The effect of carrier particle size on the performance of adhesive mixtures for inhalation

Abstract

Despite being subject to a multitude of investigations, the effect of carrier particle size on the performance of adhesive mixtures for inhalation is still not well understood. This study, involving three differently sized lactose carriers, all with the regular ‘tomahawk’ particle shape, aims to provide fundamental insight into this topic. Fine particle fraction (FPF) data for binary formulations with 2% budesonide, blended both in the Diosna high shear mixer and in a Turbula blender, are analyzed in terms of the applied mixing force and mixing energy (ME).

For high shear blended formulations, the results clearly indicate that the mixing force acting between adhesive units is directly proportional to the mass of the carrier particle. Formulations produced at different mixing times and speeds display a linear decrease in FPF when plotted against ME, with similar slopes for the different carriers, in particular as regard the relative decrease in FPF. The inhaler device affects the magnitude of the FPF, but not the relative decrease rate. Interestingly, formulations blended in the Turbula mixer show an opposite behavior, with increasing FPF at a longer mixing times/energies. This points to different mechanisms playing the key role in the two mixing regimes. In conlusion, the applied mixing energy, with carrier particle mass included in the equation, seems to play a crucial role for both mixers.

Introduction

Micronized drug mixed with larger inert carrier particles were the first powder mixtures developed for dry powder inhalation and is today a main formulation approach 1, 2. Still, however, such formulations are relatively poorly understood. It is believed that this is due to the large number of parameters which are critical to the performance, such as the particle size and shape of the carrier, the properties of the drug and the drug load, and moreover the type of inhaler used for the delivery 3, 4, 5, 6.

Lactose monohydrate particles with a size range from 60 to 250 μm in diameter is the most common carrier material 2, 6. Basically, two carrier types can be discerned, leading to two somewhat different modes of action. For the regular ‘tomahawk’ shaped carrier type, which reflects the shape of the lactose monohydrate crystal, the micronized drug particles adhere to the surfaces of the carrier upon mixing to form ‘classical’ adhesive mixtures 7, 8, 9. For carriers consisting of aggregates of lactose crystals, the fine drug particles instead tend to gather in clefts and cavities, thereby finding shelter from external forces during mixing 7, 9, 10, 11. Not surprisingly, the two types can give rise to quite different behavior as regards formulation dispersibility 12, 13. It is clear, however, that most commercial carrier grades contain elements from both types, and moreover have quite irregular surfaces 7, 8, 9, 14, 15. Furthermore, the drug load and the associated surface coverage ratio are important parameters which need to be taken into account 7, 9, 16, 17.

Recently, renewed attention has been paid to the dry powder mixing process 6, 18, 19, 20, 21. The ‘mixing energy’ concept has proven fruitful for modeling the performance in the case of the ‘classical’ adhesive mixture type. It has been shown that the dispersibility of the drug, expressed as the fine particle fraction, FPF, can be modeled and predicted both for binary drug-carrier formulations and for formulations further comprising a ‘coating agent’ such as MgStearate or leucine 19, 20, 21. The applied mixing force and mixing energy are for a high shear mixer calculated based on the rotational movement of the powder bed [19]. The mixing force is related to the centrifugal acceleration , as:

(Equation 1)

where  is the tip speed of the impeller and  is the radius of the bowl. Mixing energy is obtained as mixing force multiplied with the distance traveled by the particles:

(Equation 2)

where  means distance,  is the mixing time, and rpm is revolutions per minute.

The Turbula® is another popular mixer for preparation of dry powders for inhalation. Calculation of the mixing energy is here less straightforward, due to the complex movement pattern 22, 23. An estimate can however be made based on the rotational component of the movement [21]. We thus have:

(Equation 3)

(Equation 4)

in analogy with Eqs. (Equation 1), (Equation 2) for the high shear mixer (note that the Turbula mixer makes two rotations during one revolution). At a speed of 68 rpm, which was used in this work, the peak acceleration  was estimated to 22 m/s2 [23].

The composition of the formulation is another key factor affecting the performance of adhesive mixtures. A higher load of micronized API has been shown to increase not only the fine particle dose, but also the fine particle fraction [24]. Another tool to improve the dispersibililty of the drug is addition of fine lactose particles with a size similar to that of the API. Several hypothesis were put forward as to the mechanism behind this effect, but all of them have been difficult to prove [25]. More recent hypothesis have highlighted the importance of ‘press-on forces’ 26, 27 and ‘viscoelastic damping’ during the blending process(28).

This work is focussing on the mass, which appears in all four equations above. Which is the relevant mass to use?
Should it be the mass of a single carrier particle?Or should the calculations be carried out based on the total mass of the formulation? The latter has been a standard way to assess the intensity of mixing,used among others by Hertel et al. [29]. Certainly, the load of material, or rather the degree of filling of the mixer, will influence the movement of the powder and hence the quality of the resulting mixture, both in high shear mixing and for the Turbula mixer 30, 31. For both blenders, a filling degree in the range 30 – 70% is normally recommended. Sticking to the appropriate filling degree window, the key research questions of this work are; how does carrier particle size affect the performance of the formulation?, and; is it possible to predict formulation performance when switching from one carrier grade to another?

To address the questions, three lactose monohydrate carriers of regular shape, all with a narrow size distribution but with clear differences in size, were selected for investigation. The API content was kept constant (2% of micronized budesonide) and no lactose fines was added. For each carrier, median particle mass was calculated from the median particle diameter (d50) and a density of 1520 kg/m3 for lactose monohydrate, assuming spherical particles, which is in line with the principles of the laser diffraction method used for particle sizing. Binary blends were prepared at different speeds and mixing times in a Diosna high shear blender and in the Turbula blender. All formulations were analyzed for aerodynamic performance using an RS-01 capsule inhaler and the Next Generation Impactor, NGI. In addition, drug content uniformity, particle size distribution, bulk density and SEM analyses were performed to allow in depth interpretation of the results.

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Materials

The materials used are specified in Table 1. Particle size data, assessed using Malvern Mastersizer 3000 with wet dispersion are given in Table 2. Lactose carriers were evaluated using Fraunhofer theory, budesonide using both Fraunhofer and Mie theory. For method details, see section 2.5.

Excipients mentioned in the study: Lactohale® 100, Lactohale® 206, Respitose® SV003

Kyrre Thalberg, Maja Tagesson, Lars Asking, Mårten Svensson,
The effect of carrier particle size on the performance of adhesive mixtures for inhalation.,
Journal of Drug Delivery Science and Technology, 2026, 108048, ISSN 1773-2247,
https://doi.org/10.1016/j.jddst.2026.108048.