Solid‐State Characterization and Transformation of Various Creatine Phosphate Sodium Hydrates

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·4.5H2O (H1); however, the reference standard was supplied as CPS·6H2O (H2). In this work, we present t...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2014-11, Vol.103 (11), p.3688-3695
Main Authors: Xu, Yun, Jiang, Linglei, Huang, Ying, Wang, Jian‐Rong, Mei, Xuefeng
Format: Article
Language:English
Subjects:
Calorimetry, Differential Scanning
Cardiotonic Agents - chemistry
Cardiotonic Agents - standards
Chemistry, Pharmaceutical
creatine phosphate sodium
crystal structure
Crystallization
Crystallography, X-Ray
Drug Packaging
Drug Stability
Drug Storage
form transformation
hydrates
Microscopy, Polarization
Molecular Structure
Phosphocreatine - chemistry
Phosphocreatine - standards
physical characterization
Powder Diffraction
Pressure
Quality Control
Spectroscopy, Fourier Transform Infrared
Spectrum Analysis, Raman
stability
Technology, Pharmaceutical - methods
Temperature
Thermogravimetry
Water - chemistry
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Summary: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·4.5H2O (H1); however, the reference standard was supplied as CPS·6H2O (H2). In this work, we present two newly identified hydrate forms: a thermodynamically stable low hydrate form, CPS·1.5H2O (H3), and a pressure‐sensitive transit form, CPS·7H2O (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. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3688–3695, 2014
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.24175