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

Abstract

Creatine phosphate sodium (CPS) salt is a first-line cardiovascular drug for severe diastolic heart failure. The drug exists in different hydrate forms. The marketed drug form was determined as CPS·4.5H2 O (H1); however, the reference standard was supplied as CPS·6H2 O (H2). In this work, we present two newly identified hydrate forms: a thermodynamically stable low hydrate form, CPS·1.5H2 O (H3), and a pressure-sensitive transit form, CPS·7H2 O (H4). The hydrate forms were discovered through a comprehensive solid-state screening experiment and fully characterized using a range of analytical techniques including X-ray powder diffraction (XRPD), FTIR, Raman spectroscopy, hot-stage microscopy (HSM), thermogravimetric analysis, and differential scanning calorimetry. Stability tests revealed that H3 was the most stable hydrate under thermal stimulation. H4 is a pressure-sensitive hydrate and easily transforms to H2 and then H1 upon grinding. The form transformation process was closely monitored using the HSM, variable-temperature XRPD (VT-XRPD), and VT-Raman spectroscopy techniques. Specifically, the transformation of H4 to H1 is characterized in a single-crystal-to-single-crystal transformation process. The newly discovered hydrate form H3 has superior physicochemical properties than the marketed forms and is worthy of further development.

• Authors: Yun Xu, Linglei Jiang, Ying Huang, Jian-Rong Wang, Xuefeng Mei
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 103 Issue 11 Pg. 3688-3695 (Nov 2014) ISSN: 1520-6017 [Electronic] United States
• PMID: 25223726 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Chemical References

• Cardiotonic Agents
• Phosphocreatine
• Water

Topics

• Calorimetry, Differential Scanning
• Cardiotonic Agents (chemistry, standards)
• Chemistry, Pharmaceutical
• Crystallization
• Crystallography, X-Ray
• Drug Packaging
• Drug Stability
• Drug Storage
• Microscopy, Polarization
• Molecular Structure
• Phosphocreatine (chemistry, standards)
• Powder Diffraction
• Pressure
• Quality Control
• Spectroscopy, Fourier Transform Infrared
• Spectrum Analysis, Raman
• Technology, Pharmaceutical (methods)
• Temperature
• Thermogravimetry
• Water (chemistry)