title: Rapid insight into heating-induced phase transformations in the solid state of the calcium salt of atorvastatin using multivariate data analysis.
abstract: OBJECTIVE
  To investigate the heating-induced dehydration and melting behavior of the trihydrate phase of the calcium salt of atorvastatin.
  
  
  METHODS
  Multivariate curve resolution (MCR) was used to decompose a variable-temperature synchrotron X-ray powder diffraction (VT-XRPD) data matrix into diffraction patterns and concentration profiles of pure drug phases.
  
  
  RESULTS
  By means of the MCR-estimated diffraction patterns and concentration profiles, the trihydrate phase of the drug salt was found to dehydrate sequentially into two partially dehydrated hydrate structures upon heating from 25 to 110°C, with no associated breakage of the original crystal lattice. During heating from 110 to 140°C, the remaining water was lost from the solid drug salt, which instantly collapsed into a liquid crystalline phase. An isotropic melt was formed above 155°C. Thermogravimetric analysis, hot-stage polarized light microscopy, and hot-stage Raman spectroscopy combined with principal component analysis (PCA) was shown to provide consistent results.
  
  
  CONCLUSIONS
  This study demonstrates that MCR combined with VT-XRPD is a powerful tool for rapid interpretation of complex dehydration behavior of drug hydrates, and it is also the first report on a liquid crystalline phase of the calcium salt of atorvastatin.
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels Peter Aae
authors.initials: NP
authors.lastname: Christensen
authors.forename: Bernard
authors.initials: B
authors.lastname: Van Eerdenbrugh
authors.forename: Kaho
authors.initials: K
authors.lastname: Kwok
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Bond
authors.forename: Thomas
authors.initials: T
authors.lastname: Rades
authors.forename: Jukka
authors.initials: J
authors.lastname: Rantanen
authors.forename: Claus
authors.initials: C
authors.lastname: Cornett
mesh_terms: D000924:Anticholesteremic Agents / Q000737:chemistry*; D000069059:Atorvastatin; D002152:Calorimetry, Differential Scanning; D005615:Freezing; D006361:Heating; D006538:Heptanoic Acids / Q000737:chemistry*; D015999:Multivariate Analysis; D044367:Phase Transition; D033362:Powder Diffraction; D011758:Pyrroles / Q000737:chemistry*; D013059:Spectrum Analysis, Raman; D013818:Thermogravimetry; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D011758:Pyrroles; D014867:Water; D000069059:Atorvastatin