title: Freeze drying optimization of polymeric nanoparticles for ocular flurbiprofen delivery: effect of protectant agents and critical process parameters on long-term stability.
abstract: BACKGROUND
  The stabilization of flurbiprofen loaded poly-ɛ-caprolactone nanoparticles (FB-PɛCL-NPs) for ocular delivery under accurate freeze-drying (FD) process provides the basis for a large-scale production and its commercial development.
  
  
  OBJECTIVE
  Optimization of the FD to improve long-term stability of ocular administration's FB-PɛCL-NPs.
  
  
  METHODS
  FB-PɛCL-NPs were prepared by solvent displacement method with poloxamer 188 (P188) as stabilizer. Freezing and primary drying (PD) were studied and optimized through freeze-thawing test and FD microscopy. Design of experiments was used to accurate secondary drying (SD) conditions and components concentration. Formulations were selected according to desired physicochemical properties. Furthermore, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to study interactions components.
  
  
  RESULTS
  Optimized FB-PɛCL-NPs, stabilized with 3.5% (w/w) P188 and protected with 8% (w/w) poly(ethylene glycol), was submitted to precooling at +10 °C for 1 h, freezing at -50 °C for 4 h, PD at +5 °C and 0.140 mbar for 24 h and a SD at +45 °C during 10 h. These conditions showed 188.4 ± 1.3 nm, 0.087 ± 0.014, 85.5 ± 1.4%, 0.61 ± 0.12%, -16.4 ± 0.1 mV and 325 ± 7 mOsm/kg of average size, polydispersity index, entrapment efficiency, residual moisture, surface charge and osmolality, respectively. It performed a long-term stability >12 months. DSC and XRD spectra confirmed adequate chemical interaction between formulation components and showed a semi-crystalline state after FD.
  
  
  CONCLUSIONS
  An optimal freeze dried ocular formulation was achieved. Evidently, the successful design of this promising colloidal system resulted from rational cooperation between a good formulation and the right conditions in the FD process.
authors.affiliation: a Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry , Universitat de Barcelona Facultat de Farmacia y Ciencias de la Alimentación , Barcelona , Spain.
authors.forename: Gladys Rosario
authors.initials: GR
authors.lastname: Ramos Yacasi
authors.affiliation: a Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry , Universitat de Barcelona Facultat de Farmacia y Ciencias de la Alimentación , Barcelona , Spain.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Calpena Campmany
authors.affiliation: a Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry , Universitat de Barcelona Facultat de Farmacia y Ciencias de la Alimentación , Barcelona , Spain.
authors.forename: María Antonia
authors.initials: MA
authors.lastname: Egea Gras
authors.affiliation: a Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry , Universitat de Barcelona Facultat de Farmacia y Ciencias de la Alimentación , Barcelona , Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Espina García
authors.affiliation: a Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry , Universitat de Barcelona Facultat de Farmacia y Ciencias de la Alimentación , Barcelona , Spain.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: García López
mesh_terms: D060433:Administration, Ophthalmic; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002208:Caproates / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003451:Cryoprotective Agents / Q000737:chemistry; D004355:Drug Stability; D005480:Flurbiprofen / Q000737:chemistry*; D005612:Freeze Drying / Q000379:methods; D007783:Lactones / Q000737:chemistry; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D002208:Caproates; D003451:Cryoprotective Agents; D007783:Lactones; D011108:Polymers; D020442:Poloxamer; D011092:Polyethylene Glycols; C121056:caprolactone; D005480:Flurbiprofen
keywords: Flurbiprofen; d-(+)-trehalose; design of experiments; freeze-drying optimization; nanoparticles; poly(ethylene glycol); poly-ɛ-caprolactone