The Cohesive-Adhesive Balances in Dry Powder Inhaler Formulations II: Influence on Fine Particle Delivery Characteristics Philippe Begat, 1 David A. V. Morton, 2 John N. Staniforth, 2 and Robert Price 1,3 Received February 20, 2004; accepted June 10, 2004 Purpose. To investigate the influence of the cohesive-adhesive bal- ances on dry powder formulation aerosolization and delivery charac- teristics. Methods. De-agglomeration properties of pharmaceutical powders were investigated using an Aerosizer at various shear forces. Aerosol drug deposition properties of drug-only formulations and carrier- based formulations were investigated using a low-resistance device (Rotahaler) and a high-resistance device (Turbuhaler) via a twin- stage impinger. Results. A paradoxical relationship between particle cohesive strength and de-agglomeration efficiencies of drug-only formulations was observed, where an increase in cohesive strength led to a higher fine particle fraction. A possible explanation for the variation in the fluidization and aerosolization properties between low and high co- hesive particles was modeled on the relationship between cohesion, metastable agglomerate size, and the resulting aerodynamic drag force acting on the fluidized agglomerates. The addition of a fine particle lactose carrier influenced the drug deposition patterns in different ways depending on the relative cohesive and adhesive force balances within the formulation. Conclusions. The use of the colloid Atomic Force Microscrope (AFM) technique in combination with the cohesive-adhesive balance (CAB) system provides a novel preformulation tool for investigating the likely behavior of a dry powder formulation and a possible means of interpreting the possible de-aggregation and dispersion mecha- nisms of carrier-based formulations. KEY WORDS: adhesion; cohesion; Atomic Force Microscope (AFM); DPI; drag force; particle. INTRODUCTION Dry powder inhaler (DPI) formulations are commonly prepared as a binary blend of a coarse carrier, typically -lac- tose monohydrate, and micronized drug (1). The homogene- ity of the blend and the de-aggregation and dispersion prop- erties of the respirable particles upon activation (driven by the patients inspirational energy) are, on a microscopic scale, governed by the resulting cohesive (drug-drug) and adhe- sive (drug-excipient) interaction forces within the formula- tion. Excessive adhesive forces may prevent elutriation of the respirable particles from the carrier surfaces, leading to upper airway deposition. Similarly, strong cohesive forces may enhance segregation and agglomerate formation, which could directly affect the fluidization and dispersion character- istics of the formulation (2,3). Numerous studies have in- vestigated the in vitro deposition characteristics of respir- able drug particles from carrier-based DPI formulations (4– 6). Many of these studies have indicated that the choice of inhaler device and inspiration flow rate is of crucially impor- tant in the fluidization and aerosol characteristics of a formu- lation (7–9). This suggests that the aerodynamic forces, gen- erated within the device, play a crucial role in powder aero- solization by overcoming the force balances within the formulation. In an attempt to modify and optimise particulate inter- actions within a DPI formulation, the majority of research and development has been focused on modifying the physical properties of the carrier, such as particle shape (10), size (1,11), rugosity, or surface passivation of high surface free energy sites by the addition of ternary agents (12,13). Al- though these alterations have been shown to directly influ- ence the de-aggregation and dispersion of active particles, their specific influences on drug-carrier and drug-drug inter- action forces have not yet been fully quantified. Recently, a novel Atomic Force Microscope (AFM)- based approach has been developed to evaluate the various interaction forces within a model carrier-based DPI formula- tion (14). This study has shown that upon maintaining a stable environment (temperature and relative humidity) and uni- form contact area of interaction, direct quantification of the cohesive-adhesive balances within a dry powder formulation is achievable. A predictive cohesive-adhesive balance (CAB) graph of binary and complex formulation systems can readily be generated. This process may subsequently be utilised as a rapid preformulation tool to ascertain the relative strength of the various interaction forces and possibly to predict the be- havior of DPI formulations. The aim of this study was to investigate the specific role of the cohesive and adhesive force balances via the AFM colloid probe technique on the de-agglomeration efficiencies and deposition characteristics of drug only and model drug- lactose formulations. MATERIALS AND METHODS Materials Micronized budesonide was supplied from Sicor (batch no.6157/MI, Santhia, Italy), micronized salbutamol sulfate from Becpharm Ltd (batch no. 940077, London, UK), and Sorbalac 400 lactose from Meggle (Wasserburg, Germany). All materials were used as supplied. Methanol and acetoni- trile were HPLC grade (Fisher Chemicals, Loughborough, UK). AnalaR grade ethanol and acetic glacial were supplied by BDH (Poole, UK). Water was produced by reverse osmo- sis (milliQ/milliRo; Millipore, Molsheim, France). Preparation of Powder Formulations Drug-lactose blends were prepared by geometrically mixing 1g of drug and 1 g of Lactochem lactose in 100-mg increments via a Whirlimixer (Fisons Scientific Apparatus, UK). The resulting blend was further mixed in a Turbula 1 Pharmaceutical Technology Research Group, Department of Phar- macy & Pharmacology, University of Bath, Bath BA2 7AY, United Kingdom. 2 Vectura Ltd., Chippenham, SN14 6FH, United Kingdom. 3 To whom correspondence should be addressed. (e-mail: r.price@ bath.ac.uk) Pharmaceutical Research, Vol. 21, No. 10, October 2004 (© 2004) Research Paper 1826 0724-8741/04/1000-1826/0 © 2004 Springer Science+Business Media, Inc.