title: Effect of ball milling on the physicochemical properties of atorvastatin calcium sesquihydrate: the dissolution kinetic behaviours of milled amorphous solids.
abstract: OBJECTIVE
  The purposes of this study were to clarify the amorphization by ball milling of atorvastatin calcium sesquihydrate (AT) and to analyse the change in dissolution kinetics.
  
  
  METHODS
  The amorphous AT was prepared from crystal AT by ball milling and analysed in terms of the changes of its physicochemical properties by powder X-ray diffraction analysis (XRD), thermal analysis and infrared spectroscopy (IR). Moreover, to evaluate the usefulness of the amorphous form for pharmaceutical development, intrinsic solubility of the ground product was evaluated using a dissolution kinetic method.
  
  
  RESULTS
  The XRD results indicated that crystalline AT was transformed into amorphous solids by more than 30-min milling. The thermal analysis result suggested that chemical potential of the ground AT are changed significantly by milling. The IR spectra of the AT showed the band shift from the amide group at 3406 cm-1with an intermolecular hydrogen bond to a free amide group at 3365 cm-1by milling. The dissolution of amorphous AT follows a dissolution kinetic model involving phase transformation.
  
  
  CONCLUSIONS
  The initial dissolution rate of the ground product increased with the increase in milling time to reflect the increase in the intrinsic solubility based on the amorphous state.
authors: Faculty of Pharmacy, Musashino University, Nishi-Tokyo, Japan.
authors: Makiko
authors: M
authors: Kobayashi
authors: Research Institute of Pharmaceutical Sciences, Musashino University, Nishi-Tokyo, Japan.
authors: Yusuke
authors: Y
authors: Hattori
authors: Research Institute of Electronics, Shizuoka University, Hamamatsu, Japan.
authors: Tetsuo
authors: T
authors: Sasaki
authors: Research Institute of Pharmaceutical Sciences, Musashino University, Nishi-Tokyo, Japan.
authors: Makoto
authors: M
authors: Otsuka
mesh_terms: D000069059:Atorvastatin / Q000008:administration & dosage / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004355:Drug Stability; D007700:Kinetics; D011208:Powders; D012995:Solubility
chemical_list: D011208:Powders; D000069059:Atorvastatin
keywords: amorphization; atorvastatin calcium sesquihydrate; dissolution kinetics involving phase transformation; during milling; physicochemical properties