Complementing high-throughput X-ray powder diffraction data with quantum-chemical calculations: Application to...

Area of Science:

• Crystallography and Materials Science
• Computational Chemistry and Drug Discovery

Background:

• High-throughput screening is crucial for pre-formulation, but determining crystal structures of new solid phases is often a bottleneck.
• Traditional methods require producing single crystals or bulk samples for X-ray diffraction, which is time-consuming and not always feasible.

Purpose of the Study:

• To develop a more efficient method for crystal structure determination directly from high-throughput X-ray powder diffraction (XRPD) data.
• To integrate quantum-chemical calculations with experimental XRPD data for robust structural analysis.

Main Methods:

• Utilized dispersion-corrected density functional theory (DFT-D) quantum-chemical calculations.
• Applied these calculations to complement high-throughput XRPD data.
• Determined the crystal structure of piroxicam form III as a case study.

Main Results:

• Demonstrated the feasibility of using DFT-D calculations for small organic molecules, including active pharmaceutical ingredients.
• Successfully determined the crystal structure of piroxicam form III by combining experimental XRPD and computational methods.
• Showcased the synergy between high-throughput experimental screening and quantum-chemical modeling.

Conclusions:

• The combined experimental and quantum-chemical approach provides reliable structural information efficiently.
• This method is valuable for intensive solid-form screening and for analyzing polymorphs obtained via high-energy processing (e.g., spray drying, milling).
• Enables structural determination when single crystals are not viable.