title: Characterization of Supersaturated Danazol Solutions - Impact of Polymers on Solution Properties and Phase Transitions.
abstract: OBJECTIVE
  Excipients are essential for solubility enhancing formulations. Hence it is important to understand how additives impact key solution properties, particularly when supersaturated solutions are generated by dissolution of the solubility enhancing formulation. Herein, the impact of different concentrations of dissolved polymers on the thermodynamic and kinetic properties of supersaturated solutions of danazol were investigated.
  
  
  METHODS
  A variety of experimental techniques was used, including nanoparticle tracking analysis, fluorescence and ultraviolet spectroscopy and flux measurements to characterize the solution phase behavior.
  
  
  RESULTS
  Neither the crystalline nor amorphous solubility of danazol was impacted by common amorphous solid dispersion polymers, polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC) or HPMC-acetate succinate. Consequently, the maximum membrane transport rate was limited only by the amorphous solubility, and not by the presence of the polymers. The polymers were able to inhibit crystallization to some extent at concentrations as low as 1 μg/mL, with the maximum effectiveness being reached at 10 μg/mL. Aqueous danazol solutions formed a drug-rich phase with a mean size of 250 nm when the concentration exceeded the amorphous solubility, and the polymers modified the surface properties of this drug-rich phase.
  
  
  CONCLUSIONS
  The phase behavior of supersaturated solutions is complex and the kinetics of phase transformations can be substantially modified by polymeric additives present at low concentrations. However, fortunately, these additives do not appear to impact the bulk thermodynamic properties of the solution, thus enabling supersaturated solutions, which provide enhanced membrane transport relative to saturated solutions to be generated.
authors.affiliation: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Dr, West Lafayette, Indiana, 47907, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Jackson
authors.affiliation: Bristol-Myers Squibb Company, New Brunswick, New Jersey, 08903, USA.
authors.forename: Umesh S
authors.initials: US
authors.lastname: Kestur
authors.affiliation: Bristol-Myers Squibb Company, New Brunswick, New Jersey, 08903, USA.
authors.forename: Munir A
authors.initials: MA
authors.lastname: Hussain
authors.affiliation: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Dr, West Lafayette, Indiana, 47907, USA. lstaylor@purdue.edu.
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
mesh_terms: D003460:Crystallization; D003613:Danazol / Q000737:chemistry*; D004965:Estrogen Antagonists / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry*; D065347:Hypromellose Derivatives / Q000737:chemistry; D007700:Kinetics; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D010316:Particle Size; D044367:Phase Transition; D011205:Povidone / Q000737:chemistry; D012995:Solubility; D012996:Solutions / Q000737:chemistry
chemical_list: D004965:Estrogen Antagonists; D005079:Excipients; D012996:Solutions; D065347:Hypromellose Derivatives; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; D011205:Povidone; D003613:Danazol
keywords: crystallization; liquid liquid phase separation; membrane transport; supersaturation