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Capabilities and limitations of using powder rheology and permeability to predict dry powder inhaler performance
European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 417–423
Contents lists available at SciVerse ScienceDirect
European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb
Research paper
Capabilities and limitations of using powder rheology and permeability to predict dry powder inhaler performance Eike Cordts, Hartwig Steckel ⇑ Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University, Kiel, Germany
a r t i c l e
i n f o
Article history: Received 3 May 2012 Accepted in revised form 27 July 2012 Available online 9 August 2012 Keywords: Powder rheology Ternary adhesive mixtures Excipient fines Fluidization Permeability Dry powder inhaler
a b s t r a c t Dry Powder Inhalers play a major role in today’s treatment of various respiratory diseases. A lot of effort has been put into the optimization of a device and the appropriate formulation regarding its local lung deposition. However, the complexity and interactions of different factors governing powder dispersion and, therefore, its inhalable fraction challenge research groups around the world. In the current work, binary lactose blends and adhesive ternary powder mixtures containing additional budesonide fines were produced and analyzed with dispersion measurements on the one hand and permeability and aeration measurements conducted with a powder rheometer on the other hand. By comparing the results of the bulk property and dispersion tests, it was expected to gain a better understanding about the effect of excipient fines addition to an adhesive powder mixture. It could be observed that with permeability testing it was possible to clearly differentiate between different amounts of fines within mixtures. However, no correlation between permeability or aeration test values and drug fine particle fraction could be determined for the observed range. Nevertheless, the use of different characterization techniques led to a clearer understanding about the influence of fines addition to an adhesive mixture. It could be demonstrated that after the surface of carrier crystals had been fully saturated, drug particles got incorporated in more stable fines’ agglomerates, which resulted in a decrease in fine particle fraction upon dispersion. Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction Over the past years, a lot of effort has been put into the development of Dry Powder Inhalers (DPIs). Originally designed as a substitute for chlorofluorocarbon pressurized metered dose inhalers (CFC-pMDIs), the dry dispersion devices play an important role in today’s treatment of several respiratory diseases and present an economic alternative to the simultaneously developed hydrofluoroalkane pMDIs [1–3]. In most of the dry powder inhaler formulations on the market, the active pharmaceutical ingredient (API) is not administered solely, but formulated as an adhesive mixture containing further excipients, such as lactose. The need to utilize drug particles smaller than 5 lm in order to obtain a local deposition within the lungs leads to a variety of challenges arising upon handling, dosing, and inhalation of the powder. The micronized powder tends to form agglomerates and stick to production and filling equipment due to triboelectrification, thus complicating the technical handling of ⇑ Corresponding author. Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University, Gutenbergstr. 76, 24118 Kiel, Germany. Tel.: +49 431 880 1330; fax: +49 431 880 1352. E-mail addresses: [email protected] (E. Cordts), hsteckel@pharma zie.uni-kiel.de (H. Steckel). 0939-6411/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejpb.2012.07.018
the powdered product. In order to avoid these problems as far as possible, the micronized API is either formulated together with a coarse carrier, mostly lactose, or as a ternary adhesive mixture including a third, micronized component. The addition of excipient fines as a ternary component was found to increase the resulting inhalable fraction of the API significantly [4] and is, therefore, referred to as performance modifying additive. Despite yearlong research by various groups, the complex interactions between powder particles in mixtures for inhalation are still not fully understood. Whereas with the ‘‘active site’’ theory differences in surface energies of the carrier are being discussed [5], other approaches such as the formation of less stable fine multiplets within a mixture have been debated as a reason for an observed increase in drug fine particle fraction (FPF) [6]. Also, not only the characteristics of the powder excipients should be made responsible for the dispersion properties of a ternary blend, the influence of the mixing process has to be reflected as well [7]. Finally, dispersion efficiency is also influenced by the device used to apply the powder blend [8]. The current work used techniques provided by a powder rheometer to gain a better understanding of the change in bulk powder properties upon addition of fine lactose particles to a lactose carrier or a drug fines/lactose carrier mixture. The particular rheometer used in this study gives the opportunity to collect data
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during the induction of air through the powder sample. This being an indispensable part during the inhalation process through a DPI, it was expected to obtain a better understanding about changes in decisive powder properties within the bulk. In a previous study, Le et al. proposed a linear correlation between permeability values and the resulting drug fine particle fraction upon dispersion of a ternary adhesive powder mixture [9]. Also, Price’s group has found a linear correlation between Aeration Energy and FPF of a ternary budesonide mixture [10]. Both groups used commercially available, capsule based dry powder inhalers (Inhalator Ingelheim and Cyclohaler, respectively) for their dispersion experiments. In the present study, a device with comparably low turbulent air flow was used for dispersion measurements, thus lowering the device impact on the magnitude of FPF (fraction <5 lm). Therefore, the aim of this study was to relate the different bulk powder test results to the change in FPF upon aerosolization. With this, it was expected to obtain a further understanding of the actual effect of fines within a ternary adhesive mixture.
performed according to the preparation of the binary lactose mixtures. Table 1 lists the used materials and corresponding particle size distributions obtained with laser diffraction measurements (HELOS RODOS dry powder disperser, 3 bar, n = 3). After mixing, homogeneity (Section 2.1.2.1) and the exact content of budesonide in the blends were determined via HPLC (Section 2.3.2.1).
2. Materials and methods
A Freeman FT4 powder rheometer (Freeman Technology, Gloucestershire, UK) was used to analyze rheological properties of the obtained adhesive mixtures. It was of particular interest to observe the powder’s behavior upon air entrainment and the change of permeability with increasing amounts of fines within the mixtures.
2.1. Preparation of adhesive mixtures The blends were produced with a T2C turbula blender (W.A. Bachofen AG, Basel, Switzerland) at 42 rpm in cylindrical 250 ml polypropylene vessels (height, 75.5 mm; diameter, 65 mm). The starting materials were sieved through a 355 lm sieve in order to destroy larger agglomerates prior to weighing and bringing together the separate powders. The addition of starting materials to the mixing vessel was carried out in alternate layers: lactose carrier – lactose fines – lactose carrier [–micronized API – lactose carrier] – lactose fines – lactose carrier. The vessel’s filling volume ranged from approximately 30–50%. During the mixing process, the powder blends were given through a 355 lm sieve after 15 and 30 min to destroy agglomerates of fine material that might have been formed during the beginning of the mixing process. The overall duration of the mixing sums up to 45 min for each powder blend. 2.1.1. Binary mixtures For the binary powder blends, RespitoseÒ SV003 (DMV-Fonterra, Vehgel, The Netherlands) was used as a carrier and increasing amounts of a micronized lactose, LactohaleÒ LH 300 (Friesland Foods Domo, Zwolle, The Netherlands), acted as the second component. The material’s particle size distribution (PSD) is shown in Table 1. Different amounts of LH 300 fines were added to the lactose carrier in order to obtain mixtures with a stepwise (2.5%) increase in fines content, covering a range from 0% to 20.0% (w/w) in the final mixtures of 60.0 g. 2.1.2. Ternary mixtures Ternary adhesive mixtures contained additionally 0.8–1% (w/w) micronized budesonide (Shanghai Hengtian Pharmaceutical Co., Ltd., Shanghai, China). The preparation of the ternary blends was
2.1.2.1. Homogeneity. Nine 15 mg samples from the ternary blend containing 2.5% LH300 – three samples from the top, three from the middle and three from the bottom of the mixing vessel – have been analyzed via HPLC. The ternary mixture containing 20.0% LH300 has been analyzed accordingly. From the remaining blends, three samples were taken and analyzed. Sufficient homogeneity was assumed for the mixtures if the coefficient of variation (CV) remained below 5%. 2.2. Powder rheology measurements
2.2.1. Permeability testing The permeability test set-up (Fig. 1) consisted of a 25 mm 10 mL bore borosilicate split vessel, a porous aeration base connected to an aeration control unit (ACU), a 24 mm vented piston, and a 23.5 mm blade for conditioning. The ACU kept the air flow through the porous base constant at 2 mm/s while the normal stress applied by the vented piston increased in eight steps up to 15 kPa normal stress. Thus, permeability values for each applied normal stress could be obtained. The pressure drop across the powder bed served as a parameter for comparison of the different powder blends. The corresponding permeability values can be calculated using Darcy’s law:
Q¼
k A DP l L
ð1Þ
Q is the volume air flow (cm3/s), A the cross-sectional area of the powder bed (cm2), DP expresses the pressure drop across the powder bed (Pa), l represents the viscosity of the air (1.74 105 Pa s), and L is the length of the powder bed (cm). After rearranging and simplifying Eq. (1) with the introduction of the flux q (cm/s) (2), a value for the permeability k (cm2) can be obtained (3):
q¼
Q A
ð2Þ
k¼
qlL DP
ð3Þ
Each test was repeated three times; for every repeat, a new powder sample from the original blend was used.
Quality Sieved
Lactohale® LH 300
Micronized
Budesonide
Micronized
x10 (±SD) 14.13 µm (±4.91 µm) 0.90 µm (±0.00 µm) 0.41 µm (±0.02 µm)
x 50 (±SD) 56.76 µm (±0.74 µm) 3.25 µm (±0.09 µm) 1.35 µm (±0.01 µm)
x 90 (±SD) 93.04 µm (±1.44 µm) 7.46 µm (±0.18 µm) 3.70 µm (±0.04 µm)
Binary
Material Respitose® SV003
Ternary
Table 1 Particle size distributions of each component used in the blends.
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normal stress
Δp
air 2 mm/s
air
Fig. 1. Schematic of permeability test set-up.
Fig. 2. Schematic of aeration test set-up.
2.2.2. Aeration testing The aeration test set-up included a porous aeration base connected to the ACU, a 25 mm 35 mL bore borosilicate nonsplit vessel and the 23.5 mm blade (Fig. 2). After filling the vessel with 25 mL of powder sample, the twisted blade started its downward helical path through the powder bulk, which induces a specific flow pattern within the bulk. The energy needed to establish this specific flow was recorded. Regulated by the ACU, increasing amounts of air were fed through the porous base while measuring the resulting total energies of the blade. With the up-regulation of supplied air, the energy measured by the blade decreases until reaching a constant minimum. At this point, the powder sample had been fully fluidized; the energy measured at this point is called the minimum fluidization energy. Further, each powder sample can be characterized by the calculation of the Aeration Ratio (AR) [11]:
However, the sample mass can be reduced from the equation when calculating the AR by dividing one total energy value of a sample by another. For this study, a test program was generated starting at an air throughput of 0 mm/s and ranging up to 8 mm/s. Prior to the aeration tests, multiple basic flowability energy (BFE) measurements without air throughput had been carried out to ensure that the powder samples remained stable for the duration of the aeration test sequence and the measured flow energies were not influenced by other factors, such as segregation, further consolidation. The aeration tests were then performed in triplicate.
2.3. Dispersion measurements
ð4Þ
Binary and ternary mixtures were dispersed with a model device developed at the department of Pharmaceutics and Biopharmaceutics, University of Kiel [12], at an inspiration flow of 80 L/min. This corresponds to a pressure drop of 4 kPa for this particular application system.
The calculation of AR takes into account that different flow energies are being recorded not only because of the reaction to air throughput, but also due to differences in sample masses. The decrease in bulk density that goes along with increasing amounts of fines within a mixture already leads to differences in measured flow energies and makes comparability between mixtures difficult.
2.3.1. Laser diffraction The particle fraction <5 lm of the binary powder blends was determined with a Sympatec Helium–Neon Laser Optical System (HELOS) and the corresponding INHALER module (all Sympatec GmbH, Clausthal-Zellerfeld, Germany). The calculation of the parti-
AR ¼
total energy at 0 mm=s air throughput minimum fluidization energy
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cle diameter was done via the system’s Windox 5 software based on FREE (Fraunhofer Enhanced Evaluation). For each measurement, 15 mg of the binary blends were applied through the model device. 2.3.2. Impaction measurements To determine the drug’s fine particle fraction (FPF, fraction <5 lm) of the ternary blends, a Next Generation Impactor with preseparator (NGI) (Copley Scientific, Nottingham, UK) was used. Again, the model device was utilized at 80 L/min (4 kPa) to apply the powder mixture. To increase the amount of drug per stage, ten doses of 15 mg were administered before rinsing the cups with defined volumes of a double-distilled water (ddH20): methanol mixture (25%:75%) followed by analysis via HPLC. Prior to the application of the powder blends, the preseparator and stages had been coated with small layers of a BrijÒ 35 – glycerol – ethanol solution to reduce possible bouncing of the particles. Without this coating, the measured particle size distributions would have shifted toward lower aerodynamic particle diameters. The FPF of the delivered dose was calculated with CITDAS 3.0 software (Copley Scientific, Nottingham, UK). 2.3.2.1. HPLC analysis. The budesonide content of the samples was quantified with the following HPLC method: – LiChroCARTÒ 125-4 LiChrospherÒ 100 RP-18 (5 lm) with precolumn (Merck KGaA, Darmstadt, Germany) – Mobile phase: ddH2O: methanol (25%:75%) – Flow: 1 mL/min – Wavelength of UV detector: 248 nm A calibration curve (R2 = 1.0000) was generated and utilized to calculate the amount of budesonide within the samples. 3. Results and discussion 3.1. Fraction <5 lm 3.1.1. Binary adhesive mixtures Laser diffraction results for the binary lactose powder mixtures (Fig. 3) show, as expected, a significant increase in the fraction of particles <5 lm with increasing amounts of LH300 fines within the mixtures. However, above a LH300 content of 7.5%, the curve approaches a plateau at around 15%. A possible explanation for this behavior is the formation of stable agglomerates with further addition of lactose fines. Whereas, at
the beginning, lactose fines are able to bind to the lactose carrier surface in monolayers and are easily detached during dispersion, further addition of fines may lead to the saturation of the carrier surface. Thus, an excess of fines results in the formation of agglomerates, which remain stable to a certain extent upon dispersion.
3.1.2. Ternary adhesive mixtures Up to 7.5% LH300 fines within the ternary blends, an increase in budesonide FPF can be observed. This trend accords to the changes seen for the lactose fraction <5 lm of the binary mixtures: The addition of LH300 fines leads to a clear increase in resulting FPF, but only up to a certain threshold. After reaching this threshold, the budesonide FPF drops again – a content of 20.0% LH300 results in an even lower FPF compared to the FPF of the starting mixture of untreated RespitoseÒ SV003 and budesonide without additional fines (Fig. 4). Again, this behavior could be explained with the formation of stable agglomerates. During the mixing process, budesonide fines start adhering to the carrier surface and get detached upon dispersion. With the addition of lactose fines, budesonide fines compete for binding sites on the carrier surface, resulting in a distribution toward lower energy binding sites. This shift toward lower energy binding sites leads to a higher dispersion efficiency and thus to the increase in FPF seen by NGI measurements. A fines content of 7.5% (+ the amount of intrinsic fines of the RespitoseÒ SV003) seems to be the most beneficial for this particular set-up. The addition of more LH300 fines leads to a further displacement of budesonide fines, supposedly toward either drug fines agglomerates or drug/lactose fines agglomerates, which are more dispersion insensitive. Since with higher amounts of LH300 fines more budesonide gets displaced from the carrier surface and gets incorporated in the described agglomerates, the resulting FPF drops significantly. This hypothesis can be supported by studies from Young et al. [13] and Louey et al. [14]. Both groups proposed a linear increase in FPF with increasing amounts of excipient fines up to a certain threshold value (10% and 13.9%, respectively). Further addition of fines resulted in a clear decrease in fine particle fraction. Young et al. speculated that above this threshold value, drug fines/lactose agglomerates fail to adhere to the larger lactose monohydrate carrier particles and become segregated. The authors further assumed that this biphasic system is likely to result in deviation from an expected agglomerate–carrier relationship and therefore can be seen as a cause for the decrease in FPF.
HELOS INHALER binary adhesive mixtures
NGI ternary adhesive mixtures
20.0
35.0
fraction < 5 µm, %
fraction < 5 µm, %
30.0 15.0
10.0
5.0
25.0 20.0 15.0 10.0 5.0
0.0 0.0
5.0
10.0
15.0
LH300 fines, % Fig. 3. Laser diffraction data, FPF versus LH300 content.
20.0
0.0 0.0
5.0
10.0
15.0
LH300 fines, % Fig. 4. NGI data, FPF versus LH300 content.
20.0
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0.0% LH300 2.5% LH300 5.0% LH300 7.5% LH300 10.0% LH300 12.5% LH300 15.0% LH300 17.5% LH300 20.0% LH300
pressure drop across powder bed ternary adhesive mixtures
pressure drop across powder bed, mbar
permeability * 109, cm²
permeability binary adhesive mixtures
20.0% LH300 17.5% LH300 15.0% LH300 12.5% LH300 10.0% LH300 7.5% LH300 5.0% LH300 2.5% LH300 0.0% LH300
normal stress, mJ
normal stress, mJ
Fig. 6b. Pressure drop across powder bed of ternary powder blends.
pressure drop across powder bed, mbar
Fig. 5a. Permeability of binary lactose powder blends.
pressure drop across powder bed binary adhesive mixtures
20.0% LH300 17.5% LH300 15.0% LH300 12.5% LH300 10.0% LH300 7.5% LH300 5.0% LH300 2.5% LH300 0.0% LH300
normal stress, mJ Fig. 5b. Pressure drop across powder bed of binary lactose powder blends.
permeability * 109, cm²
permeability ternary adhesive mixtures
0.0% LH300 2.5% LH300 5.0% LH300 7.5% LH300 10.0% LH300 12.5% LH300 15.0% LH300 17.5% LH300 20.0% LH300
agglomerates was discussed as an explanation for the behavior seen in dispersion performance (Sections 3.1.1 and 3.1.2 and 3.1.2), the applied normal stress in the permeability test set-up leads to a destruction of agglomerates and prevents influences caused by these particle formations. For the binary blends, a linear correlation (R2 = 0.9924, 15 kPa) between the pressure drop across the powder bed (DP) and the amount of added fines can be detected. In contrast, permeability values seem to drop exponentially with the increase in fines since its calculation accounts for the higher compressibility of blends with larger contents of fines. Taking a look at the analysis of linear regression of the pressure drop across the powder bed and added LH300 fines of the ternary mixtures, the coefficient of determination drops to 0.9683. The drop in R2 value is attended by the larger error bars within the graphs for the ternary blends. Whereas the prediction of fines within the mixture based on the linear regression of the pressure drop across the powder bed works well for each separate system (binary and ternary, respectively), no generalized equation for the prediction of overall fines via permeability measurements can be obtained. This is not surprising, since differences in lactose and budesonide fines morphology lead to different characteristics of the overall blends, that is, different reactions to air throughput.
3.2.2. Aeration tests As stated in the methods section, for aeration testing, the induced air flow was increased from 0 to 8 mm/s and the resulting
aeration tests binary adhesive mixtures normal stress, mJ
200
3.2. Powder rheology measurements 3.2.1. Permeability measurements Permeability results and the corresponding values for the pressure drop across the powder bed of the binary (Figs. 5a and 5b) and ternary blends (Figs. 6a and 6b) indicate a correlation to the overall fines content. As expected, the more fines within the mixtures, the smaller the permeability value at a given applied normal stress. The fine particles fill up residual spaces between the larger carrier particles and, therefore, upon compression lead to an increase in resistance to air throughput. Whereas the formation of fines
total energy, mJ
Fig. 6a. Permeability of ternary powder blends. 150
0.0% LH300 2.5% LH300 5.0% LH300 7.5% LH300 10.0% LH300 12.5% LH300 15.0% LH300 17.5% LH300 20.0% LH300
100
50
0 0
1
2
3
4
5
6
7
8
9
air speed, mm/s Fig. 7. Aeration test results of binary lactose blends.
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aeration tests ternary adhesive mixtures 300
total energy, mJ
250 0.0% LH300 2.5% LH300 5.0% LH300 7.5% LH300 10.0% LH300 12.5% LH300 15.0% LH300 17.5% LH300 20.0% LH300
200 150 100 50 0
0
1
2
3
4
5
6
7
8
9
air speed, mm/s Fig. 8. Aeration test results of ternary blends.
total energy of the blade was measured at set points within this range. To understand the characteristics of the aeration test curves (Figs. 7 and 8), the main influencing factors on the measured energy values of the blade should be pointed out. The larger the sample mass – respectively, the denser the powder bulk – the larger the expected energy values for the blade movement. Since the twisted blade needs to displace a larger mass, the resulting total energy increases accordingly. This behavior can be observed for the energy values at 0 mm/s air throughput. This trend turns over when taking a look at the minimum fluidization energies. At this point, the powder was fully fluidized and therefore the influence of the mass is negligible. Ideally, each powder particle is entrained separately within the airflow. In addition, attracting interparticle forces decrease as well. However, for the powder blends containing larger amounts of fines, the fines get entrained as stable agglomerates rather than as single particles. This results in an increase in total energy measured by the blade, since larger amounts of energy are needed to cut through these agglomerates. To exclude the influence of different sample masses, the aeration ratio should be used for comparison instead (Fig. 9). It is apparent that the addition of fines to a coarse lactose carrier results in a drop in aeration ratio. However, above an addition of 5.0% LH300 fines, the AR remains nearly constant. 3.3. Comparison of dispersion and powder rheology measurements While the comparison of permeability values to the total amount of fines added to a mixture results in a decent correlation, Aeration Ratio (AR)
60.0
Aeration Ratio
50.0 40.0 30.0
no significance of the permeability toward the amount of released fines <5 lm upon dispersion can be obtained. This seems to be contrary to the findings of Le et al. [9], who proposed a linear correlation between the drug fine particle fraction of lactose mixtures containing fluticasone propionate or terbutaline sulfate and the air permeability measured with an adapted Blaine apparatus. But a more detailed look at the findings in their paper reveals the differences to the current study: The authors varied the amounts of ternary fines in their mixtures only within ranges that remain below 7.5% overall fines. Having this in mind, the findings indeed match the results obtained for the ternary budesonide mixtures, since the increase in FPF stays linear up to a LH300 addition of 7.5%. Again, a further increase in fines within the mixtures leads to the loss of linear correlation. Also, the data generated by Price [10] suggest a linear correlation of fluidization energy (measured with a Freeman FT4 powder rheometer) and budesonide fine particle dose (FPD) up to an excipient fines content of 20.0%. This group did not detect a drop in FPD above an excipient fines content of 7.5% as seen in this current work. Since the main parameters of the adhesive powder blends used by Price and the ones used for this work are alike, the differences in results have to be linked to the impact of the different devices used for dispersion. Price’s group has used the Cyclohaler for their tests, in which the formulation is effected by more turbulent air flow at a higher air flow rate compared to the model device used in this work. The experimental data of the current work match well with the already stated theory of a stable agglomerate formation with higher amounts of excipient fines. Drug/excipient fines in amounts up to approximately 7.5% adhere mostly to the lactose carrier surface, which results in an increase in particle fraction <5 lm upon dispersion as supported by the HELOS and NGI data. This trend is consistent with the decrease in aeration ratio measured with the powder rheometer. Direct correlation of the increase in fraction <5 lm to the drop in AR shows a discrepancy toward larger amounts of added fines. Whereas the aeration ratio remains constant above a fines content of 5%, the fraction <5 lm detected with dispersion measurements still increases up to a LH300 addition of 10.0% for the binary mixtures or 7.5% for the ternary adhesive mixtures, respectively. To understand this discrepancy, the formation of stable agglomerates still serves as a good explanation for both trends. It has to be considered that for dispersion measurements, larger forces take effect on the powder sample during dispersion. For aeration tests, however, a comparatively small amount of air gets fed through the powder sample and, therefore, the integrity of the sample is a lot less disturbed by the air throughput. As a result, more formed fine agglomerates remain intact for the aeration tests compared to the dispersion measurements, which explains the discrepancy in the obtained values around 7.5–10.0% LH300. If this was the case, a small part of the increase in budesonide FPF needs to be attributed to a better dispersion of less stable drug/fines agglomerates as well, rather than to attribute the FPF increase only to the displacement of budesonide fines toward lower energy sites on the lactose carrier.
20.0
4. Conclusion 10.0 0.0
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
LH300 fines, % ternary budesonide blends
binary lactose blends
Fig. 9. Aeration ratios of lactose and budesonide blends.
20.0
By comparing the results of dispersion measurements with data from permeability and aeration tests provided by a Freeman FT4 powder rheometer, it was possible to obtain a better understanding about the influence of excipient fines to a budesonide fines/lactose carrier mixture with respect to the achieved fine particle fraction.
E. Cordts, H. Steckel / European Journal of Pharmaceutics and Biopharmaceutics 82 (2012) 417–423
Whereas small amounts of excipient fines are able to displace drug fines toward lower energy binding sites on the lactose carrier surface and therefore lead to an increase in FPF, the results obtained with the powder rheometer suggest the formation of stable, and therefore less dispersible, fines agglomerates with the further, successive increase in excipient fines within a ternary adhesive mixture. This agglomerate theory takes account of the decrease in drug FPF seen in the dispersion test results. However, this study has not confirmed that powder permeability and aeration measurements can generally be used to predict the drug fine particle fraction of a ternary adhesive mixture. This work clearly shows the need for a carefully composed powder mixture, in order to maximize the resulting lung deposition upon inhalation. Powder rheology measurements can help to gain a better understanding about the impact of complex interactions between powder particles within a mixture.
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[3] M.P. Timsina, G.P. Martin, C. Marriott, D. Ganderton, M. Yianneskis, Drug delivery to the respiratory tract using dry powder inhalers, International Journal of Pharmaceutics 101 (1994) 1–13. [4] M.D. Louey, P.J. Stewart, Particle interactions involved in aerosol dispersion of ternary interactive mixtures, Pharmaceutical Research 19 (2002) 1524–1531. [5] J.N. Staniforth, Pre-formulation aspects of dry powder aerosols, in: Proceedings from Respiratory Drug Delivery V, Phoenix, AZ, 1996, pp. 65–73. [6] M. Jones, R. Price, The influence of fine excipient particles on the performance of carrier-based dry powder inhalation formulations, Pharmaceutical Research 23 (2006) 1665–1674. [7] B.H.J. Dickhoff, A.H. de Boer, D. Lambregts, H.W. Frijlink, The effect of carrier surface treatment on drug particle detachment from crystalline carriers in adhesive mixtures for inhalation, International Journal of Pharmaceutics 327 (2006) 17–25. [8] A.H. de Boer, H.K. Chan, R. Price, A critical view on lactose-based drug formulation and device studies for dry powder inhalation: Which are relevant and what interactions to expect?: Lactose as a carrier for inhalation products, Advanced Drug Delivery Reviews 64 (2012) 257–274. [9] V.N.P. Le, E. Robins, M.P. Flament, Air permeability of powder: a potential tool for dry powder inhaler formulation development, European Journal of Pharmaceutics and Biopharmaceutics 76 (2010) 464–469. [10] R. Price, The Fluidisation Behaviour of Pharmaceutical Powders and their Influence on Particle Deaggregation, London, 2009. [11] Freeman Technology, Instruction Documents: W7015 Aeration Method, 2006. [12] H. Steckel, N. Bolzen, Alternative sugars as potential carriers for dry powder inhalations, International Journal of Pharmaceutics 270 (2004) 297–306. [13] P.M. Young, H.K. Chan, H. Chiou, S. Edge, T.H.S. Tee, D. Traini, The influence of mechanical processing of dry powder inhaler carriers on drug aerosolization performance, Journal of Pharmaceutical Sciences 96 (2007) 1331–1341. [14] M.D. Louey, S. Razia, P.J. Stewart, Influence of physico-chemical carrier properties on the in vitro aerosol deposition from interactive mixtures, International Journal of Pharmaceutics 252 (2003) 87–98.
Contents lists available at SciVerse ScienceDirect
European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb
Research paper
Capabilities and limitations of using powder rheology and permeability to predict dry powder inhaler performance Eike Cordts, Hartwig Steckel ⇑ Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University, Kiel, Germany
a r t i c l e
i n f o
Article history: Received 3 May 2012 Accepted in revised form 27 July 2012 Available online 9 August 2012 Keywords: Powder rheology Ternary adhesive mixtures Excipient fines Fluidization Permeability Dry powder inhaler
a b s t r a c t Dry Powder Inhalers play a major role in today’s treatment of various respiratory diseases. A lot of effort has been put into the optimization of a device and the appropriate formulation regarding its local lung deposition. However, the complexity and interactions of different factors governing powder dispersion and, therefore, its inhalable fraction challenge research groups around the world. In the current work, binary lactose blends and adhesive ternary powder mixtures containing additional budesonide fines were produced and analyzed with dispersion measurements on the one hand and permeability and aeration measurements conducted with a powder rheometer on the other hand. By comparing the results of the bulk property and dispersion tests, it was expected to gain a better understanding about the effect of excipient fines addition to an adhesive powder mixture. It could be observed that with permeability testing it was possible to clearly differentiate between different amounts of fines within mixtures. However, no correlation between permeability or aeration test values and drug fine particle fraction could be determined for the observed range. Nevertheless, the use of different characterization techniques led to a clearer understanding about the influence of fines addition to an adhesive mixture. It could be demonstrated that after the surface of carrier crystals had been fully saturated, drug particles got incorporated in more stable fines’ agglomerates, which resulted in a decrease in fine particle fraction upon dispersion. Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction Over the past years, a lot of effort has been put into the development of Dry Powder Inhalers (DPIs). Originally designed as a substitute for chlorofluorocarbon pressurized metered dose inhalers (CFC-pMDIs), the dry dispersion devices play an important role in today’s treatment of several respiratory diseases and present an economic alternative to the simultaneously developed hydrofluoroalkane pMDIs [1–3]. In most of the dry powder inhaler formulations on the market, the active pharmaceutical ingredient (API) is not administered solely, but formulated as an adhesive mixture containing further excipients, such as lactose. The need to utilize drug particles smaller than 5 lm in order to obtain a local deposition within the lungs leads to a variety of challenges arising upon handling, dosing, and inhalation of the powder. The micronized powder tends to form agglomerates and stick to production and filling equipment due to triboelectrification, thus complicating the technical handling of ⇑ Corresponding author. Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University, Gutenbergstr. 76, 24118 Kiel, Germany. Tel.: +49 431 880 1330; fax: +49 431 880 1352. E-mail addresses: [email protected] (E. Cordts), hsteckel@pharma zie.uni-kiel.de (H. Steckel). 0939-6411/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejpb.2012.07.018
the powdered product. In order to avoid these problems as far as possible, the micronized API is either formulated together with a coarse carrier, mostly lactose, or as a ternary adhesive mixture including a third, micronized component. The addition of excipient fines as a ternary component was found to increase the resulting inhalable fraction of the API significantly [4] and is, therefore, referred to as performance modifying additive. Despite yearlong research by various groups, the complex interactions between powder particles in mixtures for inhalation are still not fully understood. Whereas with the ‘‘active site’’ theory differences in surface energies of the carrier are being discussed [5], other approaches such as the formation of less stable fine multiplets within a mixture have been debated as a reason for an observed increase in drug fine particle fraction (FPF) [6]. Also, not only the characteristics of the powder excipients should be made responsible for the dispersion properties of a ternary blend, the influence of the mixing process has to be reflected as well [7]. Finally, dispersion efficiency is also influenced by the device used to apply the powder blend [8]. The current work used techniques provided by a powder rheometer to gain a better understanding of the change in bulk powder properties upon addition of fine lactose particles to a lactose carrier or a drug fines/lactose carrier mixture. The particular rheometer used in this study gives the opportunity to collect data
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during the induction of air through the powder sample. This being an indispensable part during the inhalation process through a DPI, it was expected to obtain a better understanding about changes in decisive powder properties within the bulk. In a previous study, Le et al. proposed a linear correlation between permeability values and the resulting drug fine particle fraction upon dispersion of a ternary adhesive powder mixture [9]. Also, Price’s group has found a linear correlation between Aeration Energy and FPF of a ternary budesonide mixture [10]. Both groups used commercially available, capsule based dry powder inhalers (Inhalator Ingelheim and Cyclohaler, respectively) for their dispersion experiments. In the present study, a device with comparably low turbulent air flow was used for dispersion measurements, thus lowering the device impact on the magnitude of FPF (fraction <5 lm). Therefore, the aim of this study was to relate the different bulk powder test results to the change in FPF upon aerosolization. With this, it was expected to obtain a further understanding of the actual effect of fines within a ternary adhesive mixture.
performed according to the preparation of the binary lactose mixtures. Table 1 lists the used materials and corresponding particle size distributions obtained with laser diffraction measurements (HELOS RODOS dry powder disperser, 3 bar, n = 3). After mixing, homogeneity (Section 2.1.2.1) and the exact content of budesonide in the blends were determined via HPLC (Section 2.3.2.1).
2. Materials and methods
A Freeman FT4 powder rheometer (Freeman Technology, Gloucestershire, UK) was used to analyze rheological properties of the obtained adhesive mixtures. It was of particular interest to observe the powder’s behavior upon air entrainment and the change of permeability with increasing amounts of fines within the mixtures.
2.1. Preparation of adhesive mixtures The blends were produced with a T2C turbula blender (W.A. Bachofen AG, Basel, Switzerland) at 42 rpm in cylindrical 250 ml polypropylene vessels (height, 75.5 mm; diameter, 65 mm). The starting materials were sieved through a 355 lm sieve in order to destroy larger agglomerates prior to weighing and bringing together the separate powders. The addition of starting materials to the mixing vessel was carried out in alternate layers: lactose carrier – lactose fines – lactose carrier [–micronized API – lactose carrier] – lactose fines – lactose carrier. The vessel’s filling volume ranged from approximately 30–50%. During the mixing process, the powder blends were given through a 355 lm sieve after 15 and 30 min to destroy agglomerates of fine material that might have been formed during the beginning of the mixing process. The overall duration of the mixing sums up to 45 min for each powder blend. 2.1.1. Binary mixtures For the binary powder blends, RespitoseÒ SV003 (DMV-Fonterra, Vehgel, The Netherlands) was used as a carrier and increasing amounts of a micronized lactose, LactohaleÒ LH 300 (Friesland Foods Domo, Zwolle, The Netherlands), acted as the second component. The material’s particle size distribution (PSD) is shown in Table 1. Different amounts of LH 300 fines were added to the lactose carrier in order to obtain mixtures with a stepwise (2.5%) increase in fines content, covering a range from 0% to 20.0% (w/w) in the final mixtures of 60.0 g. 2.1.2. Ternary mixtures Ternary adhesive mixtures contained additionally 0.8–1% (w/w) micronized budesonide (Shanghai Hengtian Pharmaceutical Co., Ltd., Shanghai, China). The preparation of the ternary blends was
2.1.2.1. Homogeneity. Nine 15 mg samples from the ternary blend containing 2.5% LH300 – three samples from the top, three from the middle and three from the bottom of the mixing vessel – have been analyzed via HPLC. The ternary mixture containing 20.0% LH300 has been analyzed accordingly. From the remaining blends, three samples were taken and analyzed. Sufficient homogeneity was assumed for the mixtures if the coefficient of variation (CV) remained below 5%. 2.2. Powder rheology measurements
2.2.1. Permeability testing The permeability test set-up (Fig. 1) consisted of a 25 mm 10 mL bore borosilicate split vessel, a porous aeration base connected to an aeration control unit (ACU), a 24 mm vented piston, and a 23.5 mm blade for conditioning. The ACU kept the air flow through the porous base constant at 2 mm/s while the normal stress applied by the vented piston increased in eight steps up to 15 kPa normal stress. Thus, permeability values for each applied normal stress could be obtained. The pressure drop across the powder bed served as a parameter for comparison of the different powder blends. The corresponding permeability values can be calculated using Darcy’s law:
Q¼
k A DP l L
ð1Þ
Q is the volume air flow (cm3/s), A the cross-sectional area of the powder bed (cm2), DP expresses the pressure drop across the powder bed (Pa), l represents the viscosity of the air (1.74 105 Pa s), and L is the length of the powder bed (cm). After rearranging and simplifying Eq. (1) with the introduction of the flux q (cm/s) (2), a value for the permeability k (cm2) can be obtained (3):
q¼
Q A
ð2Þ
k¼
qlL DP
ð3Þ
Each test was repeated three times; for every repeat, a new powder sample from the original blend was used.
Quality Sieved
Lactohale® LH 300
Micronized
Budesonide
Micronized
x10 (±SD) 14.13 µm (±4.91 µm) 0.90 µm (±0.00 µm) 0.41 µm (±0.02 µm)
x 50 (±SD) 56.76 µm (±0.74 µm) 3.25 µm (±0.09 µm) 1.35 µm (±0.01 µm)
x 90 (±SD) 93.04 µm (±1.44 µm) 7.46 µm (±0.18 µm) 3.70 µm (±0.04 µm)
Binary
Material Respitose® SV003
Ternary
Table 1 Particle size distributions of each component used in the blends.
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normal stress
Δp
air 2 mm/s
air
Fig. 1. Schematic of permeability test set-up.
Fig. 2. Schematic of aeration test set-up.
2.2.2. Aeration testing The aeration test set-up included a porous aeration base connected to the ACU, a 25 mm 35 mL bore borosilicate nonsplit vessel and the 23.5 mm blade (Fig. 2). After filling the vessel with 25 mL of powder sample, the twisted blade started its downward helical path through the powder bulk, which induces a specific flow pattern within the bulk. The energy needed to establish this specific flow was recorded. Regulated by the ACU, increasing amounts of air were fed through the porous base while measuring the resulting total energies of the blade. With the up-regulation of supplied air, the energy measured by the blade decreases until reaching a constant minimum. At this point, the powder sample had been fully fluidized; the energy measured at this point is called the minimum fluidization energy. Further, each powder sample can be characterized by the calculation of the Aeration Ratio (AR) [11]:
However, the sample mass can be reduced from the equation when calculating the AR by dividing one total energy value of a sample by another. For this study, a test program was generated starting at an air throughput of 0 mm/s and ranging up to 8 mm/s. Prior to the aeration tests, multiple basic flowability energy (BFE) measurements without air throughput had been carried out to ensure that the powder samples remained stable for the duration of the aeration test sequence and the measured flow energies were not influenced by other factors, such as segregation, further consolidation. The aeration tests were then performed in triplicate.
2.3. Dispersion measurements
ð4Þ
Binary and ternary mixtures were dispersed with a model device developed at the department of Pharmaceutics and Biopharmaceutics, University of Kiel [12], at an inspiration flow of 80 L/min. This corresponds to a pressure drop of 4 kPa for this particular application system.
The calculation of AR takes into account that different flow energies are being recorded not only because of the reaction to air throughput, but also due to differences in sample masses. The decrease in bulk density that goes along with increasing amounts of fines within a mixture already leads to differences in measured flow energies and makes comparability between mixtures difficult.
2.3.1. Laser diffraction The particle fraction <5 lm of the binary powder blends was determined with a Sympatec Helium–Neon Laser Optical System (HELOS) and the corresponding INHALER module (all Sympatec GmbH, Clausthal-Zellerfeld, Germany). The calculation of the parti-
AR ¼
total energy at 0 mm=s air throughput minimum fluidization energy
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cle diameter was done via the system’s Windox 5 software based on FREE (Fraunhofer Enhanced Evaluation). For each measurement, 15 mg of the binary blends were applied through the model device. 2.3.2. Impaction measurements To determine the drug’s fine particle fraction (FPF, fraction <5 lm) of the ternary blends, a Next Generation Impactor with preseparator (NGI) (Copley Scientific, Nottingham, UK) was used. Again, the model device was utilized at 80 L/min (4 kPa) to apply the powder mixture. To increase the amount of drug per stage, ten doses of 15 mg were administered before rinsing the cups with defined volumes of a double-distilled water (ddH20): methanol mixture (25%:75%) followed by analysis via HPLC. Prior to the application of the powder blends, the preseparator and stages had been coated with small layers of a BrijÒ 35 – glycerol – ethanol solution to reduce possible bouncing of the particles. Without this coating, the measured particle size distributions would have shifted toward lower aerodynamic particle diameters. The FPF of the delivered dose was calculated with CITDAS 3.0 software (Copley Scientific, Nottingham, UK). 2.3.2.1. HPLC analysis. The budesonide content of the samples was quantified with the following HPLC method: – LiChroCARTÒ 125-4 LiChrospherÒ 100 RP-18 (5 lm) with precolumn (Merck KGaA, Darmstadt, Germany) – Mobile phase: ddH2O: methanol (25%:75%) – Flow: 1 mL/min – Wavelength of UV detector: 248 nm A calibration curve (R2 = 1.0000) was generated and utilized to calculate the amount of budesonide within the samples. 3. Results and discussion 3.1. Fraction <5 lm 3.1.1. Binary adhesive mixtures Laser diffraction results for the binary lactose powder mixtures (Fig. 3) show, as expected, a significant increase in the fraction of particles <5 lm with increasing amounts of LH300 fines within the mixtures. However, above a LH300 content of 7.5%, the curve approaches a plateau at around 15%. A possible explanation for this behavior is the formation of stable agglomerates with further addition of lactose fines. Whereas, at
the beginning, lactose fines are able to bind to the lactose carrier surface in monolayers and are easily detached during dispersion, further addition of fines may lead to the saturation of the carrier surface. Thus, an excess of fines results in the formation of agglomerates, which remain stable to a certain extent upon dispersion.
3.1.2. Ternary adhesive mixtures Up to 7.5% LH300 fines within the ternary blends, an increase in budesonide FPF can be observed. This trend accords to the changes seen for the lactose fraction <5 lm of the binary mixtures: The addition of LH300 fines leads to a clear increase in resulting FPF, but only up to a certain threshold. After reaching this threshold, the budesonide FPF drops again – a content of 20.0% LH300 results in an even lower FPF compared to the FPF of the starting mixture of untreated RespitoseÒ SV003 and budesonide without additional fines (Fig. 4). Again, this behavior could be explained with the formation of stable agglomerates. During the mixing process, budesonide fines start adhering to the carrier surface and get detached upon dispersion. With the addition of lactose fines, budesonide fines compete for binding sites on the carrier surface, resulting in a distribution toward lower energy binding sites. This shift toward lower energy binding sites leads to a higher dispersion efficiency and thus to the increase in FPF seen by NGI measurements. A fines content of 7.5% (+ the amount of intrinsic fines of the RespitoseÒ SV003) seems to be the most beneficial for this particular set-up. The addition of more LH300 fines leads to a further displacement of budesonide fines, supposedly toward either drug fines agglomerates or drug/lactose fines agglomerates, which are more dispersion insensitive. Since with higher amounts of LH300 fines more budesonide gets displaced from the carrier surface and gets incorporated in the described agglomerates, the resulting FPF drops significantly. This hypothesis can be supported by studies from Young et al. [13] and Louey et al. [14]. Both groups proposed a linear increase in FPF with increasing amounts of excipient fines up to a certain threshold value (10% and 13.9%, respectively). Further addition of fines resulted in a clear decrease in fine particle fraction. Young et al. speculated that above this threshold value, drug fines/lactose agglomerates fail to adhere to the larger lactose monohydrate carrier particles and become segregated. The authors further assumed that this biphasic system is likely to result in deviation from an expected agglomerate–carrier relationship and therefore can be seen as a cause for the decrease in FPF.
HELOS INHALER binary adhesive mixtures
NGI ternary adhesive mixtures
20.0
35.0
fraction < 5 µm, %
fraction < 5 µm, %
30.0 15.0
10.0
5.0
25.0 20.0 15.0 10.0 5.0
0.0 0.0
5.0
10.0
15.0
LH300 fines, % Fig. 3. Laser diffraction data, FPF versus LH300 content.
20.0
0.0 0.0
5.0
10.0
15.0
LH300 fines, % Fig. 4. NGI data, FPF versus LH300 content.
20.0
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0.0% LH300 2.5% LH300 5.0% LH300 7.5% LH300 10.0% LH300 12.5% LH300 15.0% LH300 17.5% LH300 20.0% LH300
pressure drop across powder bed ternary adhesive mixtures
pressure drop across powder bed, mbar
permeability * 109, cm²
permeability binary adhesive mixtures
20.0% LH300 17.5% LH300 15.0% LH300 12.5% LH300 10.0% LH300 7.5% LH300 5.0% LH300 2.5% LH300 0.0% LH300
normal stress, mJ
normal stress, mJ
Fig. 6b. Pressure drop across powder bed of ternary powder blends.
pressure drop across powder bed, mbar
Fig. 5a. Permeability of binary lactose powder blends.
pressure drop across powder bed binary adhesive mixtures
20.0% LH300 17.5% LH300 15.0% LH300 12.5% LH300 10.0% LH300 7.5% LH300 5.0% LH300 2.5% LH300 0.0% LH300
normal stress, mJ Fig. 5b. Pressure drop across powder bed of binary lactose powder blends.
permeability * 109, cm²
permeability ternary adhesive mixtures
0.0% LH300 2.5% LH300 5.0% LH300 7.5% LH300 10.0% LH300 12.5% LH300 15.0% LH300 17.5% LH300 20.0% LH300
agglomerates was discussed as an explanation for the behavior seen in dispersion performance (Sections 3.1.1 and 3.1.2 and 3.1.2), the applied normal stress in the permeability test set-up leads to a destruction of agglomerates and prevents influences caused by these particle formations. For the binary blends, a linear correlation (R2 = 0.9924, 15 kPa) between the pressure drop across the powder bed (DP) and the amount of added fines can be detected. In contrast, permeability values seem to drop exponentially with the increase in fines since its calculation accounts for the higher compressibility of blends with larger contents of fines. Taking a look at the analysis of linear regression of the pressure drop across the powder bed and added LH300 fines of the ternary mixtures, the coefficient of determination drops to 0.9683. The drop in R2 value is attended by the larger error bars within the graphs for the ternary blends. Whereas the prediction of fines within the mixture based on the linear regression of the pressure drop across the powder bed works well for each separate system (binary and ternary, respectively), no generalized equation for the prediction of overall fines via permeability measurements can be obtained. This is not surprising, since differences in lactose and budesonide fines morphology lead to different characteristics of the overall blends, that is, different reactions to air throughput.
3.2.2. Aeration tests As stated in the methods section, for aeration testing, the induced air flow was increased from 0 to 8 mm/s and the resulting
aeration tests binary adhesive mixtures normal stress, mJ
200
3.2. Powder rheology measurements 3.2.1. Permeability measurements Permeability results and the corresponding values for the pressure drop across the powder bed of the binary (Figs. 5a and 5b) and ternary blends (Figs. 6a and 6b) indicate a correlation to the overall fines content. As expected, the more fines within the mixtures, the smaller the permeability value at a given applied normal stress. The fine particles fill up residual spaces between the larger carrier particles and, therefore, upon compression lead to an increase in resistance to air throughput. Whereas the formation of fines
total energy, mJ
Fig. 6a. Permeability of ternary powder blends. 150
0.0% LH300 2.5% LH300 5.0% LH300 7.5% LH300 10.0% LH300 12.5% LH300 15.0% LH300 17.5% LH300 20.0% LH300
100
50
0 0
1
2
3
4
5
6
7
8
9
air speed, mm/s Fig. 7. Aeration test results of binary lactose blends.
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aeration tests ternary adhesive mixtures 300
total energy, mJ
250 0.0% LH300 2.5% LH300 5.0% LH300 7.5% LH300 10.0% LH300 12.5% LH300 15.0% LH300 17.5% LH300 20.0% LH300
200 150 100 50 0
0
1
2
3
4
5
6
7
8
9
air speed, mm/s Fig. 8. Aeration test results of ternary blends.
total energy of the blade was measured at set points within this range. To understand the characteristics of the aeration test curves (Figs. 7 and 8), the main influencing factors on the measured energy values of the blade should be pointed out. The larger the sample mass – respectively, the denser the powder bulk – the larger the expected energy values for the blade movement. Since the twisted blade needs to displace a larger mass, the resulting total energy increases accordingly. This behavior can be observed for the energy values at 0 mm/s air throughput. This trend turns over when taking a look at the minimum fluidization energies. At this point, the powder was fully fluidized and therefore the influence of the mass is negligible. Ideally, each powder particle is entrained separately within the airflow. In addition, attracting interparticle forces decrease as well. However, for the powder blends containing larger amounts of fines, the fines get entrained as stable agglomerates rather than as single particles. This results in an increase in total energy measured by the blade, since larger amounts of energy are needed to cut through these agglomerates. To exclude the influence of different sample masses, the aeration ratio should be used for comparison instead (Fig. 9). It is apparent that the addition of fines to a coarse lactose carrier results in a drop in aeration ratio. However, above an addition of 5.0% LH300 fines, the AR remains nearly constant. 3.3. Comparison of dispersion and powder rheology measurements While the comparison of permeability values to the total amount of fines added to a mixture results in a decent correlation, Aeration Ratio (AR)
60.0
Aeration Ratio
50.0 40.0 30.0
no significance of the permeability toward the amount of released fines <5 lm upon dispersion can be obtained. This seems to be contrary to the findings of Le et al. [9], who proposed a linear correlation between the drug fine particle fraction of lactose mixtures containing fluticasone propionate or terbutaline sulfate and the air permeability measured with an adapted Blaine apparatus. But a more detailed look at the findings in their paper reveals the differences to the current study: The authors varied the amounts of ternary fines in their mixtures only within ranges that remain below 7.5% overall fines. Having this in mind, the findings indeed match the results obtained for the ternary budesonide mixtures, since the increase in FPF stays linear up to a LH300 addition of 7.5%. Again, a further increase in fines within the mixtures leads to the loss of linear correlation. Also, the data generated by Price [10] suggest a linear correlation of fluidization energy (measured with a Freeman FT4 powder rheometer) and budesonide fine particle dose (FPD) up to an excipient fines content of 20.0%. This group did not detect a drop in FPD above an excipient fines content of 7.5% as seen in this current work. Since the main parameters of the adhesive powder blends used by Price and the ones used for this work are alike, the differences in results have to be linked to the impact of the different devices used for dispersion. Price’s group has used the Cyclohaler for their tests, in which the formulation is effected by more turbulent air flow at a higher air flow rate compared to the model device used in this work. The experimental data of the current work match well with the already stated theory of a stable agglomerate formation with higher amounts of excipient fines. Drug/excipient fines in amounts up to approximately 7.5% adhere mostly to the lactose carrier surface, which results in an increase in particle fraction <5 lm upon dispersion as supported by the HELOS and NGI data. This trend is consistent with the decrease in aeration ratio measured with the powder rheometer. Direct correlation of the increase in fraction <5 lm to the drop in AR shows a discrepancy toward larger amounts of added fines. Whereas the aeration ratio remains constant above a fines content of 5%, the fraction <5 lm detected with dispersion measurements still increases up to a LH300 addition of 10.0% for the binary mixtures or 7.5% for the ternary adhesive mixtures, respectively. To understand this discrepancy, the formation of stable agglomerates still serves as a good explanation for both trends. It has to be considered that for dispersion measurements, larger forces take effect on the powder sample during dispersion. For aeration tests, however, a comparatively small amount of air gets fed through the powder sample and, therefore, the integrity of the sample is a lot less disturbed by the air throughput. As a result, more formed fine agglomerates remain intact for the aeration tests compared to the dispersion measurements, which explains the discrepancy in the obtained values around 7.5–10.0% LH300. If this was the case, a small part of the increase in budesonide FPF needs to be attributed to a better dispersion of less stable drug/fines agglomerates as well, rather than to attribute the FPF increase only to the displacement of budesonide fines toward lower energy sites on the lactose carrier.
20.0
4. Conclusion 10.0 0.0
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
LH300 fines, % ternary budesonide blends
binary lactose blends
Fig. 9. Aeration ratios of lactose and budesonide blends.
20.0
By comparing the results of dispersion measurements with data from permeability and aeration tests provided by a Freeman FT4 powder rheometer, it was possible to obtain a better understanding about the influence of excipient fines to a budesonide fines/lactose carrier mixture with respect to the achieved fine particle fraction.
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Whereas small amounts of excipient fines are able to displace drug fines toward lower energy binding sites on the lactose carrier surface and therefore lead to an increase in FPF, the results obtained with the powder rheometer suggest the formation of stable, and therefore less dispersible, fines agglomerates with the further, successive increase in excipient fines within a ternary adhesive mixture. This agglomerate theory takes account of the decrease in drug FPF seen in the dispersion test results. However, this study has not confirmed that powder permeability and aeration measurements can generally be used to predict the drug fine particle fraction of a ternary adhesive mixture. This work clearly shows the need for a carefully composed powder mixture, in order to maximize the resulting lung deposition upon inhalation. Powder rheology measurements can help to gain a better understanding about the impact of complex interactions between powder particles within a mixture.
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