"Predicting" Polymorphs of Pharmaceuticals Using Hydrogen Bond Propensities: Probenecid and Its Two...

Area of Science:

• Crystallography
• Materials Science
• Pharmaceutical Science

Background:

• Polymorphism is crucial in pharmaceuticals, affecting drug stability and bioavailability.
• Predicting polymorphs aids in drug development and intellectual property protection.
• The Cambridge Structural Database (CSD) software package (Mercury) offers tools for crystal structure analysis.

Purpose of the Study:

• To evaluate the predictive capability of a new hydrogen-bonding propensity tool for identifying potential polymorphs.
• To investigate the polymorphic behavior of selected pharmaceutically relevant compounds.
• To characterize novel crystal forms and their transformations.

Main Methods:

• Hydrogen-bonding propensity analysis using Mercury software on ~60 compounds.
• Experimental crystal form screening for compounds with high polymorphism probability.
• Differential scanning calorimetry (DSC) and single-crystal X-ray diffraction (SCXRD) for characterization.

Main Results:

• The hydrogen-bonding propensity tool identified compounds with potential for polymorphism.
• Probenecid, initially resistant to crystallization screening, revealed three polymorphs via DSC.
• These probenecid polymorphs exhibit identical hydrogen bonding and undergo reversible single-crystal-to-single-crystal transformations.

Conclusions:

• The hydrogen-bonding propensity tool shows promise for predicting polymorphism.
• Calorimetry and SCXRD are essential for uncovering complex polymorphic behaviors, especially when crystallization fails.
• Understanding reversible transformations is key for controlling solid-state properties.