(233af) The Effect of Particle Engineering on the Processing and the in Vitro Performance of Inhalation Blends in Dry Powder Inhalers

Introduction

In order to use API (active
pharmaceutical ingredient) particles intended to target the tiny airways of the
deep lung in dry powder inhalers (DPIs), the range of an aerodynamic diameter
of 1 µm to 5 µm is highly preferred. Particles in this size regimen
are typically cohesive and possess poor flow properties [1], leading to
difficulties concerning volumetrically dosing. To overcome this flowability
problem, it is a general practice to formulate carrier-based formulations
wherein the API particles are attached to the surface of a larger carrier
particle (50 µm – 200 µm).

Materials and Methods

Spray dried and micronized salbutamol
sulphate (SS, Selectchemie, Zurich, Switzerland) were chosen as model API.
Spray dried active was prepared on a Nano Spray Dryer B-90 (Buechi Labortechnik
AG, Flawil, Switzerland). The spray drying conditions were chosen according to
our previous work [2]. Micronization
was done with an air jet mill (Spiral Jet Mill 50 AS, Hosokawa Alpine AG,
Augsburg, Germany) at an injection pressure of 6 bar and a pressure inside the
micronizer chamber of 3 bar. Modification of the carrier was done through wet
decantation, which was supposed to decrease the fine particles on  the carrier
material and to modify the carrier surface [3]. Spray-dried (SDSS) and
micronized API (MSS) was blended with α-lactose monohydrate (LAC_BD) and α-lactose
monohydrate decanted (LAC_AD), so four adhesive mixtures with 2% API were
prepared via sandwich method
in a tumble blender TC2 (Willy A. Bachofen Maschinenfabrik, Muttenz,
Switzerland). The mixing time was 60 min at 60 rpm. Both carriers, the APIs as
well as the adhesives mixtures were extensively characterized (e.g. particle
size, particle shape, flow properties, surface topography) to compare the
different particulate properties.

Subsequent capsule filling was
performed with different process setting (Setting 1: 3.4mm dosator, 2.5mm
dosing chamber, 5mm powder layer; Setting 2: 3.4mm dosator, 2.5mm dosing
chamber, 10mm powder layer) at a filling rate of 2500 capsules per hour (cph) on
a dosator nozzle capsule filling machine (Labby, MG2, Bologna, Italy) with a
target fill weight of 20 to 25mg. To evaluate the performance of the different
mixtures, in vitro lung deposition experiments were carried out with a next
generation impactor (NGI, Copley Scientific, Nottingham, United Kingdom), the
emitted dose (ED) and fine particle fraction (FPF) were calculated based on the
specification of the European pharmacopoeia. The inhalation device used for
these experiments was the Aerolizer®/Cyclohaler®, a capsule inhaler.

Results and Discussion

Figure 1 shows
SEM images of the spray dried (Fig. 1a) and micronized salbutamol (Fig. 1b)
particles. SEM images show that both techniques were able to produce particles
that have suitable size for inhalation but with very different shape and
morphology. Spray dried particles are spherical, whereas micronized particles
are needle shaped. Moreover, spray dried particles are amorphous while
micronized particles were largely crystalline. The mean particle size (x50) determined via laser
diffraction for spray dried and micronized particles as well as the blends can
be found in table 1.

Figure 1: SEM images of spray dried (SDSS) and micronized
(MSS) salbutamol sulphate particles

Table 1:
Particle size and distribution of engineered actives and adhesive mixtures

Table 2:
Fill weight and fill weight variability (RSD)

Table 3:
In Vitro performance: Fine particle fraction(FPF), Emitted dose (ED) and stage
reached in the impactor

The FPF for micronized powder blends
increased significantly, whilst spray-dried blends showed a decrease for
decanted mixtures in comparison to the undecanted. Also the attainable stage in
the NGI got improved through micronization of the API, but showed no
correlation to the wet decantation of the powder blends. The different powder
bed height settings in capsule filling (table 2) led to distinctions in
attainable stage and FPF but do not seem to be influencing factors on the
emitted dose. In summary,  micronization of the API has much more influence on
the ability for reaching the deep lung (API detachment from carrier) than wet
decantation of the carrier material has. The obtained data are highly useful, to
improve the understanding of the relationship between carrier morphology and
carrier type, drug detachment and capsule filling efficiency and will help to
generate DPI formulations with the desirable performance.

[1]
Pilcer, G., Wauthoz, N. and Amighi, K. (2012) “Lactose characteristics and
the generation of the aerosol” Adv. Drug Deliv. Rev., vol. 64, no. 3, pp.
233–256.

[2]
Littringer, E., Zellnitz, S., Hammernik, K., Adamer, V., Friedl, H. and
Urbanetz, N.A. (2013) “Spray Drying of Aqueous Salbutamol Sulfate Solutions
Using the Nano Spray Dryer B-90—The Impact of Process Parameters on Particle
Size” Dry. Technol., vol. 31, no. 12, pp. 1346–1353.

[3]
Faulhammer, E., Zellnitz, S., Wahl, V., Khinast, J.G., Paudel, A. (2015) “Carrier-based dry powder
inhalation: Impact of carrier modification on capsule filling processability
and in vitro aerodynamic performance”  Int J Pharm; 491: pp231–242.