title: 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.affiliation: Pharmaceutical Analytical and Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhang Jiang High-Tech Park, Shanghai 201203, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Pharmaceutical Analytical and Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhang Jiang High-Tech Park, Shanghai 201203, China.
authors.forename: Linglei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Pharmaceutical Analytical and Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhang Jiang High-Tech Park, Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Pharmaceutical Analytical and Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhang Jiang High-Tech Park, Shanghai 201203, China.
authors.forename: Jian-Rong
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Pharmaceutical Analytical and Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhang Jiang High-Tech Park, Shanghai 201203, China. Electronic address: xuefengmei@simm.ac.cn.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Mei
mesh_terms: D002152:Calorimetry, Differential Scanning; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000592:standards; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D018360:Crystallography, X-Ray; D004349:Drug Packaging; D004355:Drug Stability; D004356:Drug Storage; D008859:Microscopy, Polarization; D015394:Molecular Structure; D010725:Phosphocreatine / Q000737:chemistry* / Q000592:standards; D033362:Powder Diffraction; D011312:Pressure; D011786:Quality Control; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D013678:Technology, Pharmaceutical / Q000379:methods; D013696:Temperature; D013818:Thermogravimetry; D014867:Water / Q000737:chemistry*
chemical_list: D002316:Cardiotonic Agents; D010725:Phosphocreatine; D014867:Water
keywords: creatine phosphate sodium; crystal structure; form transformation; hydrates; physical characterization; stability