title: Assessment of the influence factors on in vitro testing of nasal sprays using Box-Behnken experimental design.
abstract: The purpose of the research was to investigate the influences of actuation parameters and formulation physical properties on nasal spray delivery performance using design of experiment (DOE) methodology. A 3-level, 4-factor Box-Behnken design with a total of 27 experimental runs was used in this study. Nine simulated aqueous formulations with different viscosities and surface tensions were prepared using carboxymethylcellulose sodium (CMC, gelling agent) and Tween80 (surfactant) each at three concentration levels. Four factors, actuation stroke length, actuation velocity, concentration of gelling agent, and concentration of surfactant were investigated for their influences on measured responses of shot weight, spray pattern, plume geometry and droplet size distribution (DSD). The models based on data from the DOE were then optimized by eliminating insignificant terms. Pfeiffer nasal spray pump units filled with the simulated formulations were used in the study. Nasal pump actuation stroke length exerts a strong, independent influence on shot weight, and also slightly affects spray pattern and plume geometry. Actuation velocity and concentration of gelling agent have significant effects on spray pattern, plume geometry and DSD, in a complicated manner through interaction terms. Concentration of surfactant has little, if any, influence on nasal spray characteristics. Results were fitted to quadratic models describing the inherent relationships between the four factors evaluated and nasal spray performance. The DOE study helped us to identify the source of variability in nasal spray product performance, and obtained better understanding in how to control the variability. Moreover, the quadratic models developed from the DOE study quantitatively describe the inherent relationships between the factors and nasal spray performance characteristics. With the assistance of the response surfaces developed from the DOE model, the time and labor in designing a nasal spray product to achieve desired product performance characteristics can be reduced.
authors.affiliation: Division of Pharmaceutical Analysis, U.S. Food and Drug Administration, 1114 Market Street, Room 1002, St. Louis, MO 63101, United States. changning.guo@fda.hhs.gov
authors.forename: Changning
authors.initials: C
authors.lastname: Guo
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Stine
authors.forename: John F
authors.initials: JF
authors.lastname: Kauffman
authors.forename: William H
authors.initials: WH
authors.lastname: Doub
mesh_terms: D000281:Administration, Intranasal; D000336:Aerosols; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry; D015233:Models, Statistical; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011136:Polysorbates / Q000737:chemistry; D012044:Regression Analysis; D012107:Research Design; D012984:Software; D013500:Surface Tension; D013501:Surface-Active Agents / Q000737:chemistry; D014783:Viscosity
chemical_list: D000336:Aerosols; D005079:Excipients; D011136:Polysorbates; D013501:Surface-Active Agents; D002266:Carboxymethylcellulose Sodium