Structural influence of cohesive mixtures of salbutamol sulphate and lactose on aerosolisation and de-agglomeration behaviour under dynamic conditions

Abstract

Purpose

The purpose of this study was to understand the behaviour of cohesive powder mixtures of salbutamol sulphate (SS) and micronized lactose (LH300) at ratios of SS:LH300 of 1:1, 1:2, 1:4 and 1:8 under varying air flow conditions.

Methods

Aerosolisation of particles less than 5.4 μm at air flow rates from 30 to 180 l min⁻¹ was investigated by determining particle size distributions of the aerosolised particles using laser diffraction and fine particle fractions of SS using the twin stage impinger modified for different air flow rates using a Rotahaler^®. The de-agglomeration data were best fitted by a 3-parameter sigmoidal equation using non-linear least squares regression and characterised by the estimated parameters.

Results

De-agglomeration air flow rate profiles showed that SS:LH300 mixtures with increased lactose content (1:4 and 1:8) improved powder aerosolisation, but lactose had negligible effect on SS aerosolisation at the higher and lower limits of air flow rates studied. De-agglomeration flow rate profiles of SS–LH300 mixtures with increased lactose content (1:4 and 1:8) were greater than theoretically expected based on weighted individual SS and LH300 profiles. This indicated that interactions between the cohesive components led to enhanced de-agglomeration. The composition of the aerosol plume changed with air flow rate.

Conclusion

This approach to characterising aerosolisation behaviour has significant applications in understanding powder structures and in formulation design for optimal aerosolisation properties.

Introduction

Formulating for respiratory drug delivery is a major challenge. The cohesive and adhesive forces of micronized particles need to be controlled in order to achieve the necessary performance in terms of in vitro aerosolisation and dose uniformity. Micronised particles can form agglomerates (cohesive interactions) and/or can interact with other particles to form mixed agglomerates (adhesive interactions) due to their high surface energy. Micronised particles also can adhere to the surface of carrier particles in a formulation to form interactive units. Aerosolisation of drug particles from such mixtures will require drug detachment from the surface of the carrier particle and/or de-agglomeration of the agglomerates (Adi et al., 2006, Chan, 2006).

The addition of fine excipients such as micronized lactose has been shown to improve drug aerosolisation of cohesive drug mixtures (summarised in review by Jones and Price (Jones and Price, 2006)) and the removal of fines from lactose carriers has decreased drug aerosolisation (Islam et al., 2004). The improved drug aerosolisation has been explained by two major mechanisms, the active site theory (Ganderton, 1992, Hersey, 1975, Lord and Staniforth, 1996, Travers and White, 1971, Zeng et al., 1996) and the re-distribution and de-agglomeration theory (Adi et al., 2006, Jones et al., 2008, Louey and Stewart, 2002, Lucas et al., 1998, Soebagyo and Stewart, 1985). The first of these is the detachment of the micronized drug from larger particulate carriers (Ganderton, 1992, Hersey, 1975, Lord and Staniforth, 1996, Travers and White, 1971, Zeng et al., 1996). The efficiency of this process will depend on the magnitude of the interaction between the drug particle and the carrier. This will depend on interacting surface area which will be influenced by drug particle orientation, carrier particle roughness, particle deformation during adhesion, and factors contributing to the interactive force itself. The second mechanism is the de-agglomeration of interacting drug particles (Adi et al., 2006, Jones et al., 2008, Louey and Stewart, 2002, Lucas et al., 1998, Soebagyo and Stewart, 1985) which will be dependent on the tensile strength of the interacting particles in the agglomerate and related to work of cohesion, packing fraction and particle size (Kendall and Stainton, 2001). The improvement of drug aerosolisation from interactive mixture due to the presence of fine lactose has been shown to depend on the particle size (Adi et al., 2006, Braun et al., 1996, Ganderton, 1992, Louey et al., 2003, Louey and Stewart, 2002, Srichana et al., 1998, Steckel and Müller, 1997b, Zeng et al., 2000) and the proportion of lactose (Braun et al., 1996, Islam et al., 2004, Louey and Stewart, 2002, Lucas et al., 1998, Steckel and Müller, 1997b, Zeng et al., 1998). Increasing the proportion of fines decreased drug–drug interactions by increasing the distances between the particles (Clarke et al., 2001). Fewer studies have focused on increasing the fine lactose content in ternary mixtures (Lord and Staniforth, 1996, Zeng et al., 1996) where the fine lactose was added to the drug in an arithematic/geometric sequence. These studies have demonstrated that increases in the amount of ternary component increased the drug fine particle fraction (Zeng et al., 1996) and decreased drug detachment force (Lord and Staniforth, 1996).

The extent of drug aerosolisation from interactive mixtures is dependant also upon air flow rate (Ganderton, 1992, Srichana et al., 1998, Steckel and Muller, 1997a, Zeng et al., 2006, Zeng et al., 1999) or air flow acceleration rate (Chavan and Dalby, 2002, Deboer et al., 1997). Considering device based de-agglomeration, the change in air flow rate will vary the particle-particle, particle-device wall, mesh, mouth piece and base impactions (Coates et al., 2005) and may also change impact angles (Moreno et al., 2003) and the velocity of impaction (Moreno et al., 2003, Samimi et al., 2003, Subero and Ghadiri, 2001, Thornton et al., 1999). With increased air flow rate, these behaviours are expected to be predominant due to increased turbulent kinetic energy (Coates et al., 2005). Apart from impactions, increased air flow rates also results in increased velocity of the flow (Coates et al., 2005) field and thus the aerodynamic drag force on agglomerates (Zimon, 1982).

A recent study (Behara et al., 2010) on a single component system developed relative de-agglomeration–air flow rate profiles over air flow rates of 30–180 l min⁻¹. The data were modelled by an empirical, three-parameter sigmoidal equation using non-linear least squares regression algorithm and the estimated sigmoidal parameters were used to characterise some cohesive drug and lactose powders. The modelling parameters explained the extent and the ease of powder aerosolisation and gave an estimate of agglomerate strength. These parameters were used to understand the way in which the micro-structure of the powder bed, i.e. the combination of the particle interactions and packing fractions within micro-segments of the powder bed, might influence the manner in which the cohesive powders de-agglomerated. A logical extension of this study was to apply the same treatment to cohesive binary mixtures to observe aerosolisation behaviour of the drug mixture over an air flow range. It is recognised that such a binary system remains a simplified formulation, and does not include a large lactose carrier. The current study is therefore a step up from the previous study (submitted for publication), and examines the behaviour of drug and lactose fines, isolated from a large carrier. This is therefore largely a fundamental exploration, where the role of the large carrier is not included. It should be noted that most real interactive powders contain substantial quantities of agglomerated drug-lactose fines (Adi et al., 2006), plus several products have contained soft agglomerates comprising only micronised drug and lactose mixtures (Schmidt, 2007). Therefore, the current study observed the aerosolisation behaviour of cohesive salbutamol sulphate and lactose binary mixtures over air flow rates up to 180 l min⁻¹ with different ratios of salbutamol sulphate and lactose.