ARTICLE pubs.acs.org/IECR
Effects of Process Variables on the Properties of Spray-Dried Mannitol and Mannitol/Disodium Cromoglycate Powders Suitable for Drug Delivery by Inhalation Katarzyna Kramek-Romanowska, Marcin Odziomek, Tomasz R. Sosnowski,* and Leon Gradon Faculty of Chemical and Process Engineering, Warsaw University of Technology, Warynskiego 1, 00-645 Warsaw, Poland ABSTRACT: Understanding the influence of process conditions on the properties of pharmaceutical products is critical to their optimal and cost-effective design and manufacture. The aim of this study was to investigate the effect of changing processing variables on the physical properties of spray-dried mannitol and co-spray-dried mannitol/disodium cromoglycate (DSCG) formulations intended for therapeutic inhalation. A 24 full factorial design was performed to assess the consequences of altering the following spray-drying parameters: feed flow rate, nozzle gas flow rate, drying gas inlet temperature, and aspirator capacity (drying gas flow rate). Aqueous solutions of mannitol and mannitol/DSCG were spray-dried using a laboratory-scale spray dryer, and the products were characterized in terms of particle size distribution, powder yield, and particle morphology. These physical properties were found to be affected mainly by two processing variables: nozzle gas flow rate and drying gas inlet temperature. In addition, optimal conditions for the production of inhalable mannitol powders were obtained, generating a yield of 90% by weight of round and smooth particles with a volume median diameter of 4.28 μm. Mannitol/DSCG formulations co-spray-dried in the same conditions had similar characteristics. The results of this study can be applied to controlled formulation of various spray-dried powders for inhalation.
1. INTRODUCTION Intensive research in the field of pharmaceutical engineering and science is critical to the economical design and manufacture of pharmaceutical products. A growing need for such research was the reason for dedicating this study to the investigation of the influence of processing variables on the properties of spray-dried powders intended for therapeutic inhalation. The capability to predict the characteristics of pharmaceutical products allows for the optimal design of drug formulations, the key issue in the discussion about cost-effective and time-saving manufacture of therapeutic materials.1 Aerosol therapy is one of the most promising and rapidly developing methods of drug administration, nowadays. Delivery of drugs to the respiratory tract can be an attractive option to other routs both for local lung diseases as well as systemic therapies because the lung and conducting airways possess a large absorptive surface area, a highly permeable membrane for the medication to transport to the blood, elevated blood flow, and considerably lower metabolic activity comparing to gastrointestinal tract. What is more, first pass metabolism in the liver is avoided.2 All of these characteristics indicate that the relative concentration of drug per unit area of tissue can be minimized during a treatment and thus adverse side effects, which depend on high local surface area concentration, can be reduced.3 For any drug to be delivered to the lungs by inhalation, it has to be a stable dispersion or suspension of solid materials or liquid droplets in a gaseous medium.4 Currently, there are three types of devices commonly used to deliver aerosolized therapeutic agents: jet or ultrasonic nebulizers, pressurized metered-dose inhalers, and dry powder inhalers (DPIs).2 Among the presented methods of generating aerosols, the dry powder system seems to possess the biggest potential, as it gives the capability to obtain, by selecting proper production conditions, dry powder r 2011 American Chemical Society
formulations with expected features such as size, shape, and surface composition. Consequently, one is allowed to control effectively the powder dispersion and particle deposition in the respiratory tract, major factors affecting the therapeutic effect of inhalations.5 The desirable respiratory formulation is characterized by high fine particle fraction (i.e., according to pharmacopeial terminology, fraction of particles smaller than 5 μm), high dose consistency and uniformity, independence of the type of device used, and inhalation flow rate. Therefore, apart from the correct size, the particles should have a relatively narrow particle size distribution and should be easily aerosolizable at relatively low aerodynamic dispersion forces. Additionally, the physical and chemical stability of the powder is required, which implies that the drug’s physical form, size distribution, and the dose content uniformity should be stable during the storage period.5 The particle size and the width of the size distribution can be controlled for example by selecting the proper production method of inhalable powders, while stability is promoted by the powder crystallinity. However, the main obstacle associated with respirable formulations and their effective distribution is the strong interparticle forces which make the powder form agglomerates.2,6,7 At present, the most widely used formulation strategy for DPI powders is a drugcarrier system in which drug particles, between 1 and 5 μm, are attached by adhesion forces to much larger (50100 μm) carrier particles.2 Such powders are produced by a simple blending of micronized particles of the Received: April 4, 2011 Accepted: November 3, 2011 Revised: October 11, 2011 Published: November 03, 2011 13922
dx.doi.org/10.1021/ie2006998 | Ind. Eng. Chem. Res. 2011, 50, 13922–13931
Industrial & Engineering Chemistry Research therapeutic substance with a carrier, which is lactose in most cases. One of the main disadvantages of the discussed system is the poor detachment of drug particles from the high-energy surface of the amorphous lactose carrier, resulting in low inhalation efficiency. In addition, lactose reacts chemically with certain drugs and peptides, and thus, the activity of the therapeutic components in such powders is reduced.8 Another important problem with an amorphous carrier is its strong tendency to undergo spontaneous recrystallization at ambient conditions.9 The presented above limitations of druglactose systems could be overcome by introducing novel crystalline respirable particles 15 μm in diameter containing one or several active ingredients and mannitol as an excipient, as proposed recently by Kumon et al.10 and Adi et al.11 Mannitol, unlike lactose, possesses formulation stabilization properties and has been widely used as a stabilizer and cryoprotectant during lyophilization.12 Besides, mannitol is a mucolytic agent reducing mucous viscosity and increasing its clearance and thus promoting the transport of therapeutic agents to receptors situated under the mucous lining in the respiratory tract. Such combination therapy can enlarge significantly the effectiveness of inhalations by lowering the required dose of active substances and, consequently, minimizing toxic side effects.13 Crystalline composite powders containing mannitol and therapeutic agents cannot be obtained by simple blending in the way drugcarrier systems are obtained. Currently, the most promising production method for such inhalable formulations is spraydrying, as spray-dried mannitol is crystalline and stable. Spraydrying is a complex technological process that is employed in various branches of industrial production as well as pharmaceutical production. During the process an atomized liquid feed is contacted with drying air in a chamber and then moisture is removed from the sprayed droplets. Simultaneous heat and mass transfer is responsible for the formation of particles that may differ from one another depending on their composition, droplet size, and drying temperature.14 There is numerous evidence that altering spray-drying conditions influences significantly the physical characteristics of the final product.1518 Despite this, selecting optimal processing parameters for the production of inhalable powders still presents substantial challenges, and few papers analyze accurately the relation between spray-drying variables and the product properties. Considering the above and the huge potential of novel composite particles intended for inhalation, it is justified to dedicate the investigation to the precise examination of the effect of changing processing parameters on the characteristics of the spray-dried therapeutic formulations. In the present study, the factorial design, being a well-established technique to identify the most significant information concerning the influence of factors on a specific problem, was employed, as it allows for analyzing complex systems.19 The effects of several factors (processing variables and their interactions) on the previously mentioned important characteristics of respiratory formulations consisting of mannitol and mannitol/disodium cromoglycate (the latter being an antiasthmatic drug) were investigated. The results of factorial experiments enabled outlining the potentially optimal spray-drying conditions for the production of respirable composite particles.
2. MATERIALS AND METHODS 2.1. Materials. Micronized mannitol was purchased from POCH. Micronized disodium cromoglycate was donated from
ARTICLE
Table 1. Processing Variables Used in the Factorial Study parameter
low ()
center point
high (+)
units
feed flow rate (F)
2
3
4
nozzle gas flow rate (N)
357
536
742
L/h
aspirator capacity (A)
25
13
13
m3/h
inlet air temperature (T)
120
170
220
°C
mL/min
GlaxoSmithKlein Pharmaceuticals. Water was purified by reverse osmosis (Puricom). 2.2. Preparation of Powder Formulations. Single and combination powders at different ratios were spray-dried as 10% dry powder/90% water (w/v) solutions using a minispray-dryer (model B-290, B€uchi Labortechnik AG, Flawil, Switzerland) fitted with a standard two-fluid nozzle with a caporifice diameter of 0.7 mm. The device was equipped with a highperformance cyclone provided by B€uchi. The volume of solution atomized in each experiment was 25 mL with air as the atomizing and drying gas. The remaining processing parameters were set according to the requirements of the individual runs as presented in the factorial design studies outlined in section 2.6. 2.3. Morphological Observation. The morphology of spraydried particles was investigated using scanning electron microscopy (SEM). Samples of powders were glued onto SEM stubs, coated with gold (25 nm thick) on a K550x sputter coater (Quorum Emitech, Kent, UK), and then examined under a TM1000 Hitachi scanning electron microscope. 2.4. Particle Size Analysis after Dispersion. Particle size distributions of spray-dried powders in aerosol state were determined by an optical aerosol spectrometer (WELAS 2100, Palas GmbH). For measurements, the value of latex’s refractive index was assumed as a good approximation of the powders’ refractive index. Approximately 20 mg of the analyzed powder was filled into HPMC capsule just prior to the experiment and dispersed immediately by a dry powder inhaler (Aerolizer, Novartis) to a glass chamber with the air flow at a stage of 60 L/min. No powder remained in the capsule after dispersion, so it was assumed that the whole powder dose had been dispersed to the glass chamber. The glass chamber was also connected to the optical aerosol spectrometer, so both dispersion and measurement were done simultaneously. Each powder was analyzed in quadruplicate. The size distribution was expressed by the volume median diameter (VMD), the equivalent volume diameter at 50% cumulative volume, and span, a measure of the width of the size distribution [span = (D90 D10)/D50, where D90, D10, and D50 are the equivalent volume diameters at 90, 10, and 50% cumulative volume, respectively. Apart from VMD, the other important parameter characterizing powders intended for inhalation is fine particle fraction (FPF). FPF is defined as the volume or mass fraction of particles smaller than 5 μm and is calculated from the cumulative size distribution. 2.5. Process Yield Determination. Yield was calculated by dividing the powder quantity gathered in the product collection vessel after each single spray-drying by the quantity introduced into the process in the feed solution. Thus, it gave the unit percent by weight (%). 2.6. Factorial Design. A 24 factorial design (a detailed description of the factorial design can be found in Data Handling in Science and Technology32) was undertaken to evaluate the effect of spray-drying processing parameters on powder characteristics. Factors analyzed in the study were feed flow rate (F, the rate at 13923
dx.doi.org/10.1021/ie2006998 |Ind. Eng. Chem. Res. 2011, 50, 13922–13931
Industrial & Engineering Chemistry Research
ARTICLE
Table 2. Design Matrix for the 24 Factorial Design and the Data Collected from the Analyses of Mannitol Powders run
F (mL/min)a N (L/h)a A (m3/h)a
T(°C)a
Tout (°C) yield (%) VMD (μm) SDVMD (μm)b
span
SDspanb
FPF (%)
SDFPF (%)b
1
4(+1)
357(1)
25(1)
120(1)
52
64.3
9.21
0.15
1.44
0.11
16.5
2
4(+1)
357(1)
25(1)
220(+1)
94
65.8
9.20
0.53
1.36
0.08
15.4
0.91 2.10
3
4(+1)
742(+1)
25(1)
120(1)
37
69.3
6.52
0.31
1.39
0.11
31.6
3.43
4
4(+1)
742(+1)
25(1)
220(+1)
72
76.3
5.34
0.21
1.17
0.04
45.0
3.51
5
4(+1)
357(1)
35(+1)
120(1)
62
49.8
7.18
0.22
1.25
0.01
24.8
2.16
6
4(+1)
357(1)
35(+1)
220(+1)
114
38.9
7.84
0.35
1.62
0.05
23.1
2.77
7
4(+1)
742(+1)
35(+1)
120(1)
58
90.8
5.40
0.19
1.33
0.04
44.9
2.89
8 9
4(+1) 2(1)
742(+1) 357(1)
35(+1) 25(1)
220(+1) 120(1)
103 67
69.0 78.5
7.77 8.47
0.37 0.40
1.25 1.53
0.03 0.03
20.3 23.1
2.98 2.18
10
2(1)
357(1)
25(1)
220(+1)
111
46.2
9.50
0.37
1.28
0.03
14.4
2.06
11
2(1)
742(+1)
25(1)
120(1)
52
83.7
5.40
0.20
1.49
0.12
44.9
2.98
12
2(1)
742(+1)
25(1)
220(+1)
93
60.3
7.33
0.27
1.30
0.03
24.7
2.52
13
2(1)
357(1)
35(+1)
120(1)
79
83.8
8.03
0.22
1.38
0.01
19.3
1.84
14
2(1)
357(1)
35(+1)
220(+1)
130
30.3
7.30
0.17
1.83
0.07
27.7
1.62
15
2(1)
742(+1)
35(+1)
120(1)
65
90.5
4.28
0.18
1.40
0.13
63.3
2.66
16 17
2(1) 3(0)
742(+1) 536(0)
35(+1) 30(0)
220(+1) 170(0)
122 84
50.8 87.7
6.53 5.70
0.28 0.20
1.39 1.22
0.07 0.04
31.5 39.6
2.75 3.14
18
3(0)
536(0)
30(0)
170(0)
87
88.2
4.97
0.33
1.61
0.45
52.4
5.83
19
3(0)
536(0)
30(0)
170(0)
83
88.1
4.82
0.26
1.19
0.06
55.1
5.29
range
24
357742
2535
120220
4.289.50
0.150.53
1.171.83 0.010.45 14.463.3
37130 30.390.8
0.915.83
+1 and 1 are the coded values by which the various terms could be compared directly regardless of their real magnitude; 1 was taken instead of the actual value for the factor on its low level and +1 was taken for the high level. b SD, standard deviation (n = 4). a
which the liquid was delivered to the atomizer), nozzle gas flow rate (N, the amount of air needed to disperse the liquid), aspirator capacity (A, the rate at which the drying air is drawn through the spray dryer), and inlet air temperature (T, the temperature of the drying air). Each factor was studied at two levels, low and high, as listed in Table 1. Between the levels a center point was chosen with the aim to assess the reproducibility of powder production by the used spray dryer. The high settings for N, A, T were the greatest practically obtainable ones with the B€uchi B-290. The feed flow rate of 4 mL/min and low settings for N, A, T were selected as being the highest and the lowest, respectively, practical levels at which no condensation of the solution on the drying chamber occurred. The low setting for the feed flow rate was the smallest value of the parameter realized safely by the spray dryer. The design matrix for the experiment is shown in Table 2. In this study, factorial design was used to fit response surface models to the experimental results. Responses, i.e. analyzed powder properties such as particle size, fine particle fraction, yield and outlet air temperature, were related to the factors by the following equation y ¼ b0 þ þ
4
4
∑
i¼1 4
bi xi þ 4
4
4
∑ ∑ bij xi xj
Table 3. Average Response Values, Standard Deviations, and Coefficients of Variation for Mannitol Powders 1719a parameter
a
Tout (°C) Y (%) VMD (μm) span FPF (%)
average SD
85 1.2
88.0 0.1
5.16 0.27
1.34 0.14
49.0 4.8
%CV
14
01
5 23
10.45
9.8
measure of absolute error
2.2
0.1
0.27
0.14
2.8
SD, standard deviation (n = 3). %CV = (SD 100%)/average.
magnitude: 1 was taken instead of the actual value for the factor on its low level and +1 for the high level. Thus, a positive parameter coefficient indicated that the response value increased with increasing variable value and the opposite with a negative coefficient; i.e., an increase of the variable value resulted in a decrease of the response. In addition, the bigger the coefficient value, the stronger the relationship between the output and given variable. The calculation of model coefficients by linear regression and the generation of three-dimensional graphs were carried out using Mathcad 14 software (PTC). The coefficients for all surface models are reported together with the results in the next section (Table 4).
i¼1 j¼1
∑ ∑ ∑ bijk xi xjxk þ b1234 x1 x2x3 x4 i¼1 j¼1 k¼1
ð1Þ
where y is the response, b0b1234 are equation coefficients, and x1x4 are factors (F, N, A, T, respectively). The equation coefficients were calculated using coded values, whereby the various terms could be compared directly regardless of their real
3. RESULTS AND DISCUSSION 3.1. Reproducibility of Powder Production. To evaluate the precision of the spray dryer used in this study, three powders (runs 1719 in Table 2) were obtained in the same process conditions defined as “center point” in section 2.6. Table 3 presents average values of parameters analyzed in this paper, standard deviation (SD) as a measure of absolute error, and the 13924
dx.doi.org/10.1021/ie2006998 |Ind. Eng. Chem. Res. 2011, 50, 13922–13931
Industrial & Engineering Chemistry Research
ARTICLE
Table 4. Coefficients of Response Surface Models for Particle Size, Fine Particle Fraction, Process Yield, and Outlet Air Temperature model coeff
D
FPF
Y
Tout
b0
7.21
29.41
65.51
81.94
b1
0.10
1.70
0.01
7.94
b2
1.13
8.87
8.32
6.69
b3
0.42
2.46
2 54
9.69
b4 b12
0.40 0.08
0.15 1.14
10.82 2.50
22 94 0.19
b14
0.16
2.40
7.79
1.19
b24
0.28
3.75
1.09
0.69
b34
0.17
2.08
4.91
2.69
b13
0.15
1.88
0.86
0.56
b23
0.34
0.73
3.95
2.06
b234
0.31
4.15
0.72
0.56
b123 b134
0.25 0.35
2.70 2.76
2.99 0.22
0.69 0.19
b124
0.21
2.70
1.76
1.06
b1234
0.05
0.54
1.33
0.56
ratio of standard deviation to average value (%CV, coefficient of variation) as a measure of relative error. SD and %CV values suggest that the spray dryer gives satisfactory repeatability in terms of the yield production and the outlet air temperature. High %CV values for fine particle fraction (FPF) and span are probably caused by the accidental malfunction of the inhaler used for the powder distribution during measurement, rather than by the lack of precision of the spray dryer. Thus, the conclusion of Chow et al.5 that certain powder properties are influenced exclusively by the chosen process conditions was confirmed in this investigation. Finally, as a measure of absolute error for VMD and FPF, the corresponding average SDs calculated for all powders (119) were selected. In the case of the production yield and span, SDs calculated for center point powders were chosen, and for the outlet air temperature, a sum of SD given in Table 3 and the precision ((1 °C) of the spray dryer measurement of this parameter (‘measure of absolute error’ in Table 3) were used. 3.2. Particle Size. Particle size distributions (PSD) on a loglinear plot were monomodal in all cases (representative distribution shown in Figure 1). VMD and FPF were in the range 4.289.50 μm and 14.463.3%, respectively (details in Table 2). Slight differences in the span indicate that the width of PSD was practically independent of changes in process conditions. Average span is comparable to values obtained for spray-dried mannitol powders in the works of Kumon et al.10 or Glover et al.20 According to the corresponding response surface model (Table 5), the greatest influence on the particle size is the nozzle gas flow rate (N). The higher atomization flow means more energy supplied for breaking up the liquid into droplets, resulting in smaller particles after drying. The significance of the drying air flow rate (A) can be connected with a higher degree of aerosolization of the solution caused by the suction forces produced by the aspirator.17 The lower air inlet temperature (T) reduces the tendency to agglomeration of smaller particles into bigger ones, as explained by Broadhead et al.21 A low level of the feed flow rate increases the effectiveness of spraying the liquid
Figure 1. Normalized volumetric particle size distribution of spraydried mannitol powder 17.
into smaller droplets22 and probably reduces the content of moisture in powders, which may result in less agglomeration. The relationship between F, A, T, and VMD is considerably weaker compared to the nozzle gas flow rate. Whereas this is commonly observed,15,16,23 the importance of the processing variables’ interactions is not that obvious. The significance of these interactions is outlined by their coefficients in the response surface model and can be studied fully when relevant response surface plots are analyzed. Figure 2 shows a comparison of such plots for four combinations of variables. Colors used in the surface plots have no physical meaning but just emphasize the way VMD values change with processing parameters—the lighter the color the bigger the VMD value. Grid plots are also graphical representations of the surface model but presented in a different way to make the three-dimensional graphs more legible. Clearly, different settings of the feed flow rate (F) and aspirator capacity (A) result in various values of the nozzle gas flow rate (N) and inlet air temperature (T) for which minimal or maximal diameter can be obtained. The lowest VMD is achieved for low levels of F and T and high levels of N and A. As was mentioned in section 2.4, for inhalation purposes it is crucial to characterize the powder not only in terms of VMD but also considering the volume fraction of particles smaller than 5 μm (FPF). Surprisingly, hardly any study discusses FPF dependence on processing parameters. The response surface model for FPF (Table 5) indicates that the higher the nozzle gas flow rate, the bigger the FPF obtained, and this is the strongest relationship linking FPF with any processing variable. Figure 3 presents response surface plots for four combinations of processing parameters. The meaning of color and grid plots is the same as for Figure 2. A significant influence of F and A on FPF values is observed, though relevant equation coefficients are relatively low, especially when compared to N and T coefficients. The biggest FPF can be attained for low F and T and high N and A. The same process conditions result in the lowest achievable value of VMD and confirms the coherence of the presented calculations. 3.3. Outlet Air Temperature. The outlet air temperature varied between 37 and 130 °C (Table 2). According to the corresponding surface model (Table 5), this response is primarily dictated by the inlet air temperature (T) and combinations of processing parameters are not significant. As expected, the higher setting of T gives the higher outlet temperature. The same effect 13925
dx.doi.org/10.1021/ie2006998 |Ind. Eng. Chem. Res. 2011, 50, 13922–13931
Industrial & Engineering Chemistry Research
ARTICLE
Table 5. Response Surface Models Relating the Physical Properties of Mannitol Powder to the Processing Variablesa particle size (μm)
D = 7.21 + 0.10F 1.13N 0.42A + 0.40T + 0.08FN 0.16FT + 0.28NT + 0.17AT + 0.15FA + 034NA +
fine particle fraction (%)
FPF = 29.41 1.70F + 8.87N + 2.46A 4.15T 1.14FN + 2.40FT 3.75NT 208AT 1.88FA 0.73NA
yield (wt %)
Y = 65.51 + 0.01F + 8.32N 2.54A 10.82T + 2.50FN + 7.79FT + 1.09NT 4.91AT 0.86FA + 3.95NA 0.72NAT + 2.99FNA 0.22FAT 1.76FNT 1.33FNAT
outlet air temperature (°C)
Tout = 81.94 7.94F 6.69N + 9.69A + 22.94T + 0.19FN 119FT 0.69NT + 2.69AT + 0.56FA + 2.06NA +
0.31NAT + 0.25FNA + 0.35FAT 0.21FNT + 0.05FNAT 4.15NAT 2.70FNA 2.76FAT + 2.70FNT 0.54FNAT
0.56NAT + 0.69FNA 0.19FAT 1.06FNT 0.56FNAT a
F, feed flow rate; N, nozzle gas flow rate; A, aspirator capacity; T, inlet air temperature.
Figure 2. Response surface plots showing the effects of processing parameters on the volume median diameter. Feed flow rate (F) and aspirator capacity (A) were kept at the following levels: (a) D1 (F = +1, A = +1), D2 (F = +1, A = 1); (b) D3 (F = 1, A = +1), D4 (F = 1, A = 1). N, nozzle gas flow rate; T, inlet air temperature; +1, high level of the parameter; 1, low level of the parameter.
Figure 3. Response surface plots showing the effects of processing parameters on the fine particle fraction. Feed flow rate (F) and aspirator capacity (A) were kept at the following levels: (a) FPF1 (F = +1, A = 1), FPF2 (F = +1, A = +1); (b) FPF3 (F = 1, A = 1), FPF4 (F = 1, A = +1). N, nozzle gas flow rate; T, inlet air temperature; +1, high level of the parameter; 1, low level of the parameter.
is caused by increasing the aspirator capacity (A), as in both cases the supply of heat energy is enlarged.15 On the other hand, the feed flow rate (F) and the nozzle gas flow (N) rate have the opposite impact on the discussed parameter. Regarding F, the more liquid delivered to the drying
chamber, the more solvent evaporates and the exhaust temperature decreases.1517 As far as N is concerned, the atomizing gas has an ambient temperature which is much lower than the drying gas inlet temperature. Consequently, the higher the volume ratio of cool gas to hot gas, the lower the outlet temperature obtained.15,17,22 13926
dx.doi.org/10.1021/ie2006998 |Ind. Eng. Chem. Res. 2011, 50, 13922–13931
Industrial & Engineering Chemistry Research
ARTICLE
Figure 4. Response surface plots showing the effects of processing parameters on the process yield. Feed flow rate (F) and nozzle gas flow rate (N) were kept at the following levels: (a) Y1 (F = +1, N = 1), Y2 (F = +1, N = +1); (b) Y3 (F = 1, N = 1), Y4 (F = 1, N = +1). T, inlet air temperature; A, aspirator capacity; +1, high level of the parameter; 1, low level of the parameter.
3.4. Process Yield. The yields varied between 30.3 and 90.8% (Table 2). Regarding the response surface model (Table 5), there is a strong negative correlation with the inlet air temperature (T) and just slightly weaker positive correlation with the atomization flow rate (N). The feed flow rate (F) influence could be omitted at first, as the corresponding factor coefficient is very low, but at the same time, values of the interaction coefficients, especially for the FT factor, indicate that interactions are occasionally even more significant than processing variables alone.24 The corresponding response surface plots (Figure 4) confirm this statement and a strong relationship linking F and the shape and orientation of presented surfaces is observed. The meaning of color and grid plots is the same as for Figure 2. Thus, it is mostly the combination of processing variables that decides the value of the production yield. Figure 4 shows that the biggest yield is achieved for the low level of T and the high level of other parameters (F, N, A).17,22 The nozzle gas flow rate is known to affect the particle size, and the higher the N that is used the smaller the particles, but a higher feed flow rate has the opposite effect on the particle size, as shown above. To investigate this observation further, a correlation between the yield and volume median diameter was carried out in this work, and the plot is depicted in Figure 5. The points on the graph are scattered (similar results were presented by Stahl et al.15 and Tajber et al.17), but a trend can be observed implying that greater yields were achieved with smaller particles. This is a consequence of using the high-performance B€uchi cyclone, which collects fine particles much more effectively than the standard B€uchi cyclone.25 According to Brandenberger,31 for particles of mean diameter 4 μm the separation rate of a highperformance cyclone is 98%. The obtained results prove that the problem of separating inhalable particles from air can be solved by the application of a high-performance cyclone, and filter alternatives suggested by Stahl et al.15 are not necessarily required. Surprisingly, Table 5 suggests that greater yield values can be obtained when the aspirator capacity (A) is set at a lower level. This can be explained again by the fact that interactions (especially NA and AT) override the meaning of the effect of the aspirator alone.
Figure 5. Relationship between the production yield and volume median diameter for mannitol powders 119.
The influence of the inlet air temperature also requires an additional comment. According to Maury et al.,23 at low drying temperatures, droplets do not dry sufficiently before the impact with walls of the drying chamber or cyclone and a wet deposit is formed on the inner surfaces of the device, resulting in a reduction of the powder yield. An increase of the outlet temperature reduces the driving force for moisture condensation and enlarges the yield [in this investigation the effect was observed for powders 14 (Table 2)]. However, too high an outlet temperature causes again the formation of wall deposits, due to an increase of the thermophoretic effect, and a decrease of the process yield, as the temperature of the inside wall of the spray dryer exceeds the socalled “sticky point”. In such conditions interparticulate cohesion sharply enlarges, which explains the low powder yields obtained in this study for powders 6, 10, 14, and 16 (Table 2) characterized by outstandingly high outlet temperature. 3.5. Particle Morphology. The definition of particle morphology by Vehring26 means particle size, shape, and surface corrugation. The majority of analyzed mannitol powders consisted of spherical particles with rather smooth surfaces, which 13927
dx.doi.org/10.1021/ie2006998 |Ind. Eng. Chem. Res. 2011, 50, 13922–13931
Industrial & Engineering Chemistry Research
ARTICLE
Figure 6. SEM micrographs of spray-dried mannitol powders obtained in various conditions (indicated in brackets): (A) powder 2 (F+, N, A, T+); (B) powder 4 (F+, N+, A, T+); (C) powder 7 (F+, N+, A+, T); (D) powder 14 (F, N, A+, T+); (E) powder 15 (F, N+, A+, T); (F) powder 16 (F, N+, A+, T+), where + denotes a high level of parameter and denotes a low level of parameter.
Table 6. Spray-Drying Variables and Results from the Characterization Work Mannitol/Disodium Cromoglycate Powdersa
a
DSCG concn
F
N
A
T
Tout
yield
VMD
SDVMD
span
SDspan
FPF
SDFPF
run
(% w/v)
(mL/min)
(L/h)
(m3/h)
(°C)
(°C)
(%)
(μm)
(μm)
(-)
(-)
(%)
(%)
1 2
0.5 1.0
2 2
742 742
35 35
120 120
62 64
94.8 92.8
4.07 4.70
0.33 0.13
1.51 1.88
0.04 0.09
65.7 54.6
5.46 1.62
3
2.5
2
742
35
120
66
84.8
6.41
0.30
1.48
0.02
33.5
3.48
SD, standard deviation (n = 3).
was already stated by other authors.10,11,22,27 The photomicrographs of various samples are presented in Figure 6. An interesting observation for some powders was the presence of apparently hollow particles noticed, for example, for powders 2, 4, and 14 (parts A, B, and D in Figure 6). The fact can be
explained by the crystalline structure of spray-dried mannitol, which is typical of this substance.28 According to Handscomb and Kraft,14 crystalline droplets, being rather inflexible, have a tendency to undergo only partial inflation during drying and consequently form hollow or semihollow dried particles. 13928
dx.doi.org/10.1021/ie2006998 |Ind. Eng. Chem. Res. 2011, 50, 13922–13931
Industrial & Engineering Chemistry Research Particle size in all cases was determined by the nozzle gas flow rate (N); an increase of N resulted in a decrease of the size. Particle shape depended evenly on the aspirator capacity (A) and the inlet air temperature (T), which confirms the conclusion of Handscomb and Kraft14 that the main differences in morphology result from the drying air temperatures and, consequently, the drying rate. Low settings of mentioned processing parameters generally gave spherical particles, while high settings of A and T resulted in agglomerated or irregularly shaped particles. The explanation is that at higher temperatures droplets usually inflate, form crusts, and blisters or break during drying.29 The conclusion
Figure 7. Normalized volumetric particle size distribution of co-spraydried mannitol/disodium cromoglycate powders at () 0.5 wt %, (O) 1 wt %, and (Δ) 2.5 wt % disodium cromoglycate.
ARTICLE
of Broadhead et al.21 that agglomeration increases with increasing inlet air temperature was thus shown by this study. The idea of Maa et al.25 that decreased outlet air temperature (realized for example by low settings of A and T) gives rise to more regular and spherical particles was also confirmed in this investigation. Similarly to shape, surface corrugation was influenced mostly by A and T. A smooth surface was obtained almost in all cases for low settings of both A and T, whereas higher values rather furthered surface roughness. Analyzing the relationship between particle morphology and process yield, FPF and VMD, it was concluded that powders with spherical particles had been obtained with higher yield than powders with irregular shapes. Low VMD and high FPF values were achieved for powders with small spherical particles, which suggests their slight tendency to form agglomerates. 3.6. Optimal Conditions. Therapeutically and economically optimal conditions for the production of spray-dried mannitol powders for inhalation are expected to result in a high process yield and such particle properties, which ensure effective distribution during inhalation and efficient pulmonary deposition. This can be achieved when powders are characterized by diameters in the range 15 μm and the biggest obtainable FPF value.2 In the presented study, minimal VMD equal to 4.28 μm and maximal FPF equal to 63.3% were achieved for powder 15 (Table 2). The powder was spray-dried for low settings of the feed flow rate and inlet air temperature and high settings of the nozzle gas flow rate and aspirator capacity. Such combination of the processing parameters is suggested also by the analysis of the response surface models discussed earlier in this paper. As far as
Figure 8. SEM micrographs of spray-dried mannitol/disodium cromoglycate powders at (A) 0.5 wt %, (B) 1 wt %, (C) 2.5 wt % disodium cromogycate, and (D) 100% mannitol powder 15. 13929
dx.doi.org/10.1021/ie2006998 |Ind. Eng. Chem. Res. 2011, 50, 13922–13931
Industrial & Engineering Chemistry Research particle morphology is concerned (Figure 6), the powder consisted of spherical particles with rather smooth surface, which should ensure satisfactory aerosol characteristics and effective distribution during inhalation.16,30 Consequently, processing conditions of powder 15 were selected as optimal for the production of spray-dried mannitol powders. 3.7. Composite Powders. Co-spray-dried mannitol/disodium cromoglycate (DSCG) powders were prepared for the conditions selected in section 3.6 as optimal to verify whether such terms were so for the production of composite powders as well. Three powders with growing DSCG concentration were spray-dried and their properties were analyzed as for mannitol powders before (Table 6). Particle size distributions on a loglinear plot were monomodal in all cases (Figure 7). Table 6 shows that increasing DSCG concentration increased VMD and decreased production yield and FPF values, which was caused by a growing viscosity of the feed solution.16 Figure 8 presents photomicrographs of the obtained composite powders. The more DSCG in the powder, the less regular the particle shape was, but the dependence is slight in the discussed range of DSCG concentration. Generally, mannitol/DSCG powders consisted of particles with spherical geometry and rather smooth surfaces, characteristics similar to mannitol powder 15. Another question to discuss about composite powders is the spatial distribution of components in spray-dried particles. During the drying, the solutes in the atomized droplets have a radial distribution as the droplet evaporates. In a binary system, as in this case, the final distribution of components in the dry solid depends on their molecular structure and relative molecular mass. More hydrophobic substances or substances with higher molecular mass accumulate preferentially at the liquidair interface during the process as a result of either their surface activity or limited molecular mobility.11 The molecular masses of mannitol and DSCG are 182 and 512 g/mol and the aqueous solubilities are approximately 181 and 100 mg/mL (DSCG is a polar salt), respectively, so overall, it may be assumed that both materials are characterized by similar molecular masses and solubilities. Consequently, it is likely that the distribution of both components in the co-spray-dried products is relatively homogeneous.
4. CONCLUSIONS The effect of four variables (feed flow rate, nozzle gas flow rate, aspirator capacity, and inlet air temperature) on the physical and aerodynamic properties of spray-dried mannitol was evaluated by 24 factorial design. Various product characteristics were investigated, and overall, the greatest influence on the powder’s properties was the nozzle gas flow rate and inlet air temperature. The atomization flow rate decides the size of obtained particles (higher airflow gives smaller droplets and consequently smaller particles), while the temperature impacts the production yield (higher temperature gives lower yield) and the outlet air temperature (higher inlet temperature gives higher outlet temperature). The inlet air temperature influences also particle shape: higher temperature promotes irregular shapes and in certain conditions results in glued particles. Out of other processing parameters, the drying gas flow rate in some situations turns out to be significant and then higher aspirator capacity gives less spherical particles. This work has demonstrated that, when spray-drying is involved in the manufacture and development of an inhalable
ARTICLE
powder, the process conditions should be carefully studied as they impact significantly product properties, which are important for the effectiveness of medical applications. The proposed approach for process design has shown to be useful as a tool to identify optimal conditions for the production of powders with desired properties. Composite products containing mannitol and disodium cromoglycate in various concentrations were obtained successfully in the optimal conditions, and increasing DSCG contents resulted in a decrease of process yield and FPF values. The ideas presented in this paper certainly require further development in terms of other powder formulations. The possible results can be of significant benefit as it expands the important knowledge of how to support the optimum design of pharmaceutical product manufacturing.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ ACKNOWLEDGMENT The work was supported by a grant from Polish governmental funds for science in the years 20092011 (project no. N209150036). ’ REFERENCES (1) Hamad, M. L.; Bowman, K.; Smith, N.; Sheng, X.; Morris, K. R. Multi-scale pharmaceutical process understanding: From particle to powder to dosage form. Chem. Eng. Sci. 2010, 65, 5625–5638. (2) Daniher, D. I.; Zhu, J. Dry powder platform for pulmonary drug delivery. Particuology 2008, 6, 225–238. (3) Leach, C. L. Inhalation aspects of therapeutic aerosols. Toxicol. Pathol. 2007, 35, 23–26. (4) Shoyele, A. S.; Slowey, A. Prospects of formulating proteins/ peptides as aerosols for pulmonary drug delivery. Int. J. Pharm. 2006, 314, 1–8. (5) Chow, A. H. L.; Tong, H. H. Y.; Chattopadhyay, P.; Shekunov, B. Y. Particle Engineering for Pulmonary Drug Delivery. Pharm. Res. 2007, 24 (3), 411–437. (6) Gac, J.; Sosnowski, T. R.; Grado n, L. Turbulent flow energy for aerosolization of powder particles. J. Aerosol Sci. 2008, 39, 113–126. (7) Grado n, L. Resuspension of particles from surfaces. Technological, environmental and pharmaceutical aspects. Adv. Powder Technol. 2009, 20, 17–28. (8) Steckel, H.; Bolzen, N. Alternative sugars as potential carriers for dry powder inhalations. Int. J. Pharm. 2004, 270, 297–306. (9) Kawashima, Y.; Serigano, T.; Hino, T.; Yamamoto, H.; Takeuchi, H. Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydrate. Int. J. Pharm. 1998, 172, 179–188. (10) Kumon, M.; Kwok, P. C. L.; Adi, H.; Heng, D.; Chan, H. K. Can low-dose combination products for inhalation be formulated in single crystalline particles? Eur. J. Pharm. Sci. 2010, 40, 16–24. (11) Adi, H.; Young, P. M.; Chan, H. K.; Agus, H.; Traini, D. Cospray-dried mannitol-ciprofloxacin dry powder inhaler formulation for cystic fibrosis and chronic obstructive pulmonary disease. Eur. J. Pharm. Sci. 2010, 40, 239–247. (12) Bosquillon, C.; Lombry, C.; Preat, V.; Vanbever, R. Influence of formulation excipients and physical characteristics of inhalation dry powders on their aerosolization performance. J. Controlled Release 2001, 70, 329–339. 13930
dx.doi.org/10.1021/ie2006998 |Ind. Eng. Chem. Res. 2011, 50, 13922–13931
Industrial & Engineering Chemistry Research
ARTICLE
(13) Sosnowski, T. R.; Gradon, L. Modification of inhalable powders by pulmonary surfactant components adsorbed on droplets during spray-drying process. Colloids Surf., A 2010, 365, 56–61. (14) Handscomb, C. S.; Kraft, M. Simulating the structural evolution of droplets following shell formation. Chem. Eng. Sci. 2010, 65, 713–725. (15) Stahl, K.; Claesson, M.; Lilliehorn, P.; Linden, H.; Backstrom, K. The effect of process variables on the degradation and physical properties of spray-dried insulin intended for inhalation. Int. J. Pharm. 2002, 233, 227–237. (16) Cabral-Marques, H.; Almeida, R. Optimization of spray-drying process variables for dry powder inhalation (DPI) formulations of corticosteroid/cyclodextrin inclusion complexes. Eur. J. Pharm. Biopharm. 2009, 73, 121–129. (17) Tajber, L.; Corrigan, O. I.; Healy, A. M. Spray drying of budesonide, formoterol fumarate and their composites—II. Statistical factorial design and in vitro deposition properties. Int. J. Pharm. 2009, 367, 86–96. (18) Nandiyanto, A. B. D.; Okuyama, K. Progress in developing spray-drying methods for the production of controlled morphology particles: From the nanometer to submicrometer size ranges. Adv. Powder Technol. 2011, 22, 1–19. (19) Costa, C. B. B.; Rivera, E. A. C.; Ferreira Rezende, M. C. A.; Wolf Maciel, M. R.; Maciel Filho, R. Prior detection of genetic algorithm significant parameters: Coupling factorial design technique to genetic algorithm. Chem. Eng. Sci. 2007, 62, 4780–4801. (20) Glover, W.; Chan, H. K.; Eberl, S.; Daviskas, E.; Verschuer, J. Effect of particle size of dry powder mannitol on the lung deposition in healthy volunteers. Int. J. Pharm. 2008, 349, 314–322. (21) Broadhead, J.; Rouan, S. K. E.; Hau, I.; Rhodes, C. T. The effect of process and formulation variables on the properties of spray-dried β-galactosidase. J. Pharm. Pharmacol. 1994, 46, 458–467. (22) Mosen, K.; Backstrom, K.; Thalberg, K.; Schaefer, T.; Kristensen, H. G.; Axelsson, A. Particle formation and capture during spray drying of inhalable particles. Pharm. Dev. Technol. 2004, 9, 409–417. (23) Maury, M.; Murphy, K.; Kumar, S.; Shi, L.; Lee, G. Effects of process variables on the powder yield of spray-dried trehalose on laboratory spray dryer. Eur. J. Pharm. Biopharm. 2005, 59, 565–573. (24) Chawla, A.; Taylor, K. M. G.; Newton, J. M.; Johnson, M. C. R. Production of spray-dried salbutamol sulfate for use in dry powder aerosol formulation. Int. J. Pharm. 1994, 108, 233–240. (25) Maa, Y. F.; Constantino, H. R.; Nguyen, P. A.; Hsu, C. C. The effect of operating and formulation variables on the morphology of spray-dried protein particles. Pharm. Dev. Technol. 1997, 2, 213–223. (26) Vehring, R. Pharmaceutical particle engineering via spray drying. Pharm. Res. 2008, 25 (5), 999–1022. (27) Chew, N. Y. K.; Chan, H. K. Influence of particle size, air flow and inhaler device on the dispersion of mannitol powders as aerosols. Pharm. Res. 1999, 16, 1098–1103. (28) Tang, P.; Chan, H. K.; Chiou, H.; Ogawa, K.; Jones, M. D.; Adi, H.; Buckton, G.; Prud’homme, R. K.; Raper, J. A. Characterisation and aerosolisation of mannitol particles produced via confined liquid impinging jets. Int. J. Pharm. 2009, 367, 51–57. (29) Alamilla-Beltran, L.; Chanona-Perez, J. J.; Jimenez-Aparicio, A. R.; Gutierrez-Lopez, G. F. Description of morphological changes of particles along spray drying. J. Food Eng. 2005, 67, 179–184. (30) Iida, K.; Hayakawa, Y.; Okamoto, H.; Danjo, K.; Leuenberger, H. Evaluation of flow properties of dry powder inhalation of salbutamol sulfate with lactose carrier. Chem. Pharm. Bull. 2001, 49, 1326–1330. (31) Brandenberger, H. Development of a novel high-performance cyclone to increase the yield in a mini spray dryer. Evaporation 2003, 27. (32) Two-level factorial designs. Data Handling in Science and Technology; Elsevier: New York, 2005; Vol. 24, pp 87117.
13931
dx.doi.org/10.1021/ie2006998 |Ind. Eng. Chem. Res. 2011, 50, 13922–13931
