib offers a viable strategy to enhance solubility and accelerate drug development.
• This metastable form demonstrates excellent stability, unlike typical amorphous materials, making it suitable for clinical use.
• The successful utilization of this disordered phase enabled fast-track entry into first-in-human clinical trials, showcasing a novel approach in pharmaceutical development.