title: Mixing time effects on the dispersion performance of adhesive mixtures for inhalation.
abstract: This paper deals with the effects of mixing time on the homogeneity and dispersion performance of adhesive mixtures for inhalation. Interactions between these effects and the carrier size fraction, the type of drug and the inhalation flow rate were studied. Furthermore, it was examined whether or not changes in the dispersion performance as a result of prolonged mixing can be explained with a balance of three processes that occur during mixing, knowing drug redistribution over the lactose carrier; (de-) agglomeration of the drug (and fine lactose) particles; and compression of the drug particles onto the carrier surface. For this purpose, mixtures containing salmeterol xinafoate or fluticasone propionate were mixed for different periods of time with a fine or coarse crystalline lactose carrier in a Turbula mixer. Drug detachment experiments were performed using a classifier based inhaler at different flow rates. Scanning electron microscopy and laser diffraction techniques were used to measure drug distribution and agglomeration, whereas changes in the apparent solubility were measured as a means to monitor the degree of mechanical stress imparted on the drug particles. No clear trend between mixing time and content uniformity was observed. Quantitative and qualitative interactions between the effect of mixing time on drug detachment and the type of drug, the carrier size fraction and the flow rate were measured, which could be explained with the three processes mentioned. Generally, prolonged mixing caused drug detachment to decrease, with the strongest decline occurring in the first 120 minutes of mixing. For the most cohesive drug (salmeterol) and the coarse carrier, agglomerate formation seemed to dominate the overall effect of mixing time at a low inhalation flow rate, causing drug detachment to increase with prolonged mixing. The optimal mixing time will thus depend on the formulation purpose and the choice for other, interacting variables.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands. F.Grasmeijer@rug.nl
authors.forename: Floris
authors.initials: F
authors.lastname: Grasmeijer
authors.forename: Paul
authors.initials: P
authors.lastname: Hagedoorn
authors.forename: Henderik W
authors.initials: HW
authors.lastname: Frijlink
authors.forename: H Anne
authors.initials: HA
authors.lastname: de Boer
mesh_terms: D000280:Administration, Inhalation; D000420:Albuterol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D000730:Androstadienes / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004337:Drug Carriers / Q000737:chemistry; D000068298:Fluticasone; D007785:Lactose / Q000737:chemistry*; D007834:Lasers; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D000068299:Salmeterol Xinafoate; D012995:Solubility; D013997:Time Factors; D014961:X-Ray Diffraction
chemical_list: D000730:Androstadienes; D004337:Drug Carriers; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D007785:Lactose; D000420:Albuterol