Drug Delivery to the Lungs 20

Drug Delivery to the Lungs, Volume 30, 2019 - Investigation into the impact of fines on electrical charging of lactose in dry powder inhalers

Drug Delivery to the Lungs, Volume 30, 2019 – Gerald Hebbink et al.

Investigation into the impact of fines on electrical charging of lactose in dry powder inhalers

Gerald Hebbink1, Guillermo Sanchez1, Ross Blezard1, Ville Niemelä2 & Esa Luntta2

1DFE Pharma, Goch, Germany.

2 Dekati, Kangasala, Finland.

Summary

Lactose powder blends have been prepared by blending in a high shear mixer, followed by filling into gelatin and HPMC capsules. The lactose blends consisted of a coarse grade of lactose, mixed with one of two types of fine grades of lactose, in order to engineer the particle size distribution. The electrical charging properties were characterized using the BOLAR, Dekati, Finland, by actuation from two different devices: The CDM-haler and the Cyclohaler. The electrical charging data was analysed in order to understand which factors were governing the charging behaviour of the described placebo powders. It was found that positive and negative charge levels were primarily governed by the amount of lactose fines and by the material of the capsule. In contrast to this, the net charging of the placebo lactose was governed by the inhalation device used. It is suggested that the way the capsules are punctured has an impact on this outcome, although more research is required to fully understand these effects.

Key Message

Electrical charging of lactose is largely determined by the particle size of lactose, however net charge is mainly determined by type of inhaler. A deeper understanding factors that influence lactose electrical charging in dry powder inhalers may improve drug product performance.

Introduction

Electrical charging is considered to be important during powder handling applications[[endnoteRef:1]]. In dry powder inhalers (DPIs), powder formulations are fluidized during inspiration to deaggregate drug particles from the lactose carrier which results in the generation of charged particles[[endnoteRef:2],[endnoteRef:3]]. Many factors, including the powder formulation, type of device and type of capsule are known to govern the charging properties of powders, however the underlying charging mechanisms and effects are still not fully understood, in part due to the inability to characterize the bipolar characteristics of the aerosols[[endnoteRef:4],[endnoteRef:5],[endnoteRef:6]]. The BOLARTM (Dekati, Kangasala, Finland) was designed to separate and detect positively and negatively charged aerosol particles within the same size fraction[5,[endnoteRef:7]]. In this study, the effects of type and amount of lactose fines, different capsule types and DPI devices on the charging properties of lactose blends were investigated. [1: Kaialy W: A review of factors affecting electrostatic charging of pharmaceuticals and adhesive mixtures for inhalation. Int. J. Pharm. 2016, 503: 262-76.] [2: Hoe S, Traini D, Chan HK, Young PM: The contribution of different formulation components on the aerosol charge in carrier-based dry powder inhaler systems. Pharm. Res. 2010, 27: 1325-36.] [3: Pilcer G, Wauthoz N, Amighi K: Lactose characteristics and the generation of the aerosol. Adv. Drug Deliv. Rev. 2012, 64: 233-56.] [4: Elajnaf A, Carter P, Rowley G: Electrostatic characterisation of inhaled powders: Effect of contact surface and relative humidity. Eur. J. Pharm. Sci. 2006, 29: 375-84.] [5: Leung SSY, Chiow ACM, Ukkonen A, Chan H-K: Applicability of bipolar charge analyzer (BOLAR) in characterizing the bipolar electrostatic charge profile of commercial metered dose inhalers (MDIs). Pharm. Res. 2016, 33: 283-91.] [6: Zafar U, Alfano F, Ghadiri M: Evaluation of a new dispersion technique for assessing triboelectric charging of powders. Int. J. Pharm. 2018, 543: 151-9.] [7: Yli-Ojanperä J, Ukkonen A, Järvinen A, Layzell S, Niemelä V, Keskinen J: Bipolar Charge Analyzer (BOLAR): A new aerosol instrument for bipolar charge measurements. J Aerosol Sci 2014, 77: 16-30. ]

Experimental method and materials

Placebo lactose blends were prepared by mixing a coarse milled grade of lactose, Lactohale® 206 (LH206, DFE Pharma, Germany), with either 5% or 20% of fine grade lactose, Lactohale® 230 (heavily milled, LH230) or Lactohale® 300 (micronized, LH300) (Table 1). Lactose blends (300 g total) were prepared by high shear mixing using a ProCepT Formate 4M8 Granulator with chopper and impeller speeds of 2000 rpm and 500 rpm, respectively, for five minutes, the blends were subsequently analysed.

Table 1. Composition of lactose blends and particle size distribution of lactose and lactose blends determined by Laser Diffraction (expressed by volume fractions).

Product

Composition (wt%)

D10 (µm)

D50 (µm)

D90 (µm)

%<10 µm

Lactohale 206

N/A

31.3

84.4

165.9

3.4

Lactohale 230

N/A

1.6

8.0

21.9

59.4

Lactohale 300

N/A

0.9

3.6

8.0

95.9

Blend 1

LH206+5% LH230

13.6

77.6

160.5

8.3

Blend 2

LH206+20% LH230

4.1

54.0

148.8

21.2

Blend 3

LH206+5% LH300

5.5

76.5

161.4

12.5

Blend 4

LH206+20% LH300

2.2

49.0

139.8

34.8

The particle size distributions (PSD) of the individual components and blends were measured using laser diffraction (Helos, Sympatec, Germany) with a Rodos dispersion line and R2 lens for Lactohale 300 and R5 lens for all other lactose samples. Size 3 hard gelatin or HPMC capsules (Qualicaps, Spain) were filled manually with 25 ± 2 mg of lactose blend at standard laboratory conditions (22°C, 45%RH), followed by storage in sealed aluminium bags prior to testing.

Figure 1. Left: CDM Haler® (Emphasys, Brazil) and right; Cyclohaler® (Teva Pharmaceuticals, Israel) capsule based dry powder inhalation devices.

Figure 2. Image of the BOLAR™ (Dekati, Finland), and schematic illustration (left and right, respectively)

The electrical charging properties of the lactose blends were characterized using the BOLAR with a standard USP induction port following dispersion using either the CDM-Haler (Emphasys, Brazil) or the Cyclohaler (Teva Pharmaceuticals, Israel). These two devices were similar in appearance, dimensions and air-flow resistance, no information was available on the material of construction. Contrasting characteristics of the two devices were the capsule opening mechanism; in the Cyclohaler the capsule was opened by piercing with two metal needles from the side. While in the CDM-Haler the capsule was opened by piercing from the top of the capsule. Another important difference was the dimensions and geometry of the mouthpiece; the CDM-Haler was shorter and wider compared to the Cyclohaler. Information regarding the device material of construction was not available. The flow rate through the DPIs was fixed at 60 L.min-1 for 30 seconds. The BOLAR system consisted of a flow divider to split the flow evenly into five electrical detection tubes each coupled with a pre-separator impactor set with a specific particle size cut-off diameter. The BOLAR classified particles <11.6 µm aerodynamic diameter into five aerodynamic particle size fractions (D50% values of 0.95 µm, 2.6 µm, 4.2 µm, 7.3 µm and 11.6 µm) and measured the total, positive and negative charge of particles in each size fraction. Charge separation occurred in the bipolar detector tubes which consisted of two concentric metal cylinders. The inner cylinder was maintained at a high positive potential (and collected negatively charged particles) and the outer cylinder was grounded (and collected positively charged particles) to create a 1 kV potential difference between the inner and outer cylinders. Each cylinder was connected to femtoampere-range electrometers which measured the current carried by the charged particles. When integrated over the measurement period the charge could be calculated[5,7]. Each experiment was performed in triplicate and the mean value reported.

Results

In Figure 3, the average charging levels were depicted for positive, negative and net charges (in nC).

Figure 3. Average charge (nC, top; positive, negative and bottom; net charge) measured by BOLAR as function of midpoint of size bins

In Figure 4, the significance of inhaler type (A), capsule type (B) and amount of lactose fines in the blend (C) on the charging of lactose is presented. The second bin (detector), with a median size: 1.775 µm was selected for further analysis, as the highest charge levels were measured in this bin. Conclusions from the negative charge results and results from the other bins were comparable (data not presented).

Figure 4. Pareto charts showing significance of type of inhaler, type of capsule and blend fines content on positive and net charges measured. The red dotted line indicates α=0.05 significance level

Discussion

From direct observation of the measured charge (Figure 3), it was observed that the level of fine particles in the blend (% <10 µm) influenced the positive and negative charge levels. This was a logical observation, as electrical charging of powders is a surface effect and more fine particles leads to a higher surface area. Statistical comparison of the bin that corresponded to a median particle size of 1.775 µm confirmed this to be a significant (α=0.05) factor (Figure 4). A second significant factor in the positive and negative electric charge was the capsule type. Differences caused by the capsule type were considered to be most likely due to the construction material. Gelatin has a different moisture content and vapor sorption curve compared to HPMC[[endnoteRef:8]], therefore this may be part of the explanation. The influence may be through direct contact of the powder blend with the surface of the capsule and/or through a difference in the internal relative humidity; further investigation would be required to understand the underlying mechanism. The device type was either not significant (positive charge) or hardly significant (negative charge, data not presented). However for the net charge results (sum of positive and negative charges), statistical analysis of data collected for the median particle size of 1.775 µm (Figure 4), revealed that the device was the only significant factor. The CDM-Haler produced significantly more negative charge compared to the Cyclohaler. Without more detailed information regarding the construction of the device only limited conclusions could be drawn. One known difference between the two devices was the way the capsules were punctured, resulting in different pathways and different interactions of charged particles. A further potential explanation was the interaction of the powder with the surfaces of the device resulted in a differing net charge. The nature of the difference may be due to material properties, for example electrical properties or surface roughness; once again further investigation was warranted. [8: Barham AS, Tewes F, Healy AM: Moisture diffusion and permeability characteristics of hydroxypropylmethylcellulose and hard gelatin capsules. Int. J. Pharm. 2015, 478: 796-803.]

During this investigation several limitations were noted; the BOLAR measurement procedure could be further optimised to more closely match real world usage (for example flow rate and measurement time). A second limitation was that the emitted dose could not be measured, so normalization of the data was not possible. Many other factors may also be explored using this technique, such as the influence of blending energy and the role of active ingredients which were not within the scope of this study. Of particular interest was the influence of the device on net charge and this will be the subject of future investigation.

Conclusions

Charging of lactose from dry powder inhalation devices is mainly governed by particle size of the lactose powder and by the capsule material. However, the main factor governing total net charge was the type of device, indicating that the CDM-Haler might retain positive charged particles more than the Cyclohaler..

References