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International Journal of Pharmaceutics xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

1 Formulating powder–device combinations for salmeterol xinafoate dry

2 powder inhalers
3 Q1 Mireille Hassoun a , Shirlene Ho a , Joanna Muddle a , Francesca Buttini a,c , Mark Parry b ,
4 Mark Hammond b , Ben Forbes a, *
5 a
Department of Pharmacy, King’s College London, 150 Stamford Street, London SE1 9NH, UK
6 b
Intertek-Melbourn Scientific Limited, Saxon Way, Melbourn SG8 6DN, UK
7 Q2 c
Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/a, Parma 43124, Italy

A R T I C L E I N F O A B S T R A C T

Article history: Using salmeterol xinafoate (SX) as an active pharmaceutical ingredient, the effects of carrier lactose
Received 31 March 2015 particle type, total lactose fines content and device resistance on dry powder inhaler performance were
Received in revised form 8 May 2015 investigated in vitro. To mimic drug levels in commercial preparations, interactive mixtures containing
Accepted 11 May 2015
0.58% w/w SX were prepared by low shear tumble mixing. Three types of milled inhalation grade lactose
Available online xxx
were used (Lactohale1 LH 200, Respitose1 ML006 and ML001) and the concentration of fine lactose
(Lactohale1 300) added was varied. The in vitro deposition of each mixture was studied using a next
Keywords:
generation impactor and inhaler devices exhibiting different resistances, Rotahaler1
Orally inhaled product (OIP)
Salmeterol xinafoate (SX)
< Aerolizer1 < Handihaler1. Aerosol performance was evaluated based on the emitted dose (ED), mass
Dry powder inhaler median aerodynamic diameter (MMAD)
geometric standard deviation (GSD) and fine particle fraction
Lactose (FPF). Increases of up to eight-fold in FPF were observed with increasing intrinsic fine lactose content. The
Rotahaler addition of extra fine lactose increased the FPF further, although the effect diminished as more fines were
Aerolizer added. The Aerolizer produced the best aerosol performance with any given powder blend, although
Handihaler suitable formulations were identified for each device as defined by the a priori success criteria: >80% ED
and MMAD
GSD between 1–5 mm. The results confirmed the factors under investigation to be
important determinants of product performance, but demonstrated using realistic conditions how
individual factor impact may be enhanced or mitigated by inter-dependency.
ã 2015 Published by Elsevier B.V.

8 1. Introduction practicalities of formulating powder blends for different inhaler 18

devices. Q4 19
9 Dry powder inhalers (DPI) are increasingly popular products for Drug particles within the respirable size range, 1–5 mm, are 20
10 delivering drugs to the lungs due to their ease of operation, generally highly cohesive and tend to form agglomerates, resulting 21
11 environmental sustainability and formulation stability (Telko and in poor flow properties, non-uniform dispersion and low dose 22
12 Hickey, 2005). Historically, DPI have delivered only 20–30% of the uniformity. Therefore, drug particles are usually blended with 23
13 emitted dose to the lungs (De Koning, 2001), but more efficient coarse carrier particles, typically a-lactose, to help provide bulk 24
14 Q3 products are emerging (Friebel et al., 2012). Although the scientific and form an ordered mix (Pilcer and Amighi, 2010; Javadzadeh 25
15 literature now provides well-established principles with which to et al., 2012). Since the active drug and lactose powders exhibit 26
16 design efficient and effective DPIs (Friebel et al., 2012; Hoppen- different sized particles, the formulation and blending process is 27
17 tocht et al., 2014), there is surprisingly little reported regarding the important to achieve uniform drug distribution and provide 28

consistency of delivered dose (Pilcer and Amighi, 2010; Saleem and 29

Smyth, 2008). Powders need to be sufficiently adhesive to possess 30

good flow properties without compromising their ability to 31

Abbreviations: SX, salmeterol xinafoate; DPI, dry powder inhaler; PSD, particle generate respirable aerosols efficiently and reproducibly (Begat 32
size distribution; ED, emitted dose; MMAD, mass median eerodynamic diameter; et al., 2004). Powder dispersion can be manipulated by modifying 33
GSD, geometric standard deviation; FPF, fine particle fraction; FPD, fine particle 34
the properties of microparticle drug surface or the carrier’s surface
dose. 35
* Corresponding author. Tel.: +44 207 8484823. morphology and size (Buttini et al., 2008; Pomazi et al., 2013; Zeng
E-mail address: ben.forbes@kcl.ac.uk (B. Forbes). et al., 2001; Islam et al., 2004; Zellnitz et al., 2011). A proportion of 36

http://dx.doi.org/10.1016/j.ijpharm.2015.05.028
0378-5173/ ã 2015 Published by Elsevier B.V.

Please cite this article in press as: Hassoun, M., et al., Formulating powder–device combinations for salmeterol xinafoate dry powder inhalers.
Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.05.028
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2 M. Hassoun et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx

37 fine lactose in the formulation, either as intrinsic or added fines, 2.1. Internal resistance of inhaler devices 85
38 will further improve dispersion and the de-aggregation of the drug
39 particles (Jones and Price, 2006; Beilmann et al., 2007; Kinnunen Each DPI inhaler was loaded with an empty pierced capsule and 86
40 et al., 2014; Shur et al., 2008; Grasmeijer et al., 2014; Thalberg et al., attached to the dosage unit sampling apparatus (Copley Scientific 87
41 2012). Limited, Nottingham, UK) connected to a high-capacity vacuum 88
42 Device properties also determine respirable aerosol generation pump (Model HCP5, Copley Scientific Limited, Nottingham, UK) via 89
43 from a carrier-based powder formulations (Martinelli et al., 2015; a critical flow controller (Model TPK, Copley Scientific Limited, 90
44 Shur et al., 2012). The airflow velocity must also overcome the Nottingham, UK). For each inhaler device, triplicate measurements 91
45 adhesion forces between the drug and carrier particles to detach of the pressure drop were recorded across the flow rate range of 92
46 the micronized drug particles and disperse them in the aerosol. To 30–100 L min1 at 10 L min1 intervals. A linear plot of the square 93
47 aid dispersion, inhaler devices may be engineered with a more root of the mean pressure drop against flow rate was obtained and 94
48 tortuous airflow that increases the resistance within the device the internal resistance of the DPI device was defined as the slope of 95
49 (Coates et al., 2006; Selvam et al., 2010). Capsule-based inhalers the linear plot (Clark and Hollingworth, 1993). 96
50 with different resistances are available, which enables the effect of
51 device resistance on dry powder aerosolisation to be investigated. 2.2. Lactose particle size 97
52 Although aerosolisation is governed by the powder formulation
53 and the inhaler device design inter-dependently (Frijlink and de To characterise the coarse lactose carriers, an amount of each 98
54 Boer, 2004), devices are generally developed as platform a-lactose grade (60 mg) was dispersed in 15 mL of propan-2-ol 99
55 technology with which to deliver different drugs to the lungs. with the aid of sonication for 1 min. The particle size distribution 100
56 Scientific studies aimed at understanding DPI performance often (PSD) of each lactose grade was characterised in terms of Dv10, Dv50 101
57 examine the influence of device or formulation as independent and Dv90 values (the volume diameter of 10%, 50% and 90% of 102
58 variables, or use model systems. For example, effect of adding fine aerosol droplets respectively); measured using a Spraytec1 103
59 excipient particles has been investigated by looking at the effect of (Malvern Instruments, Malvern, UK), equipped with a wet-cell 104
60 fine lactose on the aerosolisation of salmeterol xinafoate (SX) 1–5% dispersion unit. The span value provided an indication of the width 105
61 w/w interactive powder mixtures (Islam et al., 2004; Adi et al., of PSD and the percentage of particles with an equivalent volume 106
62 2008). The present study explored the inter-dependency of powder diameter of less than 10 mm was also determined. 107
63 formulation and device factors in typical capsule-based DPI
64 products by varying the carrier particle size distribution and the 2.3. SX blends preparation 108
65 amount of added lactose fines. Three DPI devices having different
66 intrinsic resistance were employed to aerosolize the SX blends. A Based on a 32 factorial design, nine interactive mixtures, each 109
67 32 factorial design was constructed to understand the relative containing 0.58% w/w SX and 0.08% w/w of magnesium stearate (to 110
68 influence of these variables on fine particle fraction (FPF), emitted aid mixing), were prepared in 50 g batches with 10% overage, using 111
69 dose (ED), mass median aerodynamic diameter (MMAD) and the different powder components (Table 1). The binary interactive 112
70 geometric standard deviation (GSD). mixtures consisted of SX particles and coarse carrier. Coarse 113

lactose (2 g) was first used to ‘sandwich’ SX and the powders were 114
71 2. Materials and methods mixed using a Spinmix Vortexer (Gallenkamp, Loughborough, UK). 115

Coarse lactose was subsequently added in multiple stages (2.5 g, 116

72 Micronised SX was supplied by Vamsi Labs Ltd., Maharashtra, 5 g, 10 g, 10 g, 10 g and 10.21 g) and the powder mixture blended 117
73 India. Milled inhalation a-lactose monohydrate grades using a Turbula1 T2F shaker-mixer (Willy A. Bachofen AG, Basel, 118
74 (Respitose1 ML006, Respitose1 ML001, Lactohale1 LH 200 and Switzerland) for 30 min at 67 rpm. The ternary interactive mixtures 119
75 Lactohale1 300) were obtained as samples from DFE Pharma were three-component blends of SX particles, coarse carrier and 120
76 (Veghel, Netherlands). Size 3 hard gelatin capsules were acquired added fines. The fine lactose and half of the coarse lactose were 121
77 from Farillon Limited, (Romford, UK). Rotahaler1, Aerolizer1 and pre-blended for 30 min at 67 rpm, followed by the addition of the 122
78 Handihaler1 devices were retrieved from commercial products. other half of the coarse lactose. This was blended for a further 123
79 HPLC grade methanol and hexane and laboratory grade disodium 30 min, before mixing with SX, similarly to the preparation of the 124
80 hydrogen orthophosphate dodecahydrate were supplied by Fisher binary mixtures, by gradual addition of the coarse-fine lactose pre- 125
81 Chemicals (Loughborough, UK). Magnesium stearate and analytical blend to the SX blends and mixing for 30 min at 67 rpm between 126
82 grade citric acid monohydrate were supplied by Sigma–Aldrich each addition of the pre-blend. 127
83 Company Limited (Dorset, UK) while silicone oil was obtained from
84 VWR International Limited (Lutterworth, UK).

Table 1
Composition of each interactive mixture prepared in accordance to the 32 factorial design, each containing 0.58% w/w salmeterol xinafoate
and 0.08% magnesium stearate.

Interactive mixture Concentration of fine lactose added (%w/w) Coarse lactose grade
M6F0 0 Respitose1 ML006
M6F5 5 Respitose1 ML006
M6F10 10 Respitose1 ML006
M1F0 0 Respitose1 ML001
M1F5 5 Respitose1 ML001
M1F10 10 Respitose1 ML001
LHF 0 0 Lactohale1 LH200
LHF 5 5 Lactohale1 LH200
LHF 10 10 Lactohale1 LH200
LHF 20a 20 Lactohale1 LH200
a
An additional mixture prepared to investigate poor blend homogeneity.

Please cite this article in press as: Hassoun, M., et al., Formulating powder–device combinations for salmeterol xinafoate dry powder inhalers.
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M. Hassoun et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx 3

128 2.4. Blend content uniformity for all graphs. Two-way analysis of variance (ANOVA, SPSS v17.0) 185

was used to determine the statistical significance of results. 186

129 Blend homogeneity was evaluated by dissolving ten randomly
130 selected samples (25
0.5 mg) of each interactive mixture in 65% 3. Results 187
131 v/v methanol in water mixture and quantifying SX content using
132 high-performance liquid chromatography (HPLC). An interactive 3.1. Internal resistance of inhaler devices 188
133 mixture was considered as homogeneous if no more than one
134 sample was outside the limits of 85–115% of the mean salmeterol Internal resistance was calculated for each inhaler from the 189
135 content and none was outside the limits of 75–125% of the mean linear plots (R2 > 0.99) of pressure drop versus inspiratory flow rate 190
136 salmeterol content (European Pharmacopeia, 2015). (Fig. 1). Internal resistance was different for each type of inhaler 191
p p
device: 0.0122 kPa L min1 for the Rotahaler, 0.0182 kPa L min1 192
137 p 1 193
2.5. In vitro deposition in the next generation impactor for the Aerolizer and 0.0419 kPa L min for the Handihaler and
compared favourably with those reported previously by Frijlink 194
138 The in vitro aerosolisation of each interactive mixture in and de Boer (2004). In vitro deposition studies were conducted 195
139 different inhaler devices was evaluated using a next generation using the Rotahaler, Aerolizer and Handihaler to represent devices 196
140 impactor (NGI). Ten size 3 hard gelatin capsules were loaded with with low and high resistance and at the range of 1.5–6.3 kPa 197
141 the interactive mixture (12.5
0.5 mg) and discharged in each NGI pressure drops typically attained by the patient population, in 198
142 test. The NGI collection stages were coated with 1% v/v silicone oil order to investigate the effect of this variable on the performance 199
143 in hexane and the pre-separator filled with 15 mL deionised water. (Table 2). 200
144 The NGI was connected to a high capacity vacuum pump via a
145 critical flow controller. A leak test was carried out (to ensure the 3.2. Blend homogeneity 201
146 leak rate was less than 100 Pa/s) and the P3/P2 ratio at the test flow
147 rate determined (flow rate assumed to be stable if P3/P2  0.5) (U.S. All three coarse lactose grades displayed monomodal distri- 202
148 Pharmacopeia, 2015). Each dose was actuated at 100 L min1 for butions (data not shown). They differed in terms of volume median 203
149 2.4 s with the Rotahaler and Aerolizer, and at 60 L min1 for 4 s with diameter (Dv50), span and intrinsic fines content (Table 3). An 204
150 the Handihaler. Impactor testing was performed at room inverse relationship between Dv50 and intrinsic fines content was 205
151 temperature (22.0
3  C) and a relative hsumidity of 50
10%. evident. The dimensions of the fine particles were not measured in 206
152 Each formulation–device combination was tested four times. SX this study but have been reported previously; SX (Jaffari et al., 207
153 was recovered by rinsing each component of the NGI with 65% v/v 2014) and Lactohale LH 300 (Kinnunen et al., 2014). 208
154 methanol in water mixture, into appropriate volumetric flasks. The Only six of the nine interactive blends fulfilled the criteria for 209
155 salmeterol content was quantified using HPLC. accuracy and uniformity outlined in the European Pharmacopoeia, 210

exhibiting mean drug contents ranging from 95 to 105% of the 211

156 2.6. HPLC analysis of salmeterol theoretical salmeterol content and inside the acceptance limit of 212

relative standard deviations (RSDs) of <10% set for this work 213
157 SX was analysed by HPLC. A mixture of methanol and filtered (Table 4). No consistent relationship was observed between the 214
158 buffer solution, consisting of 0.05 M citric acid and 0.1 M di-sodium total fines content and the mean drug content or RSD. To test the 215
159 hydrogen orthophosphate dodecahydrate solution (65:35, pH hypothesis that the interactive mixtures M6F5, M6F10 and 216
160 4.0
0.1), was used as the mobile phase at a flow rate of 1.1 M1F10 failed to achieve acceptable blend homogeneity because 217
161 mL min1, with UV detection at 228 nm. The HPLC system their total fines content exceeded 20% w/w, LHF 20 mixture was 218
162 consisted of a 15 cm (4.6 mm i.d.) column packed with 2.7 mm prepared using the same mixing procedure. However, it was 219
163 C-18 (Agilent Technologies, Cheshire, UK) with the column evident that despite a high total fines content (26.7% w/w), LHF 220
164 temperature maintained at 15  C. With reference to an external 20 exhibited good blend homogeneity (RSD = 3.63%). Overall, the 221
165 standard, quantification of SX content was carried out by interactive mixtures consisting of Lactohale LH 200 provided 222
166 integration of the peak corresponding to the retention time of greater blend homogeneity, with RSD values ranging from 1.89 to 223
167 3.5 min. The method was validated over a concentration range of 5.43%, compared to the mixtures prepared using the other coarse 224
168 1–50 mg/ml and the linearity was verified (R2 = 0.999) and the lactose grades. Only blend formulations exhibiting a RSD value less 225
169 method was shown to be fit for purpose with a limit of than 10% were tested in term of aerodynamic performance. 226
170 quantification within this range, a precision of 2% and accuracy
171 of 99%.

172 2.7. Data analysis

173 The emitted dose (ED), expressed as a percentage of the nominal

174 dose (50 mg), was denoted as the total amount of drug recovered in
175 the impactor per capsule. The mass median aerodynamic diameter
176 (MMAD) and geometric standard deviation (GSD) were derived from
177 a plot of cumulative fraction of salmeterol against NGI cut-off
178 diameters (European Pharmacopoeia, 2015). The fine particle dose
179 (FPD) was the mass of drug particles with aerodynamic diameter
180 lower than 5 mm and the fine particle fraction (FPF) was calculated as
181 the percentage ratio between FPD and ED.

182 2.8. Statistical analysis

Fig. 1. Pressure drop across the inhaler device as a function of flow rate. The slope of
183 Data was analysed for normality using an Anderson–Darling linear plot corresponds to the internal resistance of the device. Data represent
184 test. GraphPad Prism (v5.0) was used to perform statistical analysis mean
SD (n = 3).

Please cite this article in press as: Hassoun, M., et al., Formulating powder–device combinations for salmeterol xinafoate dry powder inhalers.
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Table 2
Pressure drop developed for each device at its test flow rate.

Inhaler device Device resistance (kPa0.5 min1) Test flow rate (L min1) Pressure drop at test flow rate (kPa)
Rotahaler 0.0122 100 1.5
Aerolizer 0.0182 100 3.3
Handihaler 0.0419 60 6.3

Table 3
Particle size distribution of coarse lactose carrier. Q5

Dv10 (mm) Dv50 (mm) Dv90 (mm) Span Intrinsic fines content (%w/w)
Respitose1 ML006 5.4 24.1 59.7 2.254 20.9
Respitose1 ML001 8.0 47.3 138.8 2.766 12.5
Lactohale1 LH 200 14.2 68.7 156.8 2.075 6.7

Intrinsic fines content defined as percentage of particles that had an equivalent volume diameter of <10 mm (selected as the cut-off diameter as the manufacturer’s batch
specifications state that Dv(90) of Lactohale1 300 should be 10 mm).

Table 4
Blend homogeneity of the interactive mixtures (target drug content = 0.58% w/w, n = 10).

Interactive mixture Total fines contentb (% w/w) Mean drug content (%) Relative standard deviation (%)
M6F0 20.9 100.32 7.44
M6F5a 25.9 108.04 23.07
M6F10a 30.9 107.71 30.21
M1F0 12.5 95.16 8.51
M1F5 17.5 105.74 3.73
M1F10a 22.5 102.62 34.90
LHF 0 6.7 99.24 1.94
LHF 5 11.7 97.32 5.43
LHF 10 16.7 103.64 1.89
LHF 20 26.7 104.37 3.63
a
Mixtures that failed to pass the content uniformity criteria outlined by the British Pharmacopoeia.
b
Total fines content calculated as the sum of intrinsic fines content and concentration of fines added.

227 3.3. In vitro deposition in the next generation impactor 3.3.2. Effect of adding fine lactose 257

For the interactive mixtures using Lactohale carrier, LHF 0, LHF 258
228 3.3.1. Salmeterol and coarse lactose carrier blends 5, LHF 10 and LHF 20, deposition in stages 2–5 was increased 259
229 Stage-by-stage deposition in the NGI for binary interactive proportionately to the amount of fines added, with the effect 260
230 mixtures for each device showed a positively skewed distribution particularly pronounced for stage 4. A gradual shift was observed 261
231 for M6F0 and LHF 0, but a symmetrical distribution for M1F0 with from a positively skewed distribution for LHF 0 to a symmetrical 262
232 its mode occurring in stage 4 (Supplementary data, Fig. S1). distribution for LHF 20 (Supplementary data, Fig. S1). Increasing 263
233 Deposition in the pre-separator for LHF 0 was markedly higher the amount of fines led to a decrease in deposition in the pre- 264
234 (two-way ANOVA, p < 0.001) compared to the other binary separator, although this effect diminished as amount of fines 265
235 interactive mixtures. The FPF obtained for M1F0 was lower than increased, and a higher FPF was generated (Fig. 3). Unlike the 266
236 that of M6F0. Significant differences in mean MMADs were differences observed between LHF 0 and LHF 5, addition of 5% w/w 267
237 observed after the aerosolisation of binary mixtures with different fines in M1F5 did not alter the deposition profile compared to 268
238 coarse lactose carrier grades (Two-way ANOVA, P < 0.05). Lower
239 mean MMADs for any specific formulation were associated with
240 aerosolisation of the powder from the Aerolizer. Differences in the
241 mean FPFs (Fig. 2) were also statistically significant (Two-way
242 ANOVA, p < 0.05). The use of Respitose1 ML001 contributed to
243 higher de-agglomeration efficiency across all levels of device
244 resistance, producing approximately an eight-fold increase in
245 mean FPF compared to Lactohale1 LH 200. The intrinsic presence
246 of a fine lactose fraction inside the carrier helped the deaggre-
247 gation of the drug microparticles. M1F0 produced the lowest mean
248 emitted dose among the binary interactive mixtures when
249 aerosolised from the same inhaler. For M6F0 and M1F0, there
250 was a significant positive relationship between inhaler device
251 resistance and the mean ED. Deposition in the pre-separator was
252 higher for the Rotahaler compared to the Aerolizer and Handihaler,
253 i.e. higher mouth and throat deposition was associated with the
254 increased pressure drop across the device. The effect of carrier size Fig. 2. Mean fine particle fraction (FPF) of salmeterol 0.58% w/w-lactose carrier
255 distribution on the mean emitted dose produced from devices binary interactive mixtures aerosolised at different levels of device resistance. Data
256 exhibiting different resistances is shown in Table 5. represent mean
SD (n = 4), significance determined using two-way ANOVA *
p < 0.05, **p < 0.01, ***p < 0.001.

Please cite this article in press as: Hassoun, M., et al., Formulating powder–device combinations for salmeterol xinafoate dry powder inhalers.
Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.05.028
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Table 5
Mean emitted dose (ED), mass median aerodynamic diameter (MMAD), geometric standard device (GSD), fine particle dose (PSD) and fine particle fraction (FPF) (n = 4) for
salmeterol 0.58% w/w-lactose powder blends, aerosolised using devices with different resistance.

Interactive mixture Inhaler device Mean emitted dose (
SD) (%) Mean MMAD (
SD) (mm) Mean GSD (
SD) (mm) Mean FPD (
SD) (mm) Mean FPF (
SD) (%)
M6F0 Rotahaler 84.99 (16.10) 4.24 (0.06) 1.54 (0.03) 7.14 (0.59) 17.06 (1.82)
Aerolizer 87.18 (3.30) 3.62 (0.10) 1.48 (0.04) 12.76 (1.21) 29.23 (1.76)
Handihaler 98.01 (10.18) 4.21 (0.07) 1.35 (0.06) 10.01 (0.62) 20.50 (1.12)

M1F0 Rotahaler 70.44 (5.63) 3.20 (0.04) 1.23 (0.04) 10.50 (0.06) 29.95 (2.48)
Aerolizer 75.26 (2.13) 2.89 (0.03) 1.21 (0.06) 18.96 (1.23) 50.36 (2.05)
Handihaler 82.27 (3.61) 3.44 (0.04) 1.27 (0.06) 13.69 (0.42) 33.34 (2.11)

M1F5 Rotahaler 68.07 (4.34) 3.35 (0.09) 1.28 (0.04) 10.17 (1.18) 29.82 (1.73)
Aerolizer 81.82 (1.25) 3.10 (0.03) 1.16 (0.05) 16.93 (0.42) 41.38 (0.77)
Handihaler 88.32 (1.36) 3.69 (0.03) 1.17 (0.03) 13.82 (0.49) 31.31 (1.24)

LHF 0 Rotahaler 84.50 (2.43) 5.43 (0.13) 1.45 (0.05) 1.32 (0.15) 3.14 (0.42)
Aerolizer 91.25 (2.35) 4.07 (0.08) 1.44 (0.04) 3.11 (0.21) 6.82 (0.30)
Handihaler 90.32 (1.44) 5.06 (0.14) 1.71 (0.11) 1.72 (0.12) 3.82 (0.21)

LHF 5 Rotahaler 72.96 (5.04) 3.53 (0.06) 1.41 (0.05) 5.54 (0.24) 15.20 (0.57)
Aerolizer 79.33 (5.07) 2.95 (0.07) 1.28 (0.01) 11.10 (1.37) 27.91 (1.94)
Handihaler 89.10 (11.80) 3.42 (0.06) 1.55 (0.10) 8.37 (0.66) 18.94 (1.93)

LHF 10 Rotahaler 71.85 (0.78) 3.30 (0.05) 1.26 (0.04) 9.19 (0.25) 25.57 (0.76)
Aerolizer 80.25 (1.27) 3.06 (0.03) 1.18 (0.03) 15.67 (0.20) 39.06 (0.89)
Handihaler 85.14 (2.16) 3.61 (0.02) 1.24 (0.02) 11.80 (0.38) 27.74 (1.28)

LHF 20 Rotahaler 82.18 (5.23) 3.17 (0.03) 1.21 (0.05) 11.93 (0.55) 29.12 (2.20)
Aeroliser 92.44 (8.91) 2.94 (0.07) 1.10 (0.03) 23.97 (3.69) 51.67 (2.93)
Handihaler 92.77 (1.10) 3.60 (0.02) 1.18 (0.05) 15.71 (0.54) 33.87 (0.98)

269 M1F0 (Fig. 4). In formulations employing a different carrier, but observed at all levels of device resistance (Fig. 3), with R2 values 289
270 equivalent overall fines, significant differences in particle deposi- >0.95. 290
271 tion in the pre-separator and stages 2–5 were found between No significant differences were observed when fine lactose was 291
272 M1F0 and LHF 5 (Two-way ANOVA, p < 0.001), which was not added to M1F0 with regards to emitted dose, MMAD, GSD and FPF 292
273 observed between M1F5 and LHF 10. (Table 5; Fig. 4). Unlike the improved aerosol performance 293
274 Initially, the mean emitted doses of interactive mixtures observed for interactive mixtures with Lactohale1 LH 200, the 294
275 aerosolised from the Rotahaler and Aerolizer reduced by approxi- addition of 5% w/w fines had no effect on drug dispersion for M1F5, 295
276 mately 10% following the addition of 5% w/w fines (Table 5). The possibly due to differences in the carrier PSD. Based on their 296
277 mean EDs were only restored to their original levels after a total of similarities in total fines content, a comparison between two pairs 297
278 20% w/w fine were added. Increased mean EDs were also of interactive mixtures was made (i) LHF 5 (11.7% w/w) and M1F0 298
279 associated with increased device resistance. A significant reduc- (12.5% w/w), and (ii) LHF 10 (16.7% w/w) and M1F5 (17.5% w/w). 299
280 tion in mean MMADs was observed following the addition of 5% w/ Significant differences in aerosol performance were seen within 300
281 w fines initially (Two-way ANOVA, p < 0.01). However, it remained both pairs of mixtures (Fig. 4; Two-way ANOVA, p < 0.001). 301
282 relatively consistent following further addition of fines. In However, between the LHF 10 and M1F5, no significant difference 302
283 comparison to Rotahaler and Handihaler, the Aerolizer produced was found when the mixtures were aerosolised by the Aerolizer. 303
284 lower mean MMADs for any given interactive mixture. Increasing
285 the concentration of fines added had a significant effect on the 4. Discussion 304
286 mean FPF of the aerosol generated (Two-way ANOVA, p < 0.005),
287 particularly when aerosolised from the Aerolizer. A strong It is widely accepted that in order to optimise the performance 305
288 correlation between mean FPF and total fines content was of a DPI, the formulation factors such as carrier particle size 306

distribution and total fines content need to be considered in 307

tandem with device factors such as internal resistance. The aim of 308

this study was to explore how formulation and device factors 309

interact to affect DPI performance, and investigate whether 310

clinically effective formulations can be tailored to devices with 311

different resistances. Successful performance criteria for DPI were 312

assigned as high FPF, an ED of 80% and an aerodynamic particle 313

size (MMAD) between 1 and 5 mm. 314

The blending process used in this study disrupted the 315

association of particles forming SX-only and fines-only agglom- 316

erates and redistributed SX particles to regions within the powder 317

mass where they would bind more strongly. The inertial and 318

frictional forces during blending depend on the carrier and mixing 319

conditions (Pilcer and Amighi, 2010; De Boer et al., 2012). There 320

was no consistent relationship between total fines content and 321

Fig. 3. Mean fine particle fractions of interactive mixtures with Lactohale LH homogeneity, suggesting that there may be an optimum amount of 322
200 aerosolised from devices with different resistances as a function of the total 323
fines required to saturate potential ‘strong' binding sites, the
fines content. Data represent mean
SD (n = 4).

Please cite this article in press as: Hassoun, M., et al., Formulating powder–device combinations for salmeterol xinafoate dry powder inhalers.
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6 M. Hassoun et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx

Fig. 4. Mean fine particle fraction (FPF) of the pairs of interactive mixtures aerosolised from devices of different resistances. Composition of interactive mixtures (coarse
lactose grade; total fines content) are (a) LHF 5 (LH 200; 11.7% w/w) and M1F0 (ML001; 12.5% w/w); and (b) LHF10 (LH200; 16.7% w/w) and M1F5 (ML001; 17.5% w/w). All
blends contained a 0.08% w/w of magnesium stearate. Data are presented as a mean
SD (n = 4) and statistical analysis was completed using a two-way ANOVA.

324 concentration being specific to each of the lactose grades, and that stages of the NGI, hence why M6F0 produced larger MMADs and 371
325 carrier PSD was critical to blend homogeneity. Large carrier lower FPFs than M1F0. 372
326 particles in Lactohale H200 for example, tend to generate higher The addition of 5% w/w fines to M1F0 (to produce M1F5) did not 373
327 forces and reduced powder cohesion in comparison to the smaller affect FPF which might suggest a high degree of carrier active site 374
328 particles, with the consequence that less energy from the occupancy by the drug in M1F0. The added fines therefore did not 375
329 aerosolisation manoeuvre was needed to break up agglomerates impact the SX-carrier adhesion and thus did not influence drug 376
330 and overcome forces adhering SX particles to the surface of the deposition, resulting in similar overall deposition profiles of 377
331 carrier particles. Lactohale may also exhibit rougher surfaces than salmeterol for both formulations. Interestingly, a significant 378
332 the other lactose grades (Pilcer et al., 2012) causing the SX particles difference in FPF was observed between M1F0 and LHF 5, which 379
333 to accumulate in surface discontinuities and remain adhered to the had similar total fines content, and might be attributable to the 380
334 carrier (Dickhoff et al., 2003), providing a possible explanation for active sites present in Lactohale LH 200 remaining only partially 381
335 why mixtures containing Lactohale H200 exhibited better blend saturated, due to the greater number of active sites on the latter 382
336 homogeneity than the other formulations despite having higher compared with Respitose ML001. The high drug deposition in the 383
337 total fines content. It would also explain why mixtures containing pre-separator observed for LHF 5, indicated that a significant 384
338 Respitose ML006 and ML001 had poor blend homogeneity; i.e. a proportion of SX particles remained adhered to carrier surface. 385
339 result of carrier surface smoothness and the higher concentrations However, further increases in fines content resulted in the LHF 386
340 of fines, which meant that there was less SX-carrier adhesion. 10 formulation exhibiting a similar aerosol performance to M1F5, 387
341 Unfortunately, a morphological evaluation of the blends was not which was consistent with active site saturation in both interactive 388
342 performed to investigate this hypothesis further. mixtures and a critical role for active site occupancy in determining 389
343 The high deposition of salmeterol in the pre-separator and the the efficiency of drug dispersion. 390
344 low FPF for the LHF 0 blend was attributed to the carrier. The addition of fines had a variable impact on ED. Fines are 391
345 Lactohale1 LH 200 consists predominantly of coarse carrier known to affect the bulk powder properties of the formulation and 392
346 particles, with large irregular surfaces and low intrinsic fines. hence the mechanism of powder entrainment and drug dispersion 393
347 Therefore, the micronized SX particles would adhere readily to the (Shur et al., 2008; Zeng et al., 2001; Grasmejjer et al., 2014). 394
348 surfaces, making it difficult to dislodge during dispersion of the Particles in formulations such as LHF 0 entrain into the air stream 395
349 aerosol from the device. For M1F0 Respitose1 ML001, the higher either as layers via an erosion mechanism or as multiple small 396
350 intrinsic fines content (defined as the proportion of particles that plugs by a fracture mechanism. The mean ED for LHF 0 was high, 397
351 had equivalent volume diameter of <10 mm, according to the indicating a powder that was poorly adhered to the capsule walls 398
352 manufacturer’s batch specifications) may have saturated the compared with other formulations. With the higher total fines 399
353 available binding sites. Alternatively the excess fines could have content present in LHF 5, the fracture mechanism is likely to 400
354 formed layers of fine lactose particles on the carrier surface become more prominent, although the tendency to reduce drug 401
355 (Grasmeijer et al., 2014). Either of these mechanisms might provide retention in the device under these conditions appears to have 402
356 an explanation for the greatly reduced adhesion between SX and been offset by an increased adhesion to the capsule walls as a 403
357 carrier particles. In addition, the broad PSD of Respitose1 reduced emitted dose was observed for LHF 5. A further increase in 404
358 ML001 indicated that this grade of lactose contained a high total fines content appear to have increased powder cohesion 405
359 proportion of intermediate-sized lactose particles, from which SX above a threshold that enables powder to entrain as a single plug, 406
360 particles might expect to detach and disperse easily, resulting in aiding the de-agglomeration process, and overcoming the strength 407
361 the low MMAD and high FPF of SX that was observed. The presence of the adhesive forces to the capsule wall and reducing drug 408
362 of intermediate-sized carriers might also account for the lower ED retention LH 20 (Shur et al., 2008). Such a mechanism could 409
363 for M1F0, as reported previously for formulations of salbutamol explain the observed increase in mean emitted dose. 410
364 sulphate (Zeng et al., 1998). The physical characteristics of The addition of fines may also improve drug dispersion by 411
365 Respitose ML006 may have allowed for formation of agglomerates reducing the SX-carrier adhesion and promoting the formation of 412
366 with the SX particles which, if sufficiently small, enable effective loose agglomerates (Jones and Price, 2006). Fine lactose preferen- 413
367 lung penetration and deposition without the need for de- tially adheres to amorphous active site regions or to areas with 414
368 agglomeration. This may have accounted for the higher FPF high surface energy, thereby possibly displacing the SX particles to 415
369 observed with M6F0 compared to LHF 0. However, due to their weaker binding sites thus allowing for easier detachment during 416
370 larger diameters, the SX-fines agglomerates deposited at earlier aerosolisation. The formation of layers of fines on carrier surfaces 417

Please cite this article in press as: Hassoun, M., et al., Formulating powder–device combinations for salmeterol xinafoate dry powder inhalers.
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418 act like a buffer against the frictional and inertial forces that A number of promising formulation–device combinations were 459
419 promote SX-carrier adhesion during mixing and thus prevent identified during this study (Fig. 5), with a total of nine 460
420 direct contact between the coarse carrier and SX particles. Instead, combinations meeting the performance specification defined at 461
421 SX-fines agglomerates are formed which have a larger detachment outset. Regardless of the device used, most formulations, except 462
422 mass, making it easier for agglomerates to dislodge from the carrier the M6F0 and LHF 0 mixtures, gave an MMAD between 1 and 5 mm, 463
423 surface than individual SX particles. This provides a rationale for showing that the coarse lactose grades formed an ordered mix and 464
424 the increase in fines content to 10% w/w (LHF 10) causing a allowed satisfactory detachment of drug particles small enough to 465
425 reduction in SX deposition in the pre-separator and an increased deposit deeper into the airways. For the M6F0 and LHF 0 binary 466
426 deposition in stages 2–5. At higher concentrations of fines the mixtures, the deficiency of fine lactose in these formulations 467
427 effect on FPF became less significant since the carrier active sites resulted in larger MMAD values. 468
428 were saturated, limiting the adhesion of the SX-fines agglomerates For effective lower airways deposition, the aerodynamic 469
429 and thus causing blend segregation. particle size of emitted aerosol particles should lie within the 470
430 The devices were utilised at flow rates that produced three range of 1–5 mm (Labiris and Dolovich, 2003). The extent of 471
431 different pressure drops. The Rotahaler and Aerolizer devices were detachment and hence the FPF values were dependent on the 472
432 tested at 100 L min1, but this flow rate cannot be attained by inhaler device (Fig. 5). For the Rotahaler, it was evident that only 473
433 patients with the Handihaler due to its high internal resistance, the well-performing LHF 20 interactive mixture fell within the 474
434 thus it was actuated at its maximum peak inspiratory flow rate, desired region. However, since the device exhibited the lowest 475
435 60 L min1 (Al-showair et al., 2007). Increased internal resistance internal resistance, airflow did not reach the required tortuosity 476
436 was associated with reduced device retention. This was as a result during actuation to overcome the interparticulate adhesion and 477
437 of the larger pressure drops that developed across the device, produce a high FPF (Coates et al., 2006). The higher resistance 478
438 generating higher air velocities and local turbulences thereby devices produced more formulation–device combinations that 479
439 generating greater particle detachment forces to overcome the met the specified performance criteria. This was due to the 480
440 adhesion of the powder to the capsule wall (Mendes et al., 2007). increased turbulence in the air stream and the larger aerodynamic 481
441 This accounted for the increased mouth and throat deposition drag forces exerted on the carrier, which promoted successful drug 482
442 observed with high device resistance and the minimal deposition detachment, producing the desired FPF and MMAD. Of these, the 483
443 seen for the LHF 0 formulation was due to its good powder LHF 20-Aerolizer1 produced the highest FPF and was selected as 484
444 flowability and higher particle size. The comparison between the the optimal formulation–device combination. 485
445 Rotahaler and Aerolizer illustrated that, at a given flow rate a
446 device with higher resistance improves drug dispersion. 5. Conclusions 486
447 Given that the inspiratory volume in this study was constant at
448 4 L, the pressure drop developed across the device was indicative of Carrier particle PSD, the concentration of added fines in the 487
449 the inspiratory effort used in the in vitro deposition studies formulation and inhaler device resistance influenced product 488
450 (Janssens et al., 2008). It was evident that despite a larger pressure performance as would be expected on the basis of results from 489
451 drop, i.e. greater inspiratory effort, aerosols generated by the previous studies. It was evident that aerosol performance was 490
452 Handihaler produced lower FPFs than the Aerolizer. Therefore, for dependent on a combination of these factors and it was paramount 491
453 any given formulation, the Aerolizer was preferred from the to optimise the formulation and the device together in order to 492
454 standpoint of dispersion efficiency and patient comfort. This may achieve an efficient deposition of micronized drug particles deep 493
455 be due to an influence of the flow field within the inhaler device, into the lungs. The optimisation process, using the 32 factorial 494
456 which affects air turbulence as well as the site and frequency of design, was not completed fully due to the failure of the interactive 495
457 particle-particle and particle-device collisions (De Boer et al., mixtures M6F0, M6F10 and M1F10 in achieving acceptable blend 496
458 2012). homogeneity. This study demonstrated how theoretically-deter- 497

mined inter-dependent formulation and device factors impact in 498

Fig. 5. Performance of the formulation–device combinations. Formulations, within the areas marked ‘x’ met the criteria of providing a mean emitted dose 80% and a mean
MMAD
GSD within the range of 1–5 mm.

Please cite this article in press as: Hassoun, M., et al., Formulating powder–device combinations for salmeterol xinafoate dry powder inhalers.
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8 M. Hassoun et al. / International Journal of Pharmaceutics xxx (2015) xxx–xxx

499 practice on product performance and how their relative signifi- Hoppentocht, M., Hagedoorn, O., Frijlink, H.W., de Boer, A.H., 2014. Technological 554
500 and practical challenges of dry powder inhalers and formulations. Adv. Drug 555
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The authors would like to kindly thank Professor Gary Martin 564
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507 Appendix A. Supplementary data
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performance of carrier-based dry powder inhalation formulations. Pharm. Res. 570
508 571
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Please cite this article in press as: Hassoun, M., et al., Formulating powder–device combinations for salmeterol xinafoate dry powder inhalers.
Int J Pharmaceut (2015), http://dx.doi.org/10.1016/j.ijpharm.2015.05.028