Solid-state characterization and transformation of various creatine phosphate sodium hydrates

Area of Science:

• Pharmaceutical Sciences
• Solid-State Chemistry
• Materials Science

Background:

• Creatine phosphate sodium (CPS) salt is a key cardiovascular drug for diastolic heart failure.
• The drug exhibits various hydrate forms, with marketed (H1) and reference (H2) forms previously identified.
• Understanding hydrate polymorphism is crucial for drug stability and efficacy.

Purpose of the Study:

• To discover and characterize novel hydrate forms of creatine phosphate sodium (CPS).
• To evaluate the stability and transformation behaviors of identified CPS hydrate forms.
• To assess the potential of newly discovered forms for pharmaceutical development.

Main Methods:

• Comprehensive solid-state screening for hydrate discovery.
• Characterization using X-ray powder diffraction (XRPD), FTIR, Raman spectroscopy, hot-stage microscopy (HSM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC).
• Stability testing and monitoring of form transformations using HSM, variable-temperature XRPD (VT-XRPD), and VT-Raman spectroscopy.

Main Results:

• Two new hydrate forms identified: CPS·1.5H2O (H3, stable low hydrate) and CPS·7H2O (H4, pressure-sensitive transit form).
• H3 demonstrated superior thermodynamic stability under thermal stress compared to known forms.
• H4 readily transformed to H2 and then H1 upon grinding, with H4 to H1 transformation observed as a single-crystal-to-single-crystal process.

Conclusions:

• The study identified novel hydrate forms of creatine phosphate sodium, expanding the understanding of its solid-state properties.
• The stable low hydrate form (H3) exhibits promising physicochemical properties, suggesting its potential for pharmaceutical applications.
• Further development of the H3 hydrate form is warranted for potential use in treating severe diastolic heart failure.