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

	x50 [µm]	Span  [x90-x10/x50]
MSS	1.99	2.21
SDSS	2.91	1.68
MSS+LAC_BD	183.26	1.05
MSS+LAC_AD	173.45	1.06
SDSS+LAC_BD	193.11	1.09
SDSS+LAC_AD	185.48	1.04

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

	Setting 1 [mg]	RSD	Setting 2 [mg]	RSD
MSS+LAC_BD	19.74	6.57	27.22	2.00
MSS+LAC_AD	24.07	2.37	25.08	1.97
SDSS+LAC_BD	20.85	4.19	27.19	2.33
SDSS+LAC_AD	24.74	2.21	27.33	2.00

 

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

	Setting 1			Setting 2
	FPF [%]	ED [µg]	max. Stage	FPF [%]	ED [µg]	max. Stage
MSS+LAC_BD	19.20	829.88	6	22.41	1131.95	7
MSS+LAC_AD	32.53	939.91	7	32.53	939.91	6
SDSS+LAC_BD	6.49	1035.02	5	5.07	1114.91	4
SDSS+LAC_AD	2.39	1261.05	4	3.35	1162.72	5

 

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.