Role of Agglomeration in the Dispersion of Salmeterol Xinafoate from Mixtures for Inhalation with Differing Drug to Fine Lactose Ratios HANDOKO ADI, 1 IAN LARSON, 2 HERBERT CHIOU, 1 PAUL YOUNG, 1 DANIELA TRAINI, 1 PETER STEWART 2 1 Advanced Drug Delivery Group, Faculty of Pharmacy (A15), University of Sydney, Sydney, NSW 2006, Australia 2 Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia Received 31 May 2007; revised 6 August 2007; accepted 13 September 2007 Published online 19 November 2007 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21228 ABSTRACT: The purpose of this study was to characterise the role of agglomeration on salmeterol xinafoate (SX) dispersion from mixtures for inhalation by varying the SX concentration and the proportion of fine lactose (FL). SX concentrations and SX:FL ratios ranged from 1.0% to 5.0% (w/w) and from 1:0 to 1:8, respectively. The in vitro deposition of SX was measured using a twin stage impinger (TSI). The aerosol was characterized by particulate capture in the TSI stages and subsequent imaging by scanning electron microscopy and by real-time particle sizing. The presence of coarse lactose reduced SX dispersion compared with SX alone, and the dispersion was independent of SX concentration. SX dispersion in binary mixtures of SX and FL was independent of SX:FL ratio and was similar to that of carrier-based mixtures with high particulate loads. Increased concentrations of SX and proportions of FL in carrier-based mixtures resulted in increased SX dispersion. Agglomerate formation coincided with increased dispersion. The study demonstrated that agglomeration is one of the important factors in SX dispersion from carrier-based mixtures at high particulate loads. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:3140–3152, 2008 Keywords: agglomeration; fine lactose; salmeterol xinafoate; dry powder inhalation; interactive mixture; drug dispersion; DPI INTRODUCTION Dry powder inhalation (DPI) mixtures are nor- mally formulated either as mixtures of micronised drug particles blended with coarse carrier parti- cles or as fine drug agglomerates. On inhalation, the drug particles must be dissociated from the carrier or from the agglomerate and dispersed into the air stream to enable transfer of airborne particles into the lung. Drug particles are normally formulated in low concentrations, with a drug to carrier ratio of 1:67.5 (1.46%, w/w) being typical. 1–3 Drug-carrier blends have been shown to be usually more readily fluidised and de-agglomerated during inhalation than pure drug. 4 Micronised drugs are highly interactive and are likely to adhere to lactose carriers. The extent of particle adhesion has been shown to be dependent on the number of interacting particles. 5 When the number of adherent particles is less than or equal to that required for a monolayer, particle detachment is less likely Correspondence to: Peter Stewart (Telephone: 61-3-9903- 9517; Fax: 61-3-9903-9583; E-mail: peter.stewart@vcp.monash.edu.au) Journal of Pharmaceutical Sciences, Vol. 97, 3140–3152 (2008) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association 3140 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 8, AUGUST 2008