title: Cocrystal formation during cogrinding and storage is mediated by amorphous phase.
abstract: OBJECTIVE
  The purpose of this work was to investigate the mechanisms of cocrystal formation during cogrinding and storage of solid reactants, and to establish the effects of water by cogrinding with hydrated form of reactants and varying RH conditions during storage.
  
  
  METHODS
  The hydrogen bonded 1:1 carbamazepine-saccharin cocrystal (CBZ-SAC) was used as a model compound. Cogrinding of solid reactants was studied under ambient and cryogenic conditions. The anhydrous, CBZ (III), and dihydrate forms of CBZ were studied. Coground samples were stored at room temperature at 0% and 75% RH. Samples were analyzed by XRPD, FTIR and DSC.
  
  
  RESULTS
  Cocrystals prepared by cogrinding and during storage were similar to those prepared by solvent methods. The rate of cocrystallization was increased by cogrinding the hydrated form of CBZ and by increasing RH during storage. Cryogenic cogrinding led to higher levels of amorphization than room temperature cogrinding. The amorphous phase exhibited a T (g) around 41 degrees C and transformed to cocrystal during storage.
  
  
  CONCLUSIONS
  Amorphous phases generated by pharmaceutical processes lead to cocrystal formation under conditions where there is increased molecular mobility and complementarity. Water, a potent plasticizer, enhances the rate of cocrystallization. This has powerful implications to control process induced transformations.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Adivaraha
authors.initials: A
authors.lastname: Jayasankar
authors.forename: Anongnat
authors.initials: A
authors.lastname: Somwangthanaroj
authors.forename: Zezhi J
authors.initials: ZJ
authors.lastname: Shao
authors.forename: Naír
authors.initials: N
authors.lastname: Rodríguez-Hornedo
mesh_terms: D002152:Calorimetry, Differential Scanning; D002220:Carbamazepine / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004339:Drug Compounding; D012439:Saccharin / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D014867:Water; D014961:X-Ray Diffraction
chemical_list: D014867:Water; D002220:Carbamazepine; D012439:Saccharin