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Force control and powder dispersibility of spray dried particles for inhalation
Force Control and Powder Dispersibility of Spray Dried Particles for Inhalation CLAUDIUS WEILER,1 MARC EGEN,1 MICHAEL TRUNK,1 PETER LANGGUTH2 1
Boehringer Ingelheim Pharma GmbH & Co. KG, 55216 Ingelheim, Germany
2
Institute of Pharmacy, Johannes Gutenberg-University Mainz, Mainz, Germany
Received 27 January 2009; revised 28 April 2009; accepted 14 May 2009 Published online 16 June 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21849
ABSTRACT: This study aims towards a deeper understanding of the correlation between particle morphology, cohesion forces, and aerosol performance of spray dried powders for inhalation. Therefore, forces affecting cohesion and dispersion are considered and some novel contact models are introduced to explain the improved powder dispersibility of corrugated particles. Particles with different degrees of corrugation are prepared by spray drying and characterized. Powder dispersibility is measured by positioning a dry powder inhaler in front of the laser diffraction device. The particle sizes of all powders are in the range of x50 ¼ 2.11 0.15 mm. The ratio of mass specific surface area Sm to volume specific surface area SV rises from 0.54 cm3/g (spherical particles) to 0.83 cm3/g (most corrugation). The fine particle fraction (FPF) rises significantly with increasing corrugation at 24 L/min which can be explained by a distinct difference in powder dispersibility. From theoretical models a reduction in cohesion up to 90% can be estimated for corrugated particles compared to spherical particles. Advantages in powder dispersibility can be expected for particles having a lower density and smaller radius of curvature in the contact zone. Both characteristics are given in case of corrugated particles and can be optimized to a certain degree of corrugation. ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:303–316, 2010
Keywords: aerosols; spray drying; microparticles; pulmonary drug delivery; morphology; powder technology
INTRODUCTION Many options have been developed in particle engineering to optimize powder properties of pharmaceutical drugs.1,2 In case of pulmonary drug delivery, powder dispersibility plays an important role to improve the performance of inhalation products. The typical size of inhalable particles is in the range of 1 to about 5 mm. Such small particles tend to form agglomerates due to
Correspondence to: Claudius Weiler (Telephone: 49-6132/ 77-7165; Fax: 49-6132/77-3823; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 303–316 (2010) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
cohesion forces. These forces are influenced by factors like particle size and shape, material properties, surface characteristics, and climatic conditions. In order to control particle size and shape, spray drying technique is widely used in the development of powders for inhalation. One advantage of spherical spray dried particles is a higher dispersibility due to a smaller surface contact area compared to jet milled plane shaped particles.3 A further optimization of aerosol performance is observed for spray dried particles having a corrugated surface.4–6 In contrast to spherical particles, corrugated particles show a higher fine particle fraction (FPF), which is less dependent on the inhaler device and the applied flow rate. This improved aerodynamic behavior is
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assumed to be related to a higher powder dispersibility caused by lower particle cohesion and possibly a reduced total accessible area for particle interactions.5 This work is focused on the scientific background to provide explanations as to why corrugated particles have advantages in aerosol performance. In order to obtain a deeper understanding of dispersion mechanisms, forces affecting cohesion and dispersion of particles are considered. Spray dried particles are usually regularly shaped with a spherical morphology and a relatively smooth surface. Sphere models that take the influence of cohesion forces into account were applied and new models of contact, which are relevant in case of corrugated particles, are introduced in this work. In order to compare theoretical assumptions with real powder systems, model particles of dextran having a different degree of surface corrugation were prepared and characterized concerning their aerosol performance. Furthermore, powder dispersibility is measured in a direct way and independent from cascade impaction because the densities of particles with different degrees of corrugation are not expected to be identical in terms of impaction behavior.
THEORY Forces Affecting Particle Cohesion In case of dry powder aerosols only cohesion mechanisms between solid particles in gaseous atmosphere are relevant. Neglecting solid material bridges, which are typical for sintered and granulated powders, cohesion mechanisms for spray dried particles made of organic substances can mainly be derived from van-der-Waals forces, electrostatic forces for insulators and in presence of humidity from capillary forces. To estimate the cohesion forces for these mechanisms, the sphere models based on the work of Rumpf7,8 and Schubert9 are applied in the following considerations. Van-der-Waals forces arise due to dipole– dipole interactions between atoms and molecules of adjacent surfaces and depend on material properties. In mathematical models, material properties are taken into account by the Hamaker constant AH or the Lifschitz–van-der-Waals constant h$ (correlation: AH ¼ 3=4p h$). Typical values for organic substances10 are in the range of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
$ ¼ 3 1021 to 9 1020 J. In case of particle h contact, van-der-Waals forces are on a maximum level and decrease to the power of two with separation distance a. Therefore van-der-Waals attraction can be neglected for a separation distance of a > 50 nm. For particles having contact, the distance a0 ¼ 0.4 nm is typically used for calculations.9,11 Van-der-Waals forces are always attractive and can be calculated for two ideally flat, rigid, and spherical particles having a diameter of x according to Eq. (1). In case of different particle sizes, the particle diameter x of Eq. (1) is given as x ¼ 2x1 x2/(x1 þ x2). FVdW ¼
$x h 32pa2
(1)
Electrostatic forces can be attractive or repulsive depending on the polarity of the particles. For antipolar charged and nonconducting spheres having a positive surface charge of w1 and a negative surface charge of w2, the electrostatic attraction is given by Eq. (2) with the permittivity of vacuum e0 ¼ 8.8542 1012 As/Vm and the relative permittivity for dry air er ¼ 1.006. For a maximum particle charge a value of wmax ¼ 1.6 105 As/m2 can be assumed. For unipolar charged particles Fel acts as a repulsive force. Fel ¼
p ’ 1 ’ 2 x2 4"0 "r ð1 þ a=xÞ2
(2)
Assuming total wetting for smooth and spherical particles of diameter x, the capillary force of a liquid bridge is given by Eq. (3), where s is the surface tension of the liquid.12 The surface tension of water is known to be s H2 O ¼ 72:7 mJ=m2 . Fc ¼ psx
(3)
Comparing the cohesion forces of these idealized sphere systems, liquid bridges and vander-Waals forces are the most significant attraction forces for particles <10 mm (Fig. 1). These forces are directly proportional to the particle size. Even by assuming a maximum antipolar charge, electrostatic forces (which rise with particle size to the power of two) become of relevance only for much larger particles. For homogenous particles of the same material, a unipolar charge is expected to be more likely than an antipolar charge, so that electrostatic attraction can be neglected or even considered as DOI 10.1002/jps
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Muller–Toporov—( FDMT) model: 3 FJKR ¼ pgxr 2
(4)
FDMT ¼ 2pgxr
(5)
x1 x2 ðx1 þ x2 Þ
(6)
xr ¼
Figure 1. Theoretical cohesion forces of two contacting, rigid, insulated, and spherical particles (Eqs. 1–3) in comparison to the DMT pull-off force (Eq. 5).
repulsion between most spray dried particles in the lower micron sized scale. Therefore the cohesion between inhalable spherical particles is known to be directly proportional to their particle size.13 In addition to the simplified considerations of these models, cohesion between real particles is influenced by some more factors like surface characteristics, climate conditions, or the circumstances of particle contact. For example, the contact distance of a0 ¼ 0.4 nm is in the range of molecules and can therefore only be assumed for perfect smooth surface areas. Real particles have a certain degree of surface roughness which keeps particles on distance by asperities and may reduce van-der-Waals forces. On the other hand, particle cohesion is raised due to capillary condensation of humidity or plastic deformation.13–18 Hence the intensity of van-der-Waals and capillary forces depends on the properties of the contact zone. In order to determine the cohesion between ‘‘real’’ particles, pull-off force measurements are carried out, for example, by atomic force microscopy.19–21 The force which is required to separate two spherical particles with the diameter x1 and x2 is usually described by the Johnson– Kendall–Roberts—( FJKR) and the Derjaguin– DOI 10.1002/jps
These models are linear functions of particle size and the surface energy g, whereas the JKR model is appropriate for large, soft bodies and the DMT model for small, hard bodies. For spherical particles of the same diameter (x1 ¼ x2), the pulloff force of the DMT model is equivalent to the capillary force model of total wetting according to Eq. (3) (in liquids, the surface energy is called surface tension, s). AFM studies with silica (SiO2) microspheres having diameters between 1 and 5 mm confirm the linear dependency of the pull-off force on particle size.19 The surface energy for these particles, measured at ambient conditions (humidity: 10–40%), is calculated with the DMT model as g ¼ 14.0 2.1 mJ/m2. Compared to the ‘‘pure’’ van-der-Waals cohesion between two silica spheres with h$SiO2 9 1020 J10 , the measured pull-off force is about one order of magnitude larger. In order to estimate the cohesion force between spherical particles, the pull-off force of the DMT or the JKR model can be applied by using experimentally determined surface energies. For example, values from AFM measurements are reported for crystalline lactose22 as g ¼ 7–44 mJ/m2, for amorphous lactose22 as g ¼ 30–57 mJ/m2, and for Budesonid21 as g ¼ 10–32 mJ/m2. Beside AFM, the surface energy of solids is determined by methods like inverse gas chromatography (IGC) or contact angle measurements. For a large number of organic polymers Lewin et al.23 reviewed values between 11 and 53 mJ/m2. Although results vary by different methods, surface energies for organic solids are supposed to be in the range of about 10–60 mJ/m2. By applying the DMT model to estimate the pulloff force for ‘‘real’’ organic and spherical particles, cohesion is expected to be 1–3 orders of magnitude higher compared to ‘‘pure’’ van-der-Waals cohesion (Fig. 1).
Forces Affecting Particle Dispersion While cohesion forces rise with the particle diameter x, forces which cause particle separation JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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like electrostatic forces for unipolar charged particles (Eq. 2) or the force of gravity (Eq. 7) are proportional to x2 and x3, respectively. p Fg ¼ x3 rP g (7) 6 In case of adhering particles with x < 10 mm, these forces are not relevant compared to the described cohesion forces. With increasing particle size, forces affecting particle dispersion become more significant. Particles of the upper micron sized range or larger are usually more influenced by gravity than by particle cohesion. This is the main reason why fine powders are observed as cohesive with poor flow ability and dispersibility in contrast to more granular powders. Therefore energy has to be introduced to get fine particles dispersed for inhalation. This is typically realized by an air stream inside an inhaler. To estimate the force which acts on an adhered particle in a homogeneous air stream, the drag force can be considered and calculated according to Eq. (8). r FDrag ¼ A f n2 cw (8) 2 where A is the area of the particle’s cross section, rf the density of the fluid (gas), v the relative velocity of the fluid with respect to the particle, and cw the drag coefficient of the particle. For spherical particles cw can be calculated from the approximation function of Kaskas according to Eq. (9) with the Reynolds number Re (Eq. 10) and h as the viscosity of the fluid (hair ¼ 0.0181 mPa s). cw ¼
24 4 þ þ 0:4 ðRe < 105 Þ Re Re0:5
(9)
nxrf h
(10)
Re ¼
According to Figure 2 the drag force of particles <10 mm is at least four orders of magnitude higher compared to the force of gravity, even at relatively low air velocities of 20 m/s. For laminar flow (Re < 0.5) the drag coefficient is given by Stokes as cw ¼ 24/Re and Eq. (8) results in the Stokes equation where the drag force rises linearly with particles size. With higher Reynolds numbers (e.g., by increasing gas velocity or particle size), the drag force becomes more dependent on x2 which can be seen from the increasing ascent of the drag force functions (Fig. 2). Therefore the chance to remove an adhered particle from a surface by an air stream is higher for a larger particle compared to a smaller one; JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
Figure 2. Theoretical forces, influencing the separation of adhering spherical particles after Eqs. (2), (7), and (8).
even when they have the same aerodynamic particle size. Particles of the same aerodynamic size xae but of different density rP differ in their geometrical size x according to Eq. (11). rffiffiffiffiffiffiffiffiffiffi rP (11) xae ¼ x rH2 O This effect is of significance for particles having a relatively low density like large porous particles and could be an explanation for their high aerosol performance.2 Finally, the connection between the effect of a homogeneous air stream and the cohesion force between two particles is schematically illustrated in Figure 3. As an indication of dispersibility, the ratio of drag force to cohesion force can be considered, where higher values stand for a higher possibility of particle release. Therefore advantages in powder dispersibility are expected
Figure 3. Ratio of drag force (Eq. 8) and DMT pull-off force (Eq. 5 with g ¼ 44 mJ/m2). The cohesion force between corrugated particles is affected by the radii of the curvatures which are in contact. DOI 10.1002/jps
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for particles having a low density by comparable aerodynamic size (or a large cross section) and for particles having a corrugated surface with elongated endings of small diameters of curvature. Novel Adhesion Models of Contact between Corrugated Particles The effect that the diameter of curvature influences cohesion in the contact zone is typically associated with a reduction of van-der-Waals forces caused by surface roughness or in presence of glidants (force control agents) in powder mixtures.8,9,24 In case of corrugated particles contact between particles is preferred at convex areas of the corrugated surface (Fig. 4). In this new approach the influence of different modes of contact between corrugated particles are discussed and cohesion forces are estimated in comparison to spherical particles.25 Therefore it is assumed, that the nanoscaled surface roughness of corrugated particles is identical to that of spherical particles. This means that the curvature of a corrugated particle is not being understood as an asperity or a part of surface roughness, rather the curvature itself has its own surface roughness which does not differ from that of a spherical particle. By analyzing many SEM pictures, we classified different contact modes between corrugated particles according to Table 1. For the van-der-Waals contact adhesion, these models are in accordance with the sphere/sphere model (Eq. 12) and the sphere with roughness element/plate model (Eq. 14) of Rumpf.8,9 All other equations (Eqs. 16, 18, and 20) are derived in
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order to describe the cohesion between corrugated particles with respect to the observed modes of contact. These equations take into account that the influence of van-der-Waals attraction between the complete particles becomes of significance for diameters of curvature of xc < 50 nm which may result in an increased van-der-Waals force by a further reduction of xc. This is of importance to assess the influence of surface roughness where the size of asperities is expected to be in that order of magnitude. To estimate the pull-off force from DMT theory, we applied Eqs. (5) and (6) on the contact models of Table 1 and derived Eqs. (13), (15), (17), (19), and (21). These equations do not include the influence of cohesion forces between the whole particles for relatively small separation distance due to small values of xc. Therefore these functions are assumed to be valid for xc > 100 nm. By applying these contact models on particles having a diameter of x ¼ 2 mm and a surface energy of g ¼ 44 mJ/m2, which is the mean value of amorphous lactose,22 the pull-off force FDMT can be represented against the ratio of xc/x as seen in Figure 5. In comparison to two contacting spherical particles (case 1, where xc/x ¼ 1), a decrease in cohesion is calculated for cases 3 and 4 with decreasing values of xc/x. For cases 2 and 5, a reduction in cohesion for xc/x < 0.5 and an increase in cohesion for xc/x > 0.5 are expected. For particles having shape fitting contact (case 6), cohesion depends on the contact area and can be estimated as much larger compared to the cohesion between spherical particles.3 The calculation of the van-der-Waals cohesion according to Table 1, with an average Lifschitz– van-der-Waals constant for organic substances10 of h$ ¼ 5 1020 , results in the same relations with the exceptions that the van-der-Waals force is about 45 times smaller and that an increase in cohesion is observed for xc/x < 0.005. That increase in van-der-Waals cohesion is not necessarily relevant for corrugated particles having elongated curvatures instead of an assumed hemisphere according to the contact models.
MATERIALS AND METHODS
Figure 4. Curved surface areas (encircled) and their contact points (arrows) of corrugated particles observed from SEM. DOI 10.1002/jps
Generation of Particles Having Comparable Geometrical Size Distribution and a Different Degree of Corrugation To assess the dispersion behavior of different powders due to their morphology, particles of a JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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Table 1. Several Possibilities of Particle Contact between Corrugated Particles of the Size x and Their Theoretical Models to Estimate van-der-Waals Contact Force (FVdW) and the Pull-Off Force (FDMT for xc > 100 nm) Contact Model
Equations
(1) Sphere/sphere h$x 32pa20
(12)
FDMT ¼ pgx
(13)
FVdW ¼
(2) Sphere/plate FVdW
$ xc h x ¼ þ 16p a20 ða0 þ xc =2Þ2
! (14)
FDMT ¼ 2pgxc
(3) Curvature/sphere FVdW
(15)
$x h 2xc 1 ¼ þ 32p a20 ðxc þ xÞ ða0 þ xc =2Þ2 FDMT ¼
(4) Curvature/curvature FVdW
2pgxxc ðx þ xc Þ
$ xc h x ¼ þ 32p a20 ða0 þ xc Þ2
FVdW
!
$ x 2xc h ¼ þ 2 32p x2c a0
FDMT ¼ 2pgxc
(16)
(17)
FDMT ¼ pgxc
(5) 2 curvature/curvature
!
(18)
(19)
(20)
(21)
(6) Shape fitting contact
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Figure 5. Pull-off force ( FDMT) of different possibilities of particle contact according to Table 1 with x ¼ 2 mm and a surface energy of g ¼ 44 mJ/m2.
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drying gas is pushed through the spray dryer and directed into a fume hood with Hepa-filter. The drying gas flow is measured by a float-type flow meter (Krohne VA20R K1, Duisburg, Germany) and the original nozzle gas flow meter was decoupled and replaced by a digital flow meter (Kobold DSM212-C4FD25L, Hofheim, Germany). The flow rates for drying and atomization-gas are at about 35 m3/h and 39 L/min, respectively. Furthermore a liquid flow rate of 12 2 mL/min and an inlet temperature of 150 28C is used. All samples were stored in desiccators with humidity absorbing molecular sieves (Tri-Sorb1, Su¨ dchemie AG Mu¨ nchen, Germany) directly after spray drying to avoid changes during storage.
Powder Characterization comparable geometrical size distribution have to be used. This is of importance because the densities of spherical and corrugated particles are not expected to be identical. The drag force which acts on an adhered micron particle and causes its release in an air stream, is higher in case of the geometrically larger particle. The saccharides dextran T1, dextran T3.5 (Pharmacosmos A/S, Holbaek, Denmark), and D-cellobiose (analytical grade, Serva, Heidelberg, Germany) are dissolved in different ratios (Tab. 2) in purified water (A10, Millipore, Billerica, MA). The solid concentration of the solutions is 10% (m/m). Particles are generated by a modified spray dryer (Bu¨ chi, B191, Flawil, Switzerland) in combination with the Bu¨ chi 0.5 mm twofluid-nozzle and by using nitrogen as dryingand nozzle-gas instead of air. In addition, all original glass components were replaced by components made of stainless steel. The aspirator and the particle filter were removed and the
Table 2. Parameters to Generate Particles by Spray Drying, Having a Comparable Particles Size Distribution and a Different Degree of Surface Corrugation Powder A B C D
Compounds Dextran Dextran Dextran Dextran
DOI 10.1002/jps
T1/cellobiose T1/dextran T3.5 T1/dextran T3.5 T3.5
Ratio (m/m)T(out) (8C) 2:1 9:1 1:1 100%
91 3 91 3 91 3 103 3
Due to their amorphous nature, the glass transition temperatures of cellobiose, dextran T1, and dextran T3.5 are measured as the mid point of the change in heat capacity using temperature modulated DSC (TA Instruments, New Castle, DE, Q1000, with 10 2 mg powder in pin holed aluminium pans at a heating rate of 28C/min modulated with 0.2128C over 40 s). The primary particle size distribution and the volume specific surface area SV is measured by laser diffraction (Sympatec Helos incl. Rodos powder dispersing unit, Clausthal-Zellerfeld, Germany) assuming spherical particle shape (form factor: 1). The mass specific surface area Sm is determined by a gas adsorption analyzer (Micromeritics, TriStar 3000, Norcross, GA). As a measure of particle surface corrugation, the ratio Sm/SV is calculated. The FPF was measured at 24 and 39 L/min to assess dispersion and deposition effects at different flow rates. Therefore an Andersen Mark II Impactor with preseparator is used in combination with the Boehringer Ingelheim HandiHaler1 device containing single capsules with 20 mg powder. At a flow rate of 39 L/min the pressure drop of the HandiHaler1 is 4 kPa which corresponds to the standard conditions for the determination of the FPF.26 At this flow rate impactor stage 1 has an aerodynamic mean cut-off size of 5.0 mm27 and is used to collect the powder on a filter directly beneath this stage. At a flow rate of 24 L/min, impactor stage 2 has an aerodynamic mean cut-off size of 5.0 mm and was additionally inserted to collect the powder directly beneath that stage at 24 L/min. The mass of powder on the filter is determined using an analytical balance and JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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corresponds to the fine particle dose (FPD). The delivered dose (DD) is defined as the mass difference between the nominal dose (loaded into the capsule initially) and the remaining powder in the inhaler. FPF was calculated as the ratio of FPD to DD in percent.
Powder Dispersibility Powder dispersibility has a significant impact on aerosol performance and is determined in this work in a direct way and independently from aerodynamic measurements. Therefore the geometrical, instead of the aerodynamic, size of dispersed particles is measured. Measurements were made by positioning the dry powder inhaler (Boehringer Ingelheim HandiHaler1,3,25 with capsules containing 20 2 mg of powder) in front of a laser diffractometer (Sympatec Helos). The inhalers capsule chamber was connected to an air supply in order to determine the particle size distribution of the exiting powder (Fig. 6). Over a time period of 10 s, the HandiHaler1 standard flow rate of 39 L/min (pressure drop: 4 kPa) was applied and controlled by a mass flow meter (Kobold DMS-614C3FD23L). Additionally the inhaler was run at a much lower pressure drop of 1 kPa which corresponds to a flow rate of 20 L/min. Powder dispersibility is assessed by comparing the particle size distribution from the inhaler with the particle size distribution from the Sympatec dispersing unit Rodos, where a total dispersion is assumed.
RESULTS AND DISCUSSION Corrugated Particles In order to generate model particles with varying degrees of corrugation, different types of dextran are dissolved in water and spray dried (Tab. 2). Due to their different molecular weights (dextran
Figure 6. Determination of geometrical particles size distribution of exiting particles from the HandiHaler1. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
T1: Mw 1000 g/mol, T3.5: Mw 3500 g/mol), properties of their aqueous solutions (e.g., viscosity) have impact on film forming conditions and influence particle morphology. In case of small molecules with a good solubility, like sugars or dextran T1, a concentration of the solution during droplet drying occurs, which results typically in a spherical and solid particle morphology. With increasing degree of polymerization (e.g., dextran T3.5), an early shell formation takes place which folds during drying and forms a wrinkled morphology. While dextran T3.5 particles (powder D) show a distinctive degree of corrugation, mixtures of T3.5 and T1 (powders B and C) become more spherical depending on the amount of dextran T1 (Fig. 7). Apart from their different molecular weights, these three powders are of the same chemical substance and have a similar geometrical particle size distribution measured by laser diffraction (Fig. 8). There are no differences in water uptake for dextran T1 and dextran T3.5 (DVS data not shown). Therefore humidity effects and surface energy differences should not be expected during aerodynamic and dispersibility measurements at equal environmental conditions. Particles without any corrugation are prepared by adding the disaccharide cellobiose to the polysaccharide dextran T1 (powder A). These spherical particles have a slightly smaller particle size distribution compared to powders B–D. Changes in morphology like crystallization or sintering effects are not expected due to dry storage conditions and the relatively high glass transition temperatures (cellobiose: 112.9 0.78C, dextran T1: 154.8 0.38C, dextran T3.5: 198.3 1.38C) and could not be seen from detail images of scanning electron microscopy. As a further indication for surface corrugation, the ratio of the mass specific surface area Sm (BET-surface) to the volume specific surface area SV (measured by laser diffraction, assuming spherical particle shape) is considered. With increasing surface corrugation, observed from SEM, Sm/SV rises from 0.54 to 0.83 cm3/g (Tab. 3). To describe the shell forming mechanism in a more general way and independently from the described dextran–H2O-system, the Peclet number Pe as the ratio of the evaporation rate k and the diffusion coefficient D can be used2: Pe ¼
k 8D
(22) DOI 10.1002/jps
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Figure 7. SEM images of spray dried powders having different degrees of corrugation.
For Pe < 1, the diffusional motion of the solutes is faster compared to the radial velocity of the receding droplet surface and is typically associated with spherical and solid particle formation. In case of Pe > 1, the surface moves faster than the dissolved or suspended components which results in shell formation. The Peclet number is influenced by spray drying parameters which control the evaporation performance of the process and by a combination of material properties of the solute and the solvent. The evaporation rate can be increased by rising the outlet temperature of the
Figure 8. Geometrical particle size distribution measured by laser diffraction in combination with Sympatec dispersing unit Rodos, where total powder dispersion is assumed. DOI 10.1002/jps
spray drying process (e.g., by increasing inlet temperature, increasing drying gas flow rate, reducing liquid flow rate, using solvents with lower evaporation enthalpy). The diffusion coefficient can be reduced by using liquid systems with reduced diffusional motion (e.g., by rising viscosity due to a higher concentration of the solution or by other solvent/solute systems). In case of dextranes, the viscosity increases significantly with the molecular weight28 which causes higher Peclet numbers and therefore a higher particle corrugation of dextran T3.5. Therefore, shell formation can be controlled by many factors and extended to other systems by varying the parameters influencing the Peclet number. But it should be noticed that the mechanisms of solidification occurs within milliseconds and the Peclet number is constantly changing during droplet drying. Based on the complexity of interactions between changing material properties and drying conditions the prediction of particle morphology can be difficult and cannot prevent experimental trials.
Aerosol Performance and Powder Dispersibility The FPF corresponds to the part of the delivered powder which has an aerodynamic particle size 5 mm. For all samples, the FPF at a flow rate of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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Table 3. Powder Properties of Spray Dried Particles Having a Different Degree of Corrugation Powder Property
A
B
C
D
a
1.96 0.01 3.84 0.02 2.09 0.01 0.54 5.0 0.3 23.6 4.3
2.26 0.03 3.40 0.04 2.03 0.01 0.60 13.2 0.8 32.4 4.8
2.22 0.03 3.45 0.04 2.18 0.01 0.63 24.8 1.5 40.4 4.5
2.26 0.01 3.32 0.02 2.77 0.02 0.83 22.5 4.6 38.1 4.9
x50 (mm) SV (m2/cm3)a Sm (m2/g)b Sm/SV (cm3/g) FPF at 24 L/min (%)a FPF at 39 L/min (%)a a
Mean value standard deviation (n 3). Mean value deviation (n ¼ 2).
b
39 L/min is significantly higher, compared to the FPF at 24 L/min (Fig. 9). Furthermore, no difference in the aerosol performance can be observed between powders C and D. With advanced surface corrugation an increase of the FPF from powders A–C is observed, which is significant for a flow rate of 24 L/min. The increase at 39 L/min describes only a tendency to higher FPF values due to the relatively high standard deviations. However, the difference between powders A and C is significant. These aerodynamic results confirm the observations of previous studies4,5 that (i) corrugated particles have a higher aerosol performance compared to spherical particles, (ii) aerosol performance is improved with surface corrugation to a certain degree, (iii) further corrugation does not necessarily improve aerosol performance, and (iv) these effects are more significant at lower flow rates which results in a lower dependency on inhaler flow rate of corrugated particles.
Figure 9. Fine particle fraction (FPF) of powders A– D at 24 and 39 L/min. The error bars indicate the mean value standard derivation of at least three measurements. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
But, considering only FPF measurements, it is not possible to explain these observations by only one reason. There are two relevant possibilities for the increasing aerosol performance. On the one hand, the particle density (and therefore the aerodynamic particle size) becomes smaller with higher degrees of surface corrugation. On the other hand, powder dispersibility is improved for corrugated particles. To quantify the dispersion behavior independently from particle density, a direct method is used, where the geometrical particle size distribution of the exiting powder from the inhaler, is measured. A nearly complete dispersion is observed for all powders at a flow rate of 39 L/ min (Fig. 10, bottom). These particle size distributions are in the range of the dispersion results measured from the Sympatec dispersing unit (Fig. 8). Thus, the increase in FPF measured by cascade impaction at 39 L/min is assumed to be related to a smaller particle density in case of corrugated particles. At much lower flow rates, significant differences in powder dispersibility can be seen from Figure 10 (top), where powder dispersibility rises with surface corrugation. At 20 L/min agglomerates up to about 80 mm are detected, in particular for the spherical particles of powder A. While this sample has about 40% of agglomerates larger than 10 mm, powder B has about 20% and powder C about 10%. Possibly, the slightly smaller particle size distribution or the added compound cellobiose has a further influence on the deagglomeration of powder A. For the corrugated particles of powder D, no agglomerates larger than 10 mm can be detected. The particle size distribution of this sample is not equal to that at 39 L/min, but slightly shifted about 0.2 mm towards larger particles. Anyway, an almost comparable powder dispersion can be assumed for powder D at 24 and 39 L/min. Thus, the discrepancy in FPF measured by cascade DOI 10.1002/jps
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Figure 11. Powder dispersibility (Qgeo(50 m)) versus fine particle fraction (Qae(5mm) ¼ FPF) at 39 L/min and 22 2 L/min for powders A–D.
Figure 10. Geometrical particle size distribution measured by laser diffraction in combination with the HandiHaler1 containing capsules of 20 mg powder at flow rates of 20 L/min (top) and 39 L/min (bottom). The error bars indicate the mean value standard derivation of at least three measurements.
impaction at 24 and 39 L/min of powder D (Fig. 9) can possibly be a result of the different cascade impactor arrangements. At 24 L/min an additional impactor stage is inserted which may cause a higher particle loss. This should be considered particularly at high powder loadings like 20 mg/capsule. These direct measurements of powder dispersibility demonstrate, in a simple manner and independent from cascade impaction experiments, that dry powder deagglomeration is influenced by the degree of surface corrugation. This approach describes a physical method where the geometrical size of agglomerates is directly measured after exiting the mouthpiece of an inhaler. In contrast to that, cascade impaction experiments are used as a pharmacopeial in vitro method to asses the lung deposition behavior of respirable particles. However, from a scientific point of view, the determination of FPF via cascade impaction is not appropriate to determine the dispersibility of powders with different DOI 10.1002/jps
morphology as long as there are further differences in particle density or geometrical particle size. The relation between both methods is illustrated in Figure 11 where Qgeo(5 mm) indicates the percentage of the exiting powder from the inhaler having a geometrical particle size <5 mm. Qae(5 mm) is equivalent to the FPF and indicates the percentage of powder having an aerodynamic particle size <5 mm. At 39 L/min the powder dispersion by the HandiHaler1 is almost constant in the range of Qgeo(5 mm) ¼ 90 3% for powders A–D. Therefore, the increase in Qae(5 mm) with advanced particle corrugation from 24% to 40% is mainly caused by a reduction in particle density. At the lower flow rate of 22 2 L/min, powder dispersibility rises with advanced particle corrugation from 49% to 87%. Therefore the increase in Qae(5mm) from 5% to 23% is due to an improved powder dispersibility and due to a reduction in particle density for increased particle corrugation. The mechanisms for the improved dispersibility of corrugated particles can be explained by a reduced cohesion force which is discussed previously. Another assumption is that less particle contacts exist inside of agglomerates due to a reduced accessible area of corrugated particles. According to theoretical models describing the mechanical stability of agglomerates, the coordination number (number of contacting JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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neighbors of a primary particle inside an agglomerate) is directly proportional to the tensilestrength7 or the dispersion-strength25,29 of model agglomerates. In case of a loose bulk system of spherical particles, the coordination number is given7 as k 7. As a rough estimate, the mechanical stability (tensile- or dispersionstrength) is reduced by about 1/7 for each absent particle contact due to a corrugated surface area. Unfortunately, the challenge of this consideration is the determination of the coordination number of ‘‘real’’ particles which is not further investigated here. Therefore a clear conclusion about the influence of unaccessible surface area of corrugated particles on improved powder dispersibility cannot be made. On the other hand, it is most likely, that contact between particles is preferred at convex areas of the corrugated surface. In that case, a reduction in cohesion can be expected depending on the diameters of curvature in the contact zone as described in the theory section. From SEM pictures of the corrugated particles of powder D, the ratio of xc/x is estimated as 0.1– 0.25 and the smallest diameters of curvature are found to be larger than 100 nm. Applying this to the contact models from Table 1, a reduction in cohesion of about 50–90% can theoretically be expected from Figure 5 for contact cases 2–5 in comparison to spherical particles. Particles having shape fitting contact (case 6), have only slight chances to be separated in an air stream during inhalation, but still have the possibility of lung deposition, depending on their aerodynamic particle size. Nonetheless, these particles will not play an important role as long as they appear only occasionally. All other possibilities of contact (with xc/x < 0.5) reduce the mechanical stability of agglomerates and support powder dispersion in an air stream. However, these observations demonstrate the significant impact of powder morphology on powder dispersibility and aerosol performance. By rising particle corrugation to a certain degree, powder dispersibility is increased and results in higher amounts of respirable particles which are less dependent on the inhaler flow rate. Therefore a uniform lung deposition which is sufficient for patients with limited respiration capacity and a more efficient use of valuable drugs can be achieved. Further advantages can be expected in an increased solubility kinetic due to the higher surface area of corrugated particles. This could be of interest to optimize the dissolution rate or the adsorption kinetic of poorly soluble drugs. AssumJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
ing no changes in wettability, the dissolution rate of the corrugated dextran particles (powder D) rises of about 1/3 compared to the more spherical particles of powder by applying dissolution models like the Nernst–Brunner equation.30
CONCLUSION The aerosol performance of powders for inhalation is influenced by the aerodynamic particle size of primary particles and by the dispersibility of the powder. Advantages in powder dispersibility can be expected for (i) particles having a lower density and therefore a larger geometrical size which causes a higher drag force in an air stream and (ii) for particles having reduced cohesion forces due to a smaller radius of curvature in the contact zone. Both characteristics are given in case of corrugated particles. In this work, novel models of different contact possibilities of corrugated particles are introduced. Experimental methods are developed and used to distinguish between both characteristics by measuring powder dispersibility in a direct way and independently from cascade impaction analysis. To optimize the fluidization of corrugated particles, elongated endings and a reduction in their radius of curvature are preferable which is typically related to an advanced degree of surface corrugation. On the other hand, highly corrugated particles may tend to form stronger connections by shape fitting or interlocking contacts which can avoid further advantages in deagglomeration or possibly a reduction in dispersibility. These statements are in agreement with theoretical considerations and basically confirmed by experimental data from spray dried model particles of different degrees of surface corrugation.
NOMENCLATURE A AH a a0 cw D Fc Fcoh FDMT Fel
cross section area (for spherical particles: A ¼ p/4 x2) (m2) Hamaker constant (J) distance (m) contact distance (a0 ¼ 0.4 nm) (m) drag coefficient diffusion coefficient (m2/s) capillary force (N) cohesion force (N) pull-off force, DMT model (N) electrostatic force for insulators (N) DOI 10.1002/jps
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Fg FJKR FVdW g m Pe Qgeo(5 mm) Qae(5mm) Re Sm SV v x xae xc xr x50 g e0 er h k rf rH2 O rP s w h$
force of gravity (N) pull-off force, JKR model (N) Van-der-Waals force (N) gravity constant (g 9.81 m/s2) (m/s2) particle mass (kg) Peclet number volume fraction of powder having a geometrical particle size <5 mm (%) mass fraction of powder having a aerodynamic particle size <5 mm (%) Reynolds number mass specific surface area (m2/g) volume specific surface area (m2/cm3) velocity (m/s) particle diameter (m) aerodynamic particle diameter (m) diameter of curvature (m) reduced particle diameter (m) median particle size (m) surface energy (J/m2) permittivity of vacuum e0 ¼ 8.8542 1012 (As/Vm) relative permittivity of dry air er ¼ 1.006 fluid viscosity (air at ambient conditions: h ¼ 0.0181 mPa s) (Pa s) evaporation rate (m2/s) fluid density (for air at ambient conditions: rf ¼ 1.2 kg/m3) (kg/m3) density of H2O (kg/m3) particle density (kg/m3) surface tension (s H2 O ¼ 72.7 mJ/m2) (J/m2) surface charge (A s/m2) Lifschitz–van-der-Vaals constant (J)
7.
8. 9. 10.
11.
12.
13. 14.
15.
16.
17.
18.
REFERENCES 19. 1. Chow AHL, Tong HHY, Chattopadhyay P, Shekunov BY. 2007. Particle engineering for pulmonary drug delivery. Pharm Res 24:411–437. 2. Vehring R. 2008. Pharmaceutical particle engineering via spray drying. Pharm Res 25:999–1022. 3. Weiler C, Egen M, Trunk M, Langguth P. 2008. Dispersibility of jet milled vs. spray dried powders. Respir Drug Deliv 2:571–575. 4. Chew NYK, Chan HK. 2001. Use of solid corrugated particles to enhance powder aerosol performance. Pharm Res 18:1570–1577. 5. Chew NYK, Tang P, Chan HK, Raper JA. 2005. How much particle surface corrugation is sufficient to improve aerosol performance of powders? Pharm Res 22:148–152. 6. Lechuga-Bellesteros D, Charan C, Stults CLM, Stevenson CL, Miller DP, Vehring R, Tep RV, DOI 10.1002/jps
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Kuo MC. 2008. Trileucine improves aerosol performance and stability of spray dried powders for inhalation. J Pharm Sci 97:287–302. Rumpf H. 1958. Grundlagen und Methoden des Granulierens. Chem Ing Techn 30:144– 158. Rumpf H. 1974. Die Wissenschaft des Agglomerierens. Chem Ing Techn 48:1–11. Schubert H. 1981. Principles of agglomeration. Int chem Eng 21:363–377. Schubert H. 2003. Handbuch der Mechanischen Verfahrenstechnik. Weinheim, Germany: WileyVCH Verlag GmbH & Co. KGaA. Krupp H. 1967. Particle adhesion—Theory and experiment. Adv Colloid Interface Sci 1:111– 239. Visser J. 1989. Van der Waals and other cohesive forces affecting powder fluidization. Powder Technol 58:1–10. Hinds WC. 1999. Aerosol technology. New York: John Wiley & Sons, Inc. Visser J, Matijevic E, editors. 1976. Adhesion of colloidal particles. Surface and colloid science. New York: Wiley. pp. 3–84. Tsai CJ, Pui DYH, Liu BYH. 1991. Elastic flattening and particle adhesion. Aerosol Sci Technol 15: 239–255. Podczeck F, Newton JM, James MB. 1997. Influence of relative humidity of storage air on adhesion and autoadhesion of micronized particles to particulate and compacted powder surfaces. J Colloid Interface Sci 187:484–491. Price R, Young PM, Edge S, Staniforth JN. 2002. The influence of relative humidity on particulate interactions in carrier-based dry powder inhalaer formulations. Int J Pharm 246:47–59. Farshchi-Tabrizi M, Kappl M, Cheng Y, Gutmann J, Butt HJ. 2006. On the adhesion between fine particles and nanocontacts: An atomic force microscopic study. Langmuir 22:2171–2184. Heim LO, Blum J, Preuss M, Butt HJ. 1999. Adhesion and friction between spherical micrometersized particles. Phys Rev Lett 83:3328–3331. Drelich J, Tormoren GW, Beach ER. 2004. Determination of solid surface tension from particle-substrate pull-off force measured with the atomic force microscope. Colloid Int Sci 280:484–497. Davies M, Brindley A, Chen X, Marlow M, Doughty SW, Shrubb I, Roberts CJ. 2005. Characterization of drug particle surface energies and Young’s modulus by atomic force microscopy and inverse gas chromatography. Pharm Res 22:1158– 1166. Zhang J, Ebbens S, Chen X, Jin Z, Luk S, Madden C, Patel N, Roberts CJ. 2006. Determination of the surface free energy of crystalline and amorphous lactose by atomic force microscopy adhesion measurement. Pharm Res 23:401–407.
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23. Lewin M, Mey-Marom A, Frank R. 2005. Surface free energies of polymeric materials, additives and minerals. Polym Adv Technol 16:429– 441. 24. Meyer K, Zimmermann I. 2004. Effect of glidants in binary powder mixtures. Powder Technol 139:40– 54. 25. Weiler C. 2008. Generierung leicht dispergierbarer Inhalationspulver mittels Spru¨ htrocknung. Dissertation Johannes Gutenberg—Universita¨ t Mainz, Germany. http://nbm.opus.hb2-nrw.de/volltexte/ 2009/1864/pdf/diss.pdf. 26. Pharmacopeia 2007. Aerosols/Physical Tests. United States Pharmacopeia, USP 24 <601>Port City Press, Baltimore, ISBN 1–889788-47-3.
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27. Nichols SC. 2000. Andersen cascade impactor. Calibration and mensuration issues for the standard and modified impactor. Pharmeuropa 12:584–588. 28. Pharmacosmos, A/S, Roervangsvej 30, DK-4300 Holbaek, Denmark. www.dextran.net/dextranphysical-properties.html. 29. Weiler C, Wolkenhauer M, Trunk M, Langguth P. 2007. Dry powder deagglomeration of spherical, submicron particles. Partec, International Congress on Particle Technology 27–29.03.2007, Nu¨ rnberg, Germany. 30. Dokoumetzidis A, Macheras P. 2006. A century of dissolution research: From Noyes and Whitney to the Biopharmaceutics Classification System. Int J Pharm 321:1–11.
DOI 10.1002/jps
Boehringer Ingelheim Pharma GmbH & Co. KG, 55216 Ingelheim, Germany
2
Institute of Pharmacy, Johannes Gutenberg-University Mainz, Mainz, Germany
Received 27 January 2009; revised 28 April 2009; accepted 14 May 2009 Published online 16 June 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21849
ABSTRACT: This study aims towards a deeper understanding of the correlation between particle morphology, cohesion forces, and aerosol performance of spray dried powders for inhalation. Therefore, forces affecting cohesion and dispersion are considered and some novel contact models are introduced to explain the improved powder dispersibility of corrugated particles. Particles with different degrees of corrugation are prepared by spray drying and characterized. Powder dispersibility is measured by positioning a dry powder inhaler in front of the laser diffraction device. The particle sizes of all powders are in the range of x50 ¼ 2.11 0.15 mm. The ratio of mass specific surface area Sm to volume specific surface area SV rises from 0.54 cm3/g (spherical particles) to 0.83 cm3/g (most corrugation). The fine particle fraction (FPF) rises significantly with increasing corrugation at 24 L/min which can be explained by a distinct difference in powder dispersibility. From theoretical models a reduction in cohesion up to 90% can be estimated for corrugated particles compared to spherical particles. Advantages in powder dispersibility can be expected for particles having a lower density and smaller radius of curvature in the contact zone. Both characteristics are given in case of corrugated particles and can be optimized to a certain degree of corrugation. ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:303–316, 2010
Keywords: aerosols; spray drying; microparticles; pulmonary drug delivery; morphology; powder technology
INTRODUCTION Many options have been developed in particle engineering to optimize powder properties of pharmaceutical drugs.1,2 In case of pulmonary drug delivery, powder dispersibility plays an important role to improve the performance of inhalation products. The typical size of inhalable particles is in the range of 1 to about 5 mm. Such small particles tend to form agglomerates due to
Correspondence to: Claudius Weiler (Telephone: 49-6132/ 77-7165; Fax: 49-6132/77-3823; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 303–316 (2010) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
cohesion forces. These forces are influenced by factors like particle size and shape, material properties, surface characteristics, and climatic conditions. In order to control particle size and shape, spray drying technique is widely used in the development of powders for inhalation. One advantage of spherical spray dried particles is a higher dispersibility due to a smaller surface contact area compared to jet milled plane shaped particles.3 A further optimization of aerosol performance is observed for spray dried particles having a corrugated surface.4–6 In contrast to spherical particles, corrugated particles show a higher fine particle fraction (FPF), which is less dependent on the inhaler device and the applied flow rate. This improved aerodynamic behavior is
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assumed to be related to a higher powder dispersibility caused by lower particle cohesion and possibly a reduced total accessible area for particle interactions.5 This work is focused on the scientific background to provide explanations as to why corrugated particles have advantages in aerosol performance. In order to obtain a deeper understanding of dispersion mechanisms, forces affecting cohesion and dispersion of particles are considered. Spray dried particles are usually regularly shaped with a spherical morphology and a relatively smooth surface. Sphere models that take the influence of cohesion forces into account were applied and new models of contact, which are relevant in case of corrugated particles, are introduced in this work. In order to compare theoretical assumptions with real powder systems, model particles of dextran having a different degree of surface corrugation were prepared and characterized concerning their aerosol performance. Furthermore, powder dispersibility is measured in a direct way and independent from cascade impaction because the densities of particles with different degrees of corrugation are not expected to be identical in terms of impaction behavior.
THEORY Forces Affecting Particle Cohesion In case of dry powder aerosols only cohesion mechanisms between solid particles in gaseous atmosphere are relevant. Neglecting solid material bridges, which are typical for sintered and granulated powders, cohesion mechanisms for spray dried particles made of organic substances can mainly be derived from van-der-Waals forces, electrostatic forces for insulators and in presence of humidity from capillary forces. To estimate the cohesion forces for these mechanisms, the sphere models based on the work of Rumpf7,8 and Schubert9 are applied in the following considerations. Van-der-Waals forces arise due to dipole– dipole interactions between atoms and molecules of adjacent surfaces and depend on material properties. In mathematical models, material properties are taken into account by the Hamaker constant AH or the Lifschitz–van-der-Waals constant h$ (correlation: AH ¼ 3=4p h$). Typical values for organic substances10 are in the range of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
$ ¼ 3 1021 to 9 1020 J. In case of particle h contact, van-der-Waals forces are on a maximum level and decrease to the power of two with separation distance a. Therefore van-der-Waals attraction can be neglected for a separation distance of a > 50 nm. For particles having contact, the distance a0 ¼ 0.4 nm is typically used for calculations.9,11 Van-der-Waals forces are always attractive and can be calculated for two ideally flat, rigid, and spherical particles having a diameter of x according to Eq. (1). In case of different particle sizes, the particle diameter x of Eq. (1) is given as x ¼ 2x1 x2/(x1 þ x2). FVdW ¼
$x h 32pa2
(1)
Electrostatic forces can be attractive or repulsive depending on the polarity of the particles. For antipolar charged and nonconducting spheres having a positive surface charge of w1 and a negative surface charge of w2, the electrostatic attraction is given by Eq. (2) with the permittivity of vacuum e0 ¼ 8.8542 1012 As/Vm and the relative permittivity for dry air er ¼ 1.006. For a maximum particle charge a value of wmax ¼ 1.6 105 As/m2 can be assumed. For unipolar charged particles Fel acts as a repulsive force. Fel ¼
p ’ 1 ’ 2 x2 4"0 "r ð1 þ a=xÞ2
(2)
Assuming total wetting for smooth and spherical particles of diameter x, the capillary force of a liquid bridge is given by Eq. (3), where s is the surface tension of the liquid.12 The surface tension of water is known to be s H2 O ¼ 72:7 mJ=m2 . Fc ¼ psx
(3)
Comparing the cohesion forces of these idealized sphere systems, liquid bridges and vander-Waals forces are the most significant attraction forces for particles <10 mm (Fig. 1). These forces are directly proportional to the particle size. Even by assuming a maximum antipolar charge, electrostatic forces (which rise with particle size to the power of two) become of relevance only for much larger particles. For homogenous particles of the same material, a unipolar charge is expected to be more likely than an antipolar charge, so that electrostatic attraction can be neglected or even considered as DOI 10.1002/jps
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Muller–Toporov—( FDMT) model: 3 FJKR ¼ pgxr 2
(4)
FDMT ¼ 2pgxr
(5)
x1 x2 ðx1 þ x2 Þ
(6)
xr ¼
Figure 1. Theoretical cohesion forces of two contacting, rigid, insulated, and spherical particles (Eqs. 1–3) in comparison to the DMT pull-off force (Eq. 5).
repulsion between most spray dried particles in the lower micron sized scale. Therefore the cohesion between inhalable spherical particles is known to be directly proportional to their particle size.13 In addition to the simplified considerations of these models, cohesion between real particles is influenced by some more factors like surface characteristics, climate conditions, or the circumstances of particle contact. For example, the contact distance of a0 ¼ 0.4 nm is in the range of molecules and can therefore only be assumed for perfect smooth surface areas. Real particles have a certain degree of surface roughness which keeps particles on distance by asperities and may reduce van-der-Waals forces. On the other hand, particle cohesion is raised due to capillary condensation of humidity or plastic deformation.13–18 Hence the intensity of van-der-Waals and capillary forces depends on the properties of the contact zone. In order to determine the cohesion between ‘‘real’’ particles, pull-off force measurements are carried out, for example, by atomic force microscopy.19–21 The force which is required to separate two spherical particles with the diameter x1 and x2 is usually described by the Johnson– Kendall–Roberts—( FJKR) and the Derjaguin– DOI 10.1002/jps
These models are linear functions of particle size and the surface energy g, whereas the JKR model is appropriate for large, soft bodies and the DMT model for small, hard bodies. For spherical particles of the same diameter (x1 ¼ x2), the pulloff force of the DMT model is equivalent to the capillary force model of total wetting according to Eq. (3) (in liquids, the surface energy is called surface tension, s). AFM studies with silica (SiO2) microspheres having diameters between 1 and 5 mm confirm the linear dependency of the pull-off force on particle size.19 The surface energy for these particles, measured at ambient conditions (humidity: 10–40%), is calculated with the DMT model as g ¼ 14.0 2.1 mJ/m2. Compared to the ‘‘pure’’ van-der-Waals cohesion between two silica spheres with h$SiO2 9 1020 J10 , the measured pull-off force is about one order of magnitude larger. In order to estimate the cohesion force between spherical particles, the pull-off force of the DMT or the JKR model can be applied by using experimentally determined surface energies. For example, values from AFM measurements are reported for crystalline lactose22 as g ¼ 7–44 mJ/m2, for amorphous lactose22 as g ¼ 30–57 mJ/m2, and for Budesonid21 as g ¼ 10–32 mJ/m2. Beside AFM, the surface energy of solids is determined by methods like inverse gas chromatography (IGC) or contact angle measurements. For a large number of organic polymers Lewin et al.23 reviewed values between 11 and 53 mJ/m2. Although results vary by different methods, surface energies for organic solids are supposed to be in the range of about 10–60 mJ/m2. By applying the DMT model to estimate the pulloff force for ‘‘real’’ organic and spherical particles, cohesion is expected to be 1–3 orders of magnitude higher compared to ‘‘pure’’ van-der-Waals cohesion (Fig. 1).
Forces Affecting Particle Dispersion While cohesion forces rise with the particle diameter x, forces which cause particle separation JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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like electrostatic forces for unipolar charged particles (Eq. 2) or the force of gravity (Eq. 7) are proportional to x2 and x3, respectively. p Fg ¼ x3 rP g (7) 6 In case of adhering particles with x < 10 mm, these forces are not relevant compared to the described cohesion forces. With increasing particle size, forces affecting particle dispersion become more significant. Particles of the upper micron sized range or larger are usually more influenced by gravity than by particle cohesion. This is the main reason why fine powders are observed as cohesive with poor flow ability and dispersibility in contrast to more granular powders. Therefore energy has to be introduced to get fine particles dispersed for inhalation. This is typically realized by an air stream inside an inhaler. To estimate the force which acts on an adhered particle in a homogeneous air stream, the drag force can be considered and calculated according to Eq. (8). r FDrag ¼ A f n2 cw (8) 2 where A is the area of the particle’s cross section, rf the density of the fluid (gas), v the relative velocity of the fluid with respect to the particle, and cw the drag coefficient of the particle. For spherical particles cw can be calculated from the approximation function of Kaskas according to Eq. (9) with the Reynolds number Re (Eq. 10) and h as the viscosity of the fluid (hair ¼ 0.0181 mPa s). cw ¼
24 4 þ þ 0:4 ðRe < 105 Þ Re Re0:5
(9)
nxrf h
(10)
Re ¼
According to Figure 2 the drag force of particles <10 mm is at least four orders of magnitude higher compared to the force of gravity, even at relatively low air velocities of 20 m/s. For laminar flow (Re < 0.5) the drag coefficient is given by Stokes as cw ¼ 24/Re and Eq. (8) results in the Stokes equation where the drag force rises linearly with particles size. With higher Reynolds numbers (e.g., by increasing gas velocity or particle size), the drag force becomes more dependent on x2 which can be seen from the increasing ascent of the drag force functions (Fig. 2). Therefore the chance to remove an adhered particle from a surface by an air stream is higher for a larger particle compared to a smaller one; JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
Figure 2. Theoretical forces, influencing the separation of adhering spherical particles after Eqs. (2), (7), and (8).
even when they have the same aerodynamic particle size. Particles of the same aerodynamic size xae but of different density rP differ in their geometrical size x according to Eq. (11). rffiffiffiffiffiffiffiffiffiffi rP (11) xae ¼ x rH2 O This effect is of significance for particles having a relatively low density like large porous particles and could be an explanation for their high aerosol performance.2 Finally, the connection between the effect of a homogeneous air stream and the cohesion force between two particles is schematically illustrated in Figure 3. As an indication of dispersibility, the ratio of drag force to cohesion force can be considered, where higher values stand for a higher possibility of particle release. Therefore advantages in powder dispersibility are expected
Figure 3. Ratio of drag force (Eq. 8) and DMT pull-off force (Eq. 5 with g ¼ 44 mJ/m2). The cohesion force between corrugated particles is affected by the radii of the curvatures which are in contact. DOI 10.1002/jps
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for particles having a low density by comparable aerodynamic size (or a large cross section) and for particles having a corrugated surface with elongated endings of small diameters of curvature. Novel Adhesion Models of Contact between Corrugated Particles The effect that the diameter of curvature influences cohesion in the contact zone is typically associated with a reduction of van-der-Waals forces caused by surface roughness or in presence of glidants (force control agents) in powder mixtures.8,9,24 In case of corrugated particles contact between particles is preferred at convex areas of the corrugated surface (Fig. 4). In this new approach the influence of different modes of contact between corrugated particles are discussed and cohesion forces are estimated in comparison to spherical particles.25 Therefore it is assumed, that the nanoscaled surface roughness of corrugated particles is identical to that of spherical particles. This means that the curvature of a corrugated particle is not being understood as an asperity or a part of surface roughness, rather the curvature itself has its own surface roughness which does not differ from that of a spherical particle. By analyzing many SEM pictures, we classified different contact modes between corrugated particles according to Table 1. For the van-der-Waals contact adhesion, these models are in accordance with the sphere/sphere model (Eq. 12) and the sphere with roughness element/plate model (Eq. 14) of Rumpf.8,9 All other equations (Eqs. 16, 18, and 20) are derived in
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order to describe the cohesion between corrugated particles with respect to the observed modes of contact. These equations take into account that the influence of van-der-Waals attraction between the complete particles becomes of significance for diameters of curvature of xc < 50 nm which may result in an increased van-der-Waals force by a further reduction of xc. This is of importance to assess the influence of surface roughness where the size of asperities is expected to be in that order of magnitude. To estimate the pull-off force from DMT theory, we applied Eqs. (5) and (6) on the contact models of Table 1 and derived Eqs. (13), (15), (17), (19), and (21). These equations do not include the influence of cohesion forces between the whole particles for relatively small separation distance due to small values of xc. Therefore these functions are assumed to be valid for xc > 100 nm. By applying these contact models on particles having a diameter of x ¼ 2 mm and a surface energy of g ¼ 44 mJ/m2, which is the mean value of amorphous lactose,22 the pull-off force FDMT can be represented against the ratio of xc/x as seen in Figure 5. In comparison to two contacting spherical particles (case 1, where xc/x ¼ 1), a decrease in cohesion is calculated for cases 3 and 4 with decreasing values of xc/x. For cases 2 and 5, a reduction in cohesion for xc/x < 0.5 and an increase in cohesion for xc/x > 0.5 are expected. For particles having shape fitting contact (case 6), cohesion depends on the contact area and can be estimated as much larger compared to the cohesion between spherical particles.3 The calculation of the van-der-Waals cohesion according to Table 1, with an average Lifschitz– van-der-Waals constant for organic substances10 of h$ ¼ 5 1020 , results in the same relations with the exceptions that the van-der-Waals force is about 45 times smaller and that an increase in cohesion is observed for xc/x < 0.005. That increase in van-der-Waals cohesion is not necessarily relevant for corrugated particles having elongated curvatures instead of an assumed hemisphere according to the contact models.
MATERIALS AND METHODS
Figure 4. Curved surface areas (encircled) and their contact points (arrows) of corrugated particles observed from SEM. DOI 10.1002/jps
Generation of Particles Having Comparable Geometrical Size Distribution and a Different Degree of Corrugation To assess the dispersion behavior of different powders due to their morphology, particles of a JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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Table 1. Several Possibilities of Particle Contact between Corrugated Particles of the Size x and Their Theoretical Models to Estimate van-der-Waals Contact Force (FVdW) and the Pull-Off Force (FDMT for xc > 100 nm) Contact Model
Equations
(1) Sphere/sphere h$x 32pa20
(12)
FDMT ¼ pgx
(13)
FVdW ¼
(2) Sphere/plate FVdW
$ xc h x ¼ þ 16p a20 ða0 þ xc =2Þ2
! (14)
FDMT ¼ 2pgxc
(3) Curvature/sphere FVdW
(15)
$x h 2xc 1 ¼ þ 32p a20 ðxc þ xÞ ða0 þ xc =2Þ2 FDMT ¼
(4) Curvature/curvature FVdW
2pgxxc ðx þ xc Þ
$ xc h x ¼ þ 32p a20 ða0 þ xc Þ2
FVdW
!
$ x 2xc h ¼ þ 2 32p x2c a0
FDMT ¼ 2pgxc
(16)
(17)
FDMT ¼ pgxc
(5) 2 curvature/curvature
!
(18)
(19)
(20)
(21)
(6) Shape fitting contact
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Figure 5. Pull-off force ( FDMT) of different possibilities of particle contact according to Table 1 with x ¼ 2 mm and a surface energy of g ¼ 44 mJ/m2.
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drying gas is pushed through the spray dryer and directed into a fume hood with Hepa-filter. The drying gas flow is measured by a float-type flow meter (Krohne VA20R K1, Duisburg, Germany) and the original nozzle gas flow meter was decoupled and replaced by a digital flow meter (Kobold DSM212-C4FD25L, Hofheim, Germany). The flow rates for drying and atomization-gas are at about 35 m3/h and 39 L/min, respectively. Furthermore a liquid flow rate of 12 2 mL/min and an inlet temperature of 150 28C is used. All samples were stored in desiccators with humidity absorbing molecular sieves (Tri-Sorb1, Su¨ dchemie AG Mu¨ nchen, Germany) directly after spray drying to avoid changes during storage.
Powder Characterization comparable geometrical size distribution have to be used. This is of importance because the densities of spherical and corrugated particles are not expected to be identical. The drag force which acts on an adhered micron particle and causes its release in an air stream, is higher in case of the geometrically larger particle. The saccharides dextran T1, dextran T3.5 (Pharmacosmos A/S, Holbaek, Denmark), and D-cellobiose (analytical grade, Serva, Heidelberg, Germany) are dissolved in different ratios (Tab. 2) in purified water (A10, Millipore, Billerica, MA). The solid concentration of the solutions is 10% (m/m). Particles are generated by a modified spray dryer (Bu¨ chi, B191, Flawil, Switzerland) in combination with the Bu¨ chi 0.5 mm twofluid-nozzle and by using nitrogen as dryingand nozzle-gas instead of air. In addition, all original glass components were replaced by components made of stainless steel. The aspirator and the particle filter were removed and the
Table 2. Parameters to Generate Particles by Spray Drying, Having a Comparable Particles Size Distribution and a Different Degree of Surface Corrugation Powder A B C D
Compounds Dextran Dextran Dextran Dextran
DOI 10.1002/jps
T1/cellobiose T1/dextran T3.5 T1/dextran T3.5 T3.5
Ratio (m/m)T(out) (8C) 2:1 9:1 1:1 100%
91 3 91 3 91 3 103 3
Due to their amorphous nature, the glass transition temperatures of cellobiose, dextran T1, and dextran T3.5 are measured as the mid point of the change in heat capacity using temperature modulated DSC (TA Instruments, New Castle, DE, Q1000, with 10 2 mg powder in pin holed aluminium pans at a heating rate of 28C/min modulated with 0.2128C over 40 s). The primary particle size distribution and the volume specific surface area SV is measured by laser diffraction (Sympatec Helos incl. Rodos powder dispersing unit, Clausthal-Zellerfeld, Germany) assuming spherical particle shape (form factor: 1). The mass specific surface area Sm is determined by a gas adsorption analyzer (Micromeritics, TriStar 3000, Norcross, GA). As a measure of particle surface corrugation, the ratio Sm/SV is calculated. The FPF was measured at 24 and 39 L/min to assess dispersion and deposition effects at different flow rates. Therefore an Andersen Mark II Impactor with preseparator is used in combination with the Boehringer Ingelheim HandiHaler1 device containing single capsules with 20 mg powder. At a flow rate of 39 L/min the pressure drop of the HandiHaler1 is 4 kPa which corresponds to the standard conditions for the determination of the FPF.26 At this flow rate impactor stage 1 has an aerodynamic mean cut-off size of 5.0 mm27 and is used to collect the powder on a filter directly beneath this stage. At a flow rate of 24 L/min, impactor stage 2 has an aerodynamic mean cut-off size of 5.0 mm and was additionally inserted to collect the powder directly beneath that stage at 24 L/min. The mass of powder on the filter is determined using an analytical balance and JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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corresponds to the fine particle dose (FPD). The delivered dose (DD) is defined as the mass difference between the nominal dose (loaded into the capsule initially) and the remaining powder in the inhaler. FPF was calculated as the ratio of FPD to DD in percent.
Powder Dispersibility Powder dispersibility has a significant impact on aerosol performance and is determined in this work in a direct way and independently from aerodynamic measurements. Therefore the geometrical, instead of the aerodynamic, size of dispersed particles is measured. Measurements were made by positioning the dry powder inhaler (Boehringer Ingelheim HandiHaler1,3,25 with capsules containing 20 2 mg of powder) in front of a laser diffractometer (Sympatec Helos). The inhalers capsule chamber was connected to an air supply in order to determine the particle size distribution of the exiting powder (Fig. 6). Over a time period of 10 s, the HandiHaler1 standard flow rate of 39 L/min (pressure drop: 4 kPa) was applied and controlled by a mass flow meter (Kobold DMS-614C3FD23L). Additionally the inhaler was run at a much lower pressure drop of 1 kPa which corresponds to a flow rate of 20 L/min. Powder dispersibility is assessed by comparing the particle size distribution from the inhaler with the particle size distribution from the Sympatec dispersing unit Rodos, where a total dispersion is assumed.
RESULTS AND DISCUSSION Corrugated Particles In order to generate model particles with varying degrees of corrugation, different types of dextran are dissolved in water and spray dried (Tab. 2). Due to their different molecular weights (dextran
Figure 6. Determination of geometrical particles size distribution of exiting particles from the HandiHaler1. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
T1: Mw 1000 g/mol, T3.5: Mw 3500 g/mol), properties of their aqueous solutions (e.g., viscosity) have impact on film forming conditions and influence particle morphology. In case of small molecules with a good solubility, like sugars or dextran T1, a concentration of the solution during droplet drying occurs, which results typically in a spherical and solid particle morphology. With increasing degree of polymerization (e.g., dextran T3.5), an early shell formation takes place which folds during drying and forms a wrinkled morphology. While dextran T3.5 particles (powder D) show a distinctive degree of corrugation, mixtures of T3.5 and T1 (powders B and C) become more spherical depending on the amount of dextran T1 (Fig. 7). Apart from their different molecular weights, these three powders are of the same chemical substance and have a similar geometrical particle size distribution measured by laser diffraction (Fig. 8). There are no differences in water uptake for dextran T1 and dextran T3.5 (DVS data not shown). Therefore humidity effects and surface energy differences should not be expected during aerodynamic and dispersibility measurements at equal environmental conditions. Particles without any corrugation are prepared by adding the disaccharide cellobiose to the polysaccharide dextran T1 (powder A). These spherical particles have a slightly smaller particle size distribution compared to powders B–D. Changes in morphology like crystallization or sintering effects are not expected due to dry storage conditions and the relatively high glass transition temperatures (cellobiose: 112.9 0.78C, dextran T1: 154.8 0.38C, dextran T3.5: 198.3 1.38C) and could not be seen from detail images of scanning electron microscopy. As a further indication for surface corrugation, the ratio of the mass specific surface area Sm (BET-surface) to the volume specific surface area SV (measured by laser diffraction, assuming spherical particle shape) is considered. With increasing surface corrugation, observed from SEM, Sm/SV rises from 0.54 to 0.83 cm3/g (Tab. 3). To describe the shell forming mechanism in a more general way and independently from the described dextran–H2O-system, the Peclet number Pe as the ratio of the evaporation rate k and the diffusion coefficient D can be used2: Pe ¼
k 8D
(22) DOI 10.1002/jps
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Figure 7. SEM images of spray dried powders having different degrees of corrugation.
For Pe < 1, the diffusional motion of the solutes is faster compared to the radial velocity of the receding droplet surface and is typically associated with spherical and solid particle formation. In case of Pe > 1, the surface moves faster than the dissolved or suspended components which results in shell formation. The Peclet number is influenced by spray drying parameters which control the evaporation performance of the process and by a combination of material properties of the solute and the solvent. The evaporation rate can be increased by rising the outlet temperature of the
Figure 8. Geometrical particle size distribution measured by laser diffraction in combination with Sympatec dispersing unit Rodos, where total powder dispersion is assumed. DOI 10.1002/jps
spray drying process (e.g., by increasing inlet temperature, increasing drying gas flow rate, reducing liquid flow rate, using solvents with lower evaporation enthalpy). The diffusion coefficient can be reduced by using liquid systems with reduced diffusional motion (e.g., by rising viscosity due to a higher concentration of the solution or by other solvent/solute systems). In case of dextranes, the viscosity increases significantly with the molecular weight28 which causes higher Peclet numbers and therefore a higher particle corrugation of dextran T3.5. Therefore, shell formation can be controlled by many factors and extended to other systems by varying the parameters influencing the Peclet number. But it should be noticed that the mechanisms of solidification occurs within milliseconds and the Peclet number is constantly changing during droplet drying. Based on the complexity of interactions between changing material properties and drying conditions the prediction of particle morphology can be difficult and cannot prevent experimental trials.
Aerosol Performance and Powder Dispersibility The FPF corresponds to the part of the delivered powder which has an aerodynamic particle size 5 mm. For all samples, the FPF at a flow rate of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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Table 3. Powder Properties of Spray Dried Particles Having a Different Degree of Corrugation Powder Property
A
B
C
D
a
1.96 0.01 3.84 0.02 2.09 0.01 0.54 5.0 0.3 23.6 4.3
2.26 0.03 3.40 0.04 2.03 0.01 0.60 13.2 0.8 32.4 4.8
2.22 0.03 3.45 0.04 2.18 0.01 0.63 24.8 1.5 40.4 4.5
2.26 0.01 3.32 0.02 2.77 0.02 0.83 22.5 4.6 38.1 4.9
x50 (mm) SV (m2/cm3)a Sm (m2/g)b Sm/SV (cm3/g) FPF at 24 L/min (%)a FPF at 39 L/min (%)a a
Mean value standard deviation (n 3). Mean value deviation (n ¼ 2).
b
39 L/min is significantly higher, compared to the FPF at 24 L/min (Fig. 9). Furthermore, no difference in the aerosol performance can be observed between powders C and D. With advanced surface corrugation an increase of the FPF from powders A–C is observed, which is significant for a flow rate of 24 L/min. The increase at 39 L/min describes only a tendency to higher FPF values due to the relatively high standard deviations. However, the difference between powders A and C is significant. These aerodynamic results confirm the observations of previous studies4,5 that (i) corrugated particles have a higher aerosol performance compared to spherical particles, (ii) aerosol performance is improved with surface corrugation to a certain degree, (iii) further corrugation does not necessarily improve aerosol performance, and (iv) these effects are more significant at lower flow rates which results in a lower dependency on inhaler flow rate of corrugated particles.
Figure 9. Fine particle fraction (FPF) of powders A– D at 24 and 39 L/min. The error bars indicate the mean value standard derivation of at least three measurements. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
But, considering only FPF measurements, it is not possible to explain these observations by only one reason. There are two relevant possibilities for the increasing aerosol performance. On the one hand, the particle density (and therefore the aerodynamic particle size) becomes smaller with higher degrees of surface corrugation. On the other hand, powder dispersibility is improved for corrugated particles. To quantify the dispersion behavior independently from particle density, a direct method is used, where the geometrical particle size distribution of the exiting powder from the inhaler, is measured. A nearly complete dispersion is observed for all powders at a flow rate of 39 L/ min (Fig. 10, bottom). These particle size distributions are in the range of the dispersion results measured from the Sympatec dispersing unit (Fig. 8). Thus, the increase in FPF measured by cascade impaction at 39 L/min is assumed to be related to a smaller particle density in case of corrugated particles. At much lower flow rates, significant differences in powder dispersibility can be seen from Figure 10 (top), where powder dispersibility rises with surface corrugation. At 20 L/min agglomerates up to about 80 mm are detected, in particular for the spherical particles of powder A. While this sample has about 40% of agglomerates larger than 10 mm, powder B has about 20% and powder C about 10%. Possibly, the slightly smaller particle size distribution or the added compound cellobiose has a further influence on the deagglomeration of powder A. For the corrugated particles of powder D, no agglomerates larger than 10 mm can be detected. The particle size distribution of this sample is not equal to that at 39 L/min, but slightly shifted about 0.2 mm towards larger particles. Anyway, an almost comparable powder dispersion can be assumed for powder D at 24 and 39 L/min. Thus, the discrepancy in FPF measured by cascade DOI 10.1002/jps
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Figure 11. Powder dispersibility (Qgeo(50 m)) versus fine particle fraction (Qae(5mm) ¼ FPF) at 39 L/min and 22 2 L/min for powders A–D.
Figure 10. Geometrical particle size distribution measured by laser diffraction in combination with the HandiHaler1 containing capsules of 20 mg powder at flow rates of 20 L/min (top) and 39 L/min (bottom). The error bars indicate the mean value standard derivation of at least three measurements.
impaction at 24 and 39 L/min of powder D (Fig. 9) can possibly be a result of the different cascade impactor arrangements. At 24 L/min an additional impactor stage is inserted which may cause a higher particle loss. This should be considered particularly at high powder loadings like 20 mg/capsule. These direct measurements of powder dispersibility demonstrate, in a simple manner and independent from cascade impaction experiments, that dry powder deagglomeration is influenced by the degree of surface corrugation. This approach describes a physical method where the geometrical size of agglomerates is directly measured after exiting the mouthpiece of an inhaler. In contrast to that, cascade impaction experiments are used as a pharmacopeial in vitro method to asses the lung deposition behavior of respirable particles. However, from a scientific point of view, the determination of FPF via cascade impaction is not appropriate to determine the dispersibility of powders with different DOI 10.1002/jps
morphology as long as there are further differences in particle density or geometrical particle size. The relation between both methods is illustrated in Figure 11 where Qgeo(5 mm) indicates the percentage of the exiting powder from the inhaler having a geometrical particle size <5 mm. Qae(5 mm) is equivalent to the FPF and indicates the percentage of powder having an aerodynamic particle size <5 mm. At 39 L/min the powder dispersion by the HandiHaler1 is almost constant in the range of Qgeo(5 mm) ¼ 90 3% for powders A–D. Therefore, the increase in Qae(5 mm) with advanced particle corrugation from 24% to 40% is mainly caused by a reduction in particle density. At the lower flow rate of 22 2 L/min, powder dispersibility rises with advanced particle corrugation from 49% to 87%. Therefore the increase in Qae(5mm) from 5% to 23% is due to an improved powder dispersibility and due to a reduction in particle density for increased particle corrugation. The mechanisms for the improved dispersibility of corrugated particles can be explained by a reduced cohesion force which is discussed previously. Another assumption is that less particle contacts exist inside of agglomerates due to a reduced accessible area of corrugated particles. According to theoretical models describing the mechanical stability of agglomerates, the coordination number (number of contacting JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
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neighbors of a primary particle inside an agglomerate) is directly proportional to the tensilestrength7 or the dispersion-strength25,29 of model agglomerates. In case of a loose bulk system of spherical particles, the coordination number is given7 as k 7. As a rough estimate, the mechanical stability (tensile- or dispersionstrength) is reduced by about 1/7 for each absent particle contact due to a corrugated surface area. Unfortunately, the challenge of this consideration is the determination of the coordination number of ‘‘real’’ particles which is not further investigated here. Therefore a clear conclusion about the influence of unaccessible surface area of corrugated particles on improved powder dispersibility cannot be made. On the other hand, it is most likely, that contact between particles is preferred at convex areas of the corrugated surface. In that case, a reduction in cohesion can be expected depending on the diameters of curvature in the contact zone as described in the theory section. From SEM pictures of the corrugated particles of powder D, the ratio of xc/x is estimated as 0.1– 0.25 and the smallest diameters of curvature are found to be larger than 100 nm. Applying this to the contact models from Table 1, a reduction in cohesion of about 50–90% can theoretically be expected from Figure 5 for contact cases 2–5 in comparison to spherical particles. Particles having shape fitting contact (case 6), have only slight chances to be separated in an air stream during inhalation, but still have the possibility of lung deposition, depending on their aerodynamic particle size. Nonetheless, these particles will not play an important role as long as they appear only occasionally. All other possibilities of contact (with xc/x < 0.5) reduce the mechanical stability of agglomerates and support powder dispersion in an air stream. However, these observations demonstrate the significant impact of powder morphology on powder dispersibility and aerosol performance. By rising particle corrugation to a certain degree, powder dispersibility is increased and results in higher amounts of respirable particles which are less dependent on the inhaler flow rate. Therefore a uniform lung deposition which is sufficient for patients with limited respiration capacity and a more efficient use of valuable drugs can be achieved. Further advantages can be expected in an increased solubility kinetic due to the higher surface area of corrugated particles. This could be of interest to optimize the dissolution rate or the adsorption kinetic of poorly soluble drugs. AssumJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 1, JANUARY 2010
ing no changes in wettability, the dissolution rate of the corrugated dextran particles (powder D) rises of about 1/3 compared to the more spherical particles of powder by applying dissolution models like the Nernst–Brunner equation.30
CONCLUSION The aerosol performance of powders for inhalation is influenced by the aerodynamic particle size of primary particles and by the dispersibility of the powder. Advantages in powder dispersibility can be expected for (i) particles having a lower density and therefore a larger geometrical size which causes a higher drag force in an air stream and (ii) for particles having reduced cohesion forces due to a smaller radius of curvature in the contact zone. Both characteristics are given in case of corrugated particles. In this work, novel models of different contact possibilities of corrugated particles are introduced. Experimental methods are developed and used to distinguish between both characteristics by measuring powder dispersibility in a direct way and independently from cascade impaction analysis. To optimize the fluidization of corrugated particles, elongated endings and a reduction in their radius of curvature are preferable which is typically related to an advanced degree of surface corrugation. On the other hand, highly corrugated particles may tend to form stronger connections by shape fitting or interlocking contacts which can avoid further advantages in deagglomeration or possibly a reduction in dispersibility. These statements are in agreement with theoretical considerations and basically confirmed by experimental data from spray dried model particles of different degrees of surface corrugation.
NOMENCLATURE A AH a a0 cw D Fc Fcoh FDMT Fel
cross section area (for spherical particles: A ¼ p/4 x2) (m2) Hamaker constant (J) distance (m) contact distance (a0 ¼ 0.4 nm) (m) drag coefficient diffusion coefficient (m2/s) capillary force (N) cohesion force (N) pull-off force, DMT model (N) electrostatic force for insulators (N) DOI 10.1002/jps
POWDER DISPERSIBILITY OF SPRAY DRIED PARTICLES FOR INHALATION
Fg FJKR FVdW g m Pe Qgeo(5 mm) Qae(5mm) Re Sm SV v x xae xc xr x50 g e0 er h k rf rH2 O rP s w h$
force of gravity (N) pull-off force, JKR model (N) Van-der-Waals force (N) gravity constant (g 9.81 m/s2) (m/s2) particle mass (kg) Peclet number volume fraction of powder having a geometrical particle size <5 mm (%) mass fraction of powder having a aerodynamic particle size <5 mm (%) Reynolds number mass specific surface area (m2/g) volume specific surface area (m2/cm3) velocity (m/s) particle diameter (m) aerodynamic particle diameter (m) diameter of curvature (m) reduced particle diameter (m) median particle size (m) surface energy (J/m2) permittivity of vacuum e0 ¼ 8.8542 1012 (As/Vm) relative permittivity of dry air er ¼ 1.006 fluid viscosity (air at ambient conditions: h ¼ 0.0181 mPa s) (Pa s) evaporation rate (m2/s) fluid density (for air at ambient conditions: rf ¼ 1.2 kg/m3) (kg/m3) density of H2O (kg/m3) particle density (kg/m3) surface tension (s H2 O ¼ 72.7 mJ/m2) (J/m2) surface charge (A s/m2) Lifschitz–van-der-Vaals constant (J)
7.
8. 9. 10.
11.
12.
13. 14.
15.
16.
17.
18.
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DOI 10.1002/jps