title: Spray granulation: importance of process parameters on in vitro and in vivo behavior of dried nanosuspensions.
abstract: The use of fluid bed granulation for drying of pharmaceutical nanoparticulates on micron-sized granule substrates is a relatively new technique, with limited understanding in the current literature of the effects of process parameters on the physical properties of the dried nanoparticle powders. This work evaluated the effects of spray mode, spray rate and atomizing pressure for spray granulation of drug nanosuspensions through a systematic study. Naproxen and a proprietary Novartis compound were converted into nanosuspensions through wet media milling and dried onto a mannitol based substrate using spray granulation. For naproxen, various physical properties of the granules, as well as the in vitro re-dispersion and dissolution characteristics of the nano-crystals, were measured. It was found that the spray mode had the most drastic effect, where top spray yielded smaller re-dispersed particle sizes and faster release rates of drug from granules than bottom spray. This was attributed to the co-current spraying in bottom spray resulting in denser, homogenous films on the substrate. Similar in vitro results were obtained for the proprietary molecule, Compound A. In vivo studies in beagle dogs with Compound A showed no significant difference between the liquid and the dried forms of the nanosuspension in terms of overall AUC, differences were observed in the tmax which correlated with the rank ordering observed from the in vitro dissolution profiles. These findings make spray granulation amenable to the production of powders with desired processing and handling properties, without compromising the overall exposure of the compound under investigation.
authors.affiliation: Department of Chemical & Biological Engineering, Princeton University, Princeton, NJ, USA.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Figueroa
authors.forename: Sonali
authors.initials: S
authors.lastname: Bose
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003890:Desiccation; D004285:Dogs; D004355:Drug Stability; D008297:Male; D008353:Mannitol / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology; D009288:Naproxen / Q000737:chemistry*; D010316:Particle Size; D011208:Powders / Q000737:chemistry; D012995:Solubility; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods*; D014961:X-Ray Diffraction
chemical_list: D011208:Powders; D008353:Mannitol; D009288:Naproxen
keywords: ANOVA; Atomizing pressure; CMC; DOE; FRI; FaSSGF; Fluid bed granulation; HPC-EXF; Jenike flow function; LOD; Naproxen; PDI; SLS; Spray mode; Spray rate; Wet media milling; X-ray diffraction; XRD; analysis of variance; critical micelle concentration; design of experiment; fasted state simulated gastric fluid; ff(c); flow rate index; hydroxypropylcellulose-EXF grade; loss on drying; polydispersity index; sodium lauryl sulfate