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Agglomeration of hydrophobic powders via solid spreading nucleation
Powder Technology 188 (2009) 248–254
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Powder Technology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p o w t e c
Agglomeration of hydrophobic powders via solid spreading nucleation K.P. Hapgood a,⁎, L. Farber b, J.N. Michaels b a b
Monash Advanced Particle Engineering Laboratory, Department of Chemical Engineering, Monash University, VIC, Australia Centre for Materials Science and Engineering, Merck & Co., Inc., PA, USA
A R T I C L E
I N F O
Article history: Received 21 January 2008 Received in revised form 20 May 2008 Accepted 20 May 2008 Available online 28 May 2008 Keywords: Hydrophobic Non-wetting Nucleation Granulation Liquid marble Granule structure
A B S T R A C T Wet granulation of a highly hydrophobic fine powder was investigated to elucidate the granule nucleation and growth processes in systems in which distribution of granulating fluid in the granulating mass is complicated by poor wetting. A mixture containing approximately 70 wt.% (90% by volume) of a micronized poorly wetting powder was granulated in a high-shear mixer using water and the microstructure of resultant agglomerates (granules) was studied using optical and electron microscopy as well as X-ray computed tomography (XRCT). The study revealed that granules are typically spherical or elliptical in shape and range in size from 200 to 500 μm. They are strong and consist of a consolidated powder shell and an empty core. Based on the microstructure, a nucleation mechanism for such a hydrophobic system is proposed. Implications for controlling granule growth and granule properties are discussed. This study demonstrates that well-controlled nuclei formation and subsequent granule growth is achievable in a highly hydrophobic system. © 2008 Elsevier B.V. All rights reserved.
1. Introduction Wettability is a key consideration in binder granulation, as wetting and spreading of the granulating fluid into the dry powder determines the size distribution of granule nuclei [1] and the strength of wet granules [2–4]. The impact of wetting and spreading on nucleation is shown schematically in Fig. 1. It is commonly assumed that the liquid must wet the powder in order for granulation to be robust and controllable, as this promotes bulk incorporation of fluid into the powder and formation of strong liquid bridges between primary particles. For this reason, a surfactant is commonly added to the granulation fluid and/or powders to reduce the liquid–solid contact angle and “convert” the non-wetting system into the wetting system. In such a system, granule nuclei are formed by penetration of liquid droplets into dry powder. When the powder is agitated, these wet nuclei grow into granules by coalescence or layering. In poorly wetting situations, the granulating fluid can not penetrate into the powder to form nuclei [2,3]. However, it is known that hydrophobic powders may spread around the drop during agitation and/or rolling of fluid drops on a hydrophobic powder. Simons and Fairbrother [5] and Hapgood [6] report the motion of powders over the surface of a large single droplet. This behaviour may be driven by spreading coefficients [7–11] as summarised in Fig. 1. We will term granules formed by spreading of powder around a liquid droplet “solid
⁎ Corresponding author. Tel.: +61 3 9905 3428. E-mail address: [email protected] (K.P. Hapgood). 0032-5910/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2008.05.004
spreading nucleation”. A few studies investigating solid spreading and spreading coefficients have been published, but they used powder compacts [12] or large particles [9, 13]) where the particles were not free to move and spread over the droplet. Spreading of hydrophobic powders around water droplets has been applied to sequester water in dry form by forming stable spherical structures. Aussillous and Quere [14,15] describe “liquid marbles” formed from water droplets covered with hydrophobic lycopodium grains, which roll and bounce like glass marbles but deform and flex like a fluid. Forny et al. [16] report “powder encapsulation” of fluid, where a hydrophobic micronised silica powder forms a powder shell encapsulating a water droplet core. They report on the effect of powder hydrophobicity and several process variables including shear levels on the formation of the powder-encapsulated aqueous phase, but they do not describe the mechanisms of formation. In this work, we investigate the application of solid spreading nucleation in granulation of poorly wetting powders. We produce powder-encapsulated droplets in a high-shear granulator and subsequently dry the particle to form structurally sound, hollow granules. 2. Experimental 2.1. Materials A sub-micron milled crystalline powder known to be highly hydrophobic (contact angle with pure water N90°) was used to investigate hydrophobic nucleation. Experiments used both neat and formulated powder (see Table 1). Formulation A was the main
K.P. Hapgood et al. / Powder Technology 188 (2009) 248–254
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Fig. 1. Nucleation formation mechanisms as a function of drop to particle size ratio and spreading coefficient values. Adapted from Schæfer and Mathiesen [20] and Tardos et al. [4].
formulation used, while formulation B (where the surfactant has been omitted) was used only for single drop experiments. In both formulations, the hydrophobic model drug was ~70 wt.% of the formulation, but approximately 90% on a volume basis due to its low bulk density, approximately 0.2 m3/kg. Microcrystalline cellulose (MCC), croscarmellose sodium, and sodium lauryl sulphate (SLS) are pharmaceutical excipients that are added to the formulation to provide mechanical strength to the final tableted product, as well as desirable disintegration and dissolution properties. All excipients were used “as received” and typical particle size and bulk density values are shown in Table 2.
2.3. Small scale granulation A Diosna P1–6 high-shear mixer with a 2 L bowl was used to granulate 200 g batches of formulation A. The dry ingredients were mixed for 5 min at 400 rpm impeller speed and 2000 rpm chopper speed, water was then sprayed using a dual fluid nozzle at 20 g/min to fluid levels between 70 and 78 wt.%, and the contents were wet massed for 1 to 7 min following the completion of solution delivery. The main impeller power was electronically recorded. The wet granulation was tray-dried in a convection oven at 45 °C. The dried granulations were milled through a 45G screen with a comil running at 1000 rpm.
2.2. Single drop nucleation experiments 2.4. Characterization To understand formation mechanism of the granules, drops of either pure USP water or 2% sodium lauryl sulfate (SLS) solution were placed onto loosely packed beds of formulation A or formulation B using a 1-cc syringe with a 21 gauge needle. The powders were blended in a plastic bag and agitated by hand before pouring carefully to a small petri dish and levelled with a spatula. The interaction between the powder and fluid was observed. The typical droplet diameter was approximately 5 mm.
Table 2 Estimated maximum droplet diameter D that can be contained within the hydrophobic matrix
Table 1 Formulation summary table (mass fraction basis) Component
Hydrophobic model drug powder Croscarmellose sodium (Ac-Di-Sol) Hydroxypropyl cellulose (HPC-LF) Sodium lauryl sulphate (SLS) Microcrystalline cellulose (Avicel PH101)
Granule size distribution was measured by sieving using US mesh sizes # 18, 35, 50, 80, 100, 140 and pan (1000, 500, 300, 180, 150, 106 μm, respectively). The sieve fractions were reserved for microstructural analysis by electron microscopy and micro X-ray tomography (µXRT).
Formulation
Formulation
A (%)
B (%)
70 5 4 1 20
71 5 4 0 20
Component
wt.%
Particle diameter d, µm
Droplet diameter D, µm
Hydrophobic powder Microcrystalline cellulose Sodium lauryl sulphate (SLS) Croscarmellose sodium (Ac-Di-Sol) Hydroxypropyl cellulose (HPC-LF)
70 20 1 5
1 100 30 50
n/a 296 293 264
4
200
1155
250
K.P. Hapgood et al. / Powder Technology 188 (2009) 248–254
Granules were imaged with a Quanta 200 environmental scanning electron microscope (FEI) using 20 kV acceleration voltage, beam size 3, and water pressure ~ 0.75 Torr. Granules from each sieve fraction were placed onto double-sided carbon tape attached to an aluminium stub. Excess granules were blown off using a duster can. The internal structure of the granules was imaged with a Skyscan 1072 X-ray microtomograph. Raw images were collected with resolution of 2.73 µm/pixel, 0.9°/step, with the X-ray source operated at 100 kV. Images were processed with Skyscan software. Individual granules from each sieve fraction (except the pan fraction) were mounted on the sample stage of the tomograph in a small cradle made of flexible putty. 3. Results 3.1. Single drop nucleation results Single drops of USP water placed onto the neat hydrophobic drug powder (i.e. with no excipients present) did not sink or penetrate the
powder at all — instead a thin film of powder spread rapidly around the outside of the drop without apparently penetrating the interior. Shaking the powder by hand caused the water drops to roll across the surface and collect a thicker powder layer, but no penetration occurred. These drops were stable for up to a few hours and were consistent with qualitative descriptions of liquid marbles [14]. The liquid-marble nuclei were oven dried overnight at two different temperatures (40 °C and 60 °C) but the structure collapsed and formed a hemisphere, suggesting that the powder shell persisted during drying and collapsed towards the end of the drying process. We presume the collapse was due to the weight of the shell and the lack of a binding agent in the dry state. In contrast, drops of 2% SLS solution placed on the hydrophobic powder penetrated immediately (b0.5 s) and formed “normal” granule nuclei. This is not unexpected as SLS is a surfactant used to aid wetting by reducing interfacial tension and contact angle. Single drop nucleation behaviour was markedly different when placed on formulations A and B. No stable spherical droplets were formed when a water drop was placed on a loose bed of formulation A, which is a mixture of predominantly hydrophobic drug blended with several hydrophilic excipients. Water penetrated into the formulation A powder within 2 s of introduction. To test whether the presence of the SLS surfactant in the powder was sufficient to overcome the hydrophobicity of the system, water droplets were placed on a bed of formulation B, in which the SLS surfactant has been omitted. Spherical droplets were formed and were stable for 10–20 s before collapse. 3.2. Small scale granulation results
Fig. 2. Particle size distributions for (a) 70% fluid after 1 and 7 min wet massing (b) 74% fluid after 4 min wet massing and (c) 78% fluid after 1 and 7 min of wet massing time.
Granule size (mass) distributions computed from mesh profiles of unmilled granulations are plotted in Fig. 2. The distributions are bimodal, with a primary mode at 300 µm and a secondary mode at approximately 20 µm (corresponding to the pan fraction). At 70% fluid level, the distributions were essentially independent of wet massing time. Increasing the fluid level to 78% at 1-minute wet massing time did not change the shape of the distribution, however the fines fraction decreased monotonically with fluid level. After adding 78% water and wet massing for 7 min, the granule size distribution became unimodal due to complete consumption of fines with no shift in the primary mode. Fig. 3 shows representative scanning electron micrographs of the major sieve cuts of the granulation produced at 70% water and 1 min of wet massing. The pan fraction was comprised of ungranulated particles. Comparison to a micrograph of the neat API, Fig. 4, indicates that the finest particles were selectively consumed during granulation. Granules between 100 and 300 µm in diameter were spherical or slightly elliptical. Granules larger than 300 µm had more varied shapes, with a significant fraction having holes or large depressions. Some of the largest granules were agglomerates of 100–300 µm granules. Fig. 5 shows representative X-ray tomographic reconstructions of the internal structure of granules retained in different sieve fractions. These images show that majority of finer granules consisted of a consolidated powder shell and an empty core (Fig. 5a). The wall thickness of the granule ranged from 25 to 50 µm. We believe that that internal hollow space was originally filled with granulating fluid which evaporated during drying. These results are consistent with granule nuclei formed by solid spreading around water droplets to form a liquid marbles with subsequent evaporation of the fluid to form a hollow granule. The majority of larger granules had hybrid internal structures: they contained several hollow nuclei which are surrounded by less dense material. Fig. 5e shows a side view of such a granule and several reconstructed cross-sections. They show that the hollow areas are typically surrounded by a denser homogenous layer which we believe is the wall of a hollow nucleus. It appears that this microstructure was
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Fig. 3. Scanning electron micrographs of sieve fractions of granules granulated with 70% water and wet massed for 1 min. Sieve mesh size is indicated on each micrograph.
formed by coalescence of hollow nuclei and subsequent layering with ungranulated fines to form a thick powder shell around the nuclei. For granules of intermediate sizes, both single- and multi-nuclei microstructures were observed, as shown in Fig. 5b–d. The effect of fluid level and wet massing time on the external morphology of 300–500 µm granules is shown in Fig. 6. At 1 min of wet massing, the morphology did not change appreciably between 70 and 78% fluid level. Wet massing for 7 min at 70% water did not change the appearance of the granule surface appreciably, however the granules are generally more deformed. The external surfaces of the granules in all of
these cases are comprised of small particles, suggesting that they were produced by layering of fines. At 78% water and 7 min of wet massing, however, the external microstructure changed significantly; these granules clearly are comprised of smaller granules rather than primary particles. These observations are consistent with the evolution of the granule size distributions, especially the absence of fines in the granulation produced at 78% water and 7 min of wet massing. Milling of the tray-dried granulations produced only a modest change in the granule size distribution, as shown in Fig. 7. Milling eliminated granules larger than mill screen opening of 1.2 mm, however
Fig. 4. Micrographs of micronised API (left) and particles in pan after granulation (same magnification).
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Fig. 5. X-ray tomographs of granules in different mesh cuts: (a) −105 + 150 mm; (b), (c) and (d) −180 + 300 mm; e) −500 + 1000 mm. (a–d: left-hand image and (e) top image: transmission shadow X-ray image; right hand on (a)–(d) and bottom images on (e) are reconstructed cross-sections. Dotted line on side view images indicate the position of the reconstructed cross-section. Arrow points to a embedded small nuclei which are comparable in size with the nuclei in (a).
qualitatively the distribution was unchanged. In particular, the fines fraction did not increase significantly. This indicates that the smaller granules largely survived milling, and the large granules broke into fragments rather than disintegrating into primary particles. 4. Discussion 4.1. Granule formation The granulation experiments demonstrated that stable hollow granules were successfully formed in the granulator from the formulation A. This is consistent with granule nucleus formation by spreading of micronized powder around water droplets, as observed
in formation of liquid marbles [14,15] However, stable liquid marbles could not be formed in the single drop experiments from this formulation. Even after removing the SLS surfactant from the system entirely, liquid marbles formed but collapsed after 10–20 s. This apparent contradiction in nucleus stability can be rationalized by comparing the drop sizes in the granulation and single drop experiments to the average distance between particles of the hydrophilic excipients dispersed in the hydrophobic powder. A simple model can be derived from first principles to estimate the average distance between hydrophilic particles. In order to penetrate into the powder matrix, the drop diameter must be larger than this average distance. Since approximately 70% (by weight) of the formulation is a hydrophobic powder of very low bulk density, we assume that the
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Fig. 6. Electron micrographs of granules produced at 70 and 78% fluid level and 1 and 7 min of wet massing. (granules from −300 + 500 µm mesh cut).
hydrophilic excipients are uniformly distributed within a low density matrix of the hydrophobic drug. The hydrophilic particles are assumed to be spherical and are arranged uniformly on a simple cubic lattice with a unit cell dimension of a. The total number of excipient particles Nex in the blend is given by the total volume of the excipient divided by the volume occupied by each individual excipient particle:
Nex ¼
mex 6 2mex ≈ ρex πd3 ρex d3ex
ð1Þ
where mex is weight fractions of the excipient in the powder matrix, ρex is the true density of the excipient, and dex is the average diameter of an excipient particle. The bulk density of the hydrophobic powder was ρm = 0.2 g/cc and we use a typical true density for the excipients of ρex = 1.5 g/cc. Since the total volume occupied by the excipient particles Vex is negligible compared to the bulk volume of the hydrophobic drug Vm, the total
volume occupied by the powder matrix (Vm Vm+ VexVex) can be approximated by VmVm. Dividing the total volume of the hydrophobic matrix VmVm by the number of excipient particles NexNex gives an estimate of the total volume occupied per excipient particle vexvex: vex ¼
Vm mm ρex d3ex ¼ Nex ρm 2mex
ð2Þ
where mm is weight fraction of the hydrophobic powder and ρm is the bulk density of the hydrophobic matrix powder. Since we have assumed a simple cubic lattice structure, the length of the cube side a is [17]: a¼
ffiffiffiffiffiffiffi p 3 vex ¼ dex
mm ρex 2mex ρm
1=3 ¼ dex K1=3
ð3Þ
where K¼
mm ρex 2mex ρm
1=3 ð4Þ
This procedure is similar to estimating the crystal lattice spacing given the density of a simple cubic crystal (e.g. [17]. Under these conditions, the maximum water droplet diameter D that can be placed in the crystal lattice cube without touching a hydrophilic excipient particle is given by the length of the lattice cube diagonal, (√3a from geometry) minus the diameter of the excipient particles dexdex: D¼
Fig. 7. Particle size distributions of unmilled and milled dry granulation produced at 74% fluid level and 4 min of wet massing.
pffiffiffi pffiffiffi 3dex K−dex ¼ dex 3K−1
ð5Þ
The estimated maximum droplet diameters that can be contained within the hydrophobic matrix without touching any hydrophilic components are summarized in Table 2. The results in Table 2 show that the maximum drop diameters are between 300 and 1000 µm, bracketing the 300–500 µm hollow granule size observed in the granulation experiments. Drops added to the formulation that are larger than the sizes shown in Table 2 may
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initially form a liquid marble, but they will interact with other formulation components to produce a hydrophilic drainage path through the powder shell. Thus, the large (~5 mm) drops used in the single drop experiments initially form a liquid marble, but this quickly collapses as liquid drains from the core. In contrast, the atomised drops used in the granulation experiments were approximately 100– 300 µm in diameter, small enough to interact predominantly with the hydrophobic powder to form stable liquid-marble nuclei. The largest droplets in the spray formed unstable nuclei which produced granules with holes or large depressions that were observed in the larger sieve fractions of the dried granulation. This is a highly simplified description of the structure of powder mixtures, which supports our hypothesis that drop size differences are at least partially responsible for the difference in lifetime of liquid–marble nuclei in the single drop nucleation and the small scale granulation experiments. This is clearly an area that requires further investigation, including experimental work where the excipient concentrations and particle sizes are varied. The liquid–marble nuclei are clearly strong enough to survive extended agitation during high-shear granulation. This is consistent with studies showing that the shear strength of liquid marbles is dominated by the properties of the fluid and that they maintain their integrity during collisions, allowing measurement of a coefficient of restitution [15]. Since the nuclei persist, trapping the progenitor water droplets, granulation occurs primarily by drop-controlled granulation [18]. At the lower fluid levels studied, no significant granule growth occurs during wet massing; the main impact of extended mixing is elongation of the hollow granules. Growth by layering of fines does not appear to be significant. In this granulation regime, increasing the fluid level increases the number of granule nuclei with a corresponding reduction in the fraction of ungranulated fines, and the granule size distribution is directly related to the droplet size distribution [1]. At the highest fluid level investigated, the same behaviour is exhibited at short wet massing times. However, a qualitative change in growth mechanism occurs at larger mixing times, shown by the rapid consumption of remaining fines, consolidation of granule nuclei into larger conglomerate granules, and a rapid increase in main impeller power draw. The reason for this change in mechanism is not clear, however we speculate that it is due to the increased probability that granulating fluid contacts and dissolves the SLS in the formulation. This would lower surface tension and allow it to wet and penetrate the powder shell. Ultimately, this would lead to shell collapse, releasing the trapped granulating fluid, and promoting rapid granulation consolidation. 4.2. Dry granule strength After tray drying, the hollow granules had sufficient mechanical strength to withstand milling. This implies that the shell contained HPC (the only binder in the dry mix) and that water permeated into the shell and dissolved the HPC during processing. On drying, this created solid bridges between particles in the shell which cemented the shell together [19]. 5. Conclusions A highly hydrophobic pharmaceutical formulation was granulated in a high-shear granulator via a solid spreading nucleation mechanism to produce granules comprised of a shell of fine powder surrounding individual water droplets. These “green” granules were strong enough to withstand extended wet massing. When tray-dried, they retained their shape and were sufficiently strong to withstand milling, and thus were suitable for further pharmaceutical processing. The formation of hollow granules was confirmed by X-ray tomography of dried granule samples.
Formation of the hollow granule structure via solid spreading nucleation opens a unique approach to granulation of hydrophobic materials. The approach can be used to manufacture “designer granules” with a number of advantageous attributes: 1. Controlled granule size by manipulating the size distribution of the spray drop “templates” at low spray flux conditions (i.e. dropcontrolled nucleation regime). 2. Controlled granule structure which produces spherical, highly porous granules with excellent flow and compression properties. 3. Very high content of hydrophobic component (e.g. drug). Formulations that nucleate via solid spreading also offer a unique experimental insight into the growth of granules. Granulation of such systems may be useful as a model system for population balance studies. Further research into the solid spreading mechanism and the dominant controlling groups is ongoing, with the ultimate aim of extending granulation theory to include non-wetting systems. Acknowledgements Thanks for Bevan Bautista for the assistance with the single drop experiments and Michael Pignatiello for assistance with the granulation experiments. References [1] K.P. Hapgood, J.D. Litster, R. Smith, Nucleation regime map for liquid bound granules, AIChE Journal 49 (2003) 350–360. [2] S.M. Iveson, J.D. Litster, K.P. Hapgood, Nucleation, growth and breakage phenomena in agitated wet granulation processes: a review, Powder Technology 117 (2001) 3–39. [3] S.M. Iveson, P.A.L. Wauters, S. Forrest, J.D. Litster, G.M.H. Meesters, B. Scarlett, Growth regime map for liquid-bound granules: further development and experimental validation, Powder Technology 117 (2001) 83–97. [4] G.I. Tardos, M.I. Khan, P.R. Mort, Critical parameters and limiting conditions in binder granulation of fine powders, Powder Technology 94 (1997) 245–258. [5] S.J.R. Simons, R.J. Fairbrother, Direct observations of liquid binder particle interactions: the role of wetting behaviour in agglomerate growth, Powder Technology 110 (2000) 44–58. [6] K.P. Hapgood, (2000). Nucleation and Binder Dispersion in Wet Granulation, PhD thesis, University of Queensland. [7] S. Wu, Polar and non polar interactions in adhesion, Journal of Adhesion 5 (1973) 39–55. [8] R.C. Rowe, Binder–substrate interactions in granulation, a theoretical approach based on surface free energy and polarity, International Journal of Pharmaceutics 52 (1989) 149–154. [9] R.C. Rowe, Surface free energy and polarity effects in the granulation of a model system, International Journal of Pharmaceutics 53 (1989) 75–78. [10] O. Planinsek, R. Pisek, A. Trojak, S. Srcic, The utilization of surface free-energy parameters for the selection of a suitable binder in fluidized bed granulation, International Journal of Pharmaceutics 207 (2000) 77–88. [11] I. Krycer, D.G. Pope, “An evaluation of tablet binding agents. Part I. Solution binders”, Powder Technology 34 (1983) 39–51. [12] L. Zajic, G. Buckton, The use of surface energy values to predict optimum binder selection for granulations, International Journal of Pharmaceutics 59 (1990) 155–164. [13] R.C. Rowe, Correlation between predicted binder spreading coefficients and measured granule and tablet properties in the granulation of paracetamol, International Journal of Pharmaceutics 58 (1990) 209–213. [14] P. Aussillous, D. Quere, Liquid marbles, Nature 411 (6840) (2001) 924–927. [15] P.J. Aussillous, D. Quere, Properties of liquid marbles, Proceedings Royal Society A 462 (2067) (2006) 973–999, doi:10.1098/rspa.2005.1581. [16] L. Forny, I. Pezron, K. Saleh, et al., Storing water in powder form by self-assembling hydrophobic silica nanoparticles, Powder Technology 171 (1) (2007) 15–24. [17] R.J. Tilley, Crystals and Crystal Structures, John Wiley & Sons, 2006. [18] J.D. Litster, K.P. Hapgood, J.N. Michaels, et al., “Liquid distribution in wet granulation. Dimensionless spray flux.”, Powder Technology 114 (2001) 32–39. [19] L. Farber, G. Tardos, J.N. Michaels, Micro-mechanical properties of drying material bridges of pharmaceutical excipients, International Journal of Pharmaceutics 306 (2005) 41–55. [20] T. Schæfer, C. Mathiesen, Melt pelletization in a high shear mixer IX. Effects of binder particle size, International Journal of Pharmaceutics 139 (1996) 139–148.
Contents lists available at ScienceDirect
Powder Technology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p o w t e c
Agglomeration of hydrophobic powders via solid spreading nucleation K.P. Hapgood a,⁎, L. Farber b, J.N. Michaels b a b
Monash Advanced Particle Engineering Laboratory, Department of Chemical Engineering, Monash University, VIC, Australia Centre for Materials Science and Engineering, Merck & Co., Inc., PA, USA
A R T I C L E
I N F O
Article history: Received 21 January 2008 Received in revised form 20 May 2008 Accepted 20 May 2008 Available online 28 May 2008 Keywords: Hydrophobic Non-wetting Nucleation Granulation Liquid marble Granule structure
A B S T R A C T Wet granulation of a highly hydrophobic fine powder was investigated to elucidate the granule nucleation and growth processes in systems in which distribution of granulating fluid in the granulating mass is complicated by poor wetting. A mixture containing approximately 70 wt.% (90% by volume) of a micronized poorly wetting powder was granulated in a high-shear mixer using water and the microstructure of resultant agglomerates (granules) was studied using optical and electron microscopy as well as X-ray computed tomography (XRCT). The study revealed that granules are typically spherical or elliptical in shape and range in size from 200 to 500 μm. They are strong and consist of a consolidated powder shell and an empty core. Based on the microstructure, a nucleation mechanism for such a hydrophobic system is proposed. Implications for controlling granule growth and granule properties are discussed. This study demonstrates that well-controlled nuclei formation and subsequent granule growth is achievable in a highly hydrophobic system. © 2008 Elsevier B.V. All rights reserved.
1. Introduction Wettability is a key consideration in binder granulation, as wetting and spreading of the granulating fluid into the dry powder determines the size distribution of granule nuclei [1] and the strength of wet granules [2–4]. The impact of wetting and spreading on nucleation is shown schematically in Fig. 1. It is commonly assumed that the liquid must wet the powder in order for granulation to be robust and controllable, as this promotes bulk incorporation of fluid into the powder and formation of strong liquid bridges between primary particles. For this reason, a surfactant is commonly added to the granulation fluid and/or powders to reduce the liquid–solid contact angle and “convert” the non-wetting system into the wetting system. In such a system, granule nuclei are formed by penetration of liquid droplets into dry powder. When the powder is agitated, these wet nuclei grow into granules by coalescence or layering. In poorly wetting situations, the granulating fluid can not penetrate into the powder to form nuclei [2,3]. However, it is known that hydrophobic powders may spread around the drop during agitation and/or rolling of fluid drops on a hydrophobic powder. Simons and Fairbrother [5] and Hapgood [6] report the motion of powders over the surface of a large single droplet. This behaviour may be driven by spreading coefficients [7–11] as summarised in Fig. 1. We will term granules formed by spreading of powder around a liquid droplet “solid
⁎ Corresponding author. Tel.: +61 3 9905 3428. E-mail address: [email protected] (K.P. Hapgood). 0032-5910/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2008.05.004
spreading nucleation”. A few studies investigating solid spreading and spreading coefficients have been published, but they used powder compacts [12] or large particles [9, 13]) where the particles were not free to move and spread over the droplet. Spreading of hydrophobic powders around water droplets has been applied to sequester water in dry form by forming stable spherical structures. Aussillous and Quere [14,15] describe “liquid marbles” formed from water droplets covered with hydrophobic lycopodium grains, which roll and bounce like glass marbles but deform and flex like a fluid. Forny et al. [16] report “powder encapsulation” of fluid, where a hydrophobic micronised silica powder forms a powder shell encapsulating a water droplet core. They report on the effect of powder hydrophobicity and several process variables including shear levels on the formation of the powder-encapsulated aqueous phase, but they do not describe the mechanisms of formation. In this work, we investigate the application of solid spreading nucleation in granulation of poorly wetting powders. We produce powder-encapsulated droplets in a high-shear granulator and subsequently dry the particle to form structurally sound, hollow granules. 2. Experimental 2.1. Materials A sub-micron milled crystalline powder known to be highly hydrophobic (contact angle with pure water N90°) was used to investigate hydrophobic nucleation. Experiments used both neat and formulated powder (see Table 1). Formulation A was the main
K.P. Hapgood et al. / Powder Technology 188 (2009) 248–254
249
Fig. 1. Nucleation formation mechanisms as a function of drop to particle size ratio and spreading coefficient values. Adapted from Schæfer and Mathiesen [20] and Tardos et al. [4].
formulation used, while formulation B (where the surfactant has been omitted) was used only for single drop experiments. In both formulations, the hydrophobic model drug was ~70 wt.% of the formulation, but approximately 90% on a volume basis due to its low bulk density, approximately 0.2 m3/kg. Microcrystalline cellulose (MCC), croscarmellose sodium, and sodium lauryl sulphate (SLS) are pharmaceutical excipients that are added to the formulation to provide mechanical strength to the final tableted product, as well as desirable disintegration and dissolution properties. All excipients were used “as received” and typical particle size and bulk density values are shown in Table 2.
2.3. Small scale granulation A Diosna P1–6 high-shear mixer with a 2 L bowl was used to granulate 200 g batches of formulation A. The dry ingredients were mixed for 5 min at 400 rpm impeller speed and 2000 rpm chopper speed, water was then sprayed using a dual fluid nozzle at 20 g/min to fluid levels between 70 and 78 wt.%, and the contents were wet massed for 1 to 7 min following the completion of solution delivery. The main impeller power was electronically recorded. The wet granulation was tray-dried in a convection oven at 45 °C. The dried granulations were milled through a 45G screen with a comil running at 1000 rpm.
2.2. Single drop nucleation experiments 2.4. Characterization To understand formation mechanism of the granules, drops of either pure USP water or 2% sodium lauryl sulfate (SLS) solution were placed onto loosely packed beds of formulation A or formulation B using a 1-cc syringe with a 21 gauge needle. The powders were blended in a plastic bag and agitated by hand before pouring carefully to a small petri dish and levelled with a spatula. The interaction between the powder and fluid was observed. The typical droplet diameter was approximately 5 mm.
Table 2 Estimated maximum droplet diameter D that can be contained within the hydrophobic matrix
Table 1 Formulation summary table (mass fraction basis) Component
Hydrophobic model drug powder Croscarmellose sodium (Ac-Di-Sol) Hydroxypropyl cellulose (HPC-LF) Sodium lauryl sulphate (SLS) Microcrystalline cellulose (Avicel PH101)
Granule size distribution was measured by sieving using US mesh sizes # 18, 35, 50, 80, 100, 140 and pan (1000, 500, 300, 180, 150, 106 μm, respectively). The sieve fractions were reserved for microstructural analysis by electron microscopy and micro X-ray tomography (µXRT).
Formulation
Formulation
A (%)
B (%)
70 5 4 1 20
71 5 4 0 20
Component
wt.%
Particle diameter d, µm
Droplet diameter D, µm
Hydrophobic powder Microcrystalline cellulose Sodium lauryl sulphate (SLS) Croscarmellose sodium (Ac-Di-Sol) Hydroxypropyl cellulose (HPC-LF)
70 20 1 5
1 100 30 50
n/a 296 293 264
4
200
1155
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Granules were imaged with a Quanta 200 environmental scanning electron microscope (FEI) using 20 kV acceleration voltage, beam size 3, and water pressure ~ 0.75 Torr. Granules from each sieve fraction were placed onto double-sided carbon tape attached to an aluminium stub. Excess granules were blown off using a duster can. The internal structure of the granules was imaged with a Skyscan 1072 X-ray microtomograph. Raw images were collected with resolution of 2.73 µm/pixel, 0.9°/step, with the X-ray source operated at 100 kV. Images were processed with Skyscan software. Individual granules from each sieve fraction (except the pan fraction) were mounted on the sample stage of the tomograph in a small cradle made of flexible putty. 3. Results 3.1. Single drop nucleation results Single drops of USP water placed onto the neat hydrophobic drug powder (i.e. with no excipients present) did not sink or penetrate the
powder at all — instead a thin film of powder spread rapidly around the outside of the drop without apparently penetrating the interior. Shaking the powder by hand caused the water drops to roll across the surface and collect a thicker powder layer, but no penetration occurred. These drops were stable for up to a few hours and were consistent with qualitative descriptions of liquid marbles [14]. The liquid-marble nuclei were oven dried overnight at two different temperatures (40 °C and 60 °C) but the structure collapsed and formed a hemisphere, suggesting that the powder shell persisted during drying and collapsed towards the end of the drying process. We presume the collapse was due to the weight of the shell and the lack of a binding agent in the dry state. In contrast, drops of 2% SLS solution placed on the hydrophobic powder penetrated immediately (b0.5 s) and formed “normal” granule nuclei. This is not unexpected as SLS is a surfactant used to aid wetting by reducing interfacial tension and contact angle. Single drop nucleation behaviour was markedly different when placed on formulations A and B. No stable spherical droplets were formed when a water drop was placed on a loose bed of formulation A, which is a mixture of predominantly hydrophobic drug blended with several hydrophilic excipients. Water penetrated into the formulation A powder within 2 s of introduction. To test whether the presence of the SLS surfactant in the powder was sufficient to overcome the hydrophobicity of the system, water droplets were placed on a bed of formulation B, in which the SLS surfactant has been omitted. Spherical droplets were formed and were stable for 10–20 s before collapse. 3.2. Small scale granulation results
Fig. 2. Particle size distributions for (a) 70% fluid after 1 and 7 min wet massing (b) 74% fluid after 4 min wet massing and (c) 78% fluid after 1 and 7 min of wet massing time.
Granule size (mass) distributions computed from mesh profiles of unmilled granulations are plotted in Fig. 2. The distributions are bimodal, with a primary mode at 300 µm and a secondary mode at approximately 20 µm (corresponding to the pan fraction). At 70% fluid level, the distributions were essentially independent of wet massing time. Increasing the fluid level to 78% at 1-minute wet massing time did not change the shape of the distribution, however the fines fraction decreased monotonically with fluid level. After adding 78% water and wet massing for 7 min, the granule size distribution became unimodal due to complete consumption of fines with no shift in the primary mode. Fig. 3 shows representative scanning electron micrographs of the major sieve cuts of the granulation produced at 70% water and 1 min of wet massing. The pan fraction was comprised of ungranulated particles. Comparison to a micrograph of the neat API, Fig. 4, indicates that the finest particles were selectively consumed during granulation. Granules between 100 and 300 µm in diameter were spherical or slightly elliptical. Granules larger than 300 µm had more varied shapes, with a significant fraction having holes or large depressions. Some of the largest granules were agglomerates of 100–300 µm granules. Fig. 5 shows representative X-ray tomographic reconstructions of the internal structure of granules retained in different sieve fractions. These images show that majority of finer granules consisted of a consolidated powder shell and an empty core (Fig. 5a). The wall thickness of the granule ranged from 25 to 50 µm. We believe that that internal hollow space was originally filled with granulating fluid which evaporated during drying. These results are consistent with granule nuclei formed by solid spreading around water droplets to form a liquid marbles with subsequent evaporation of the fluid to form a hollow granule. The majority of larger granules had hybrid internal structures: they contained several hollow nuclei which are surrounded by less dense material. Fig. 5e shows a side view of such a granule and several reconstructed cross-sections. They show that the hollow areas are typically surrounded by a denser homogenous layer which we believe is the wall of a hollow nucleus. It appears that this microstructure was
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Fig. 3. Scanning electron micrographs of sieve fractions of granules granulated with 70% water and wet massed for 1 min. Sieve mesh size is indicated on each micrograph.
formed by coalescence of hollow nuclei and subsequent layering with ungranulated fines to form a thick powder shell around the nuclei. For granules of intermediate sizes, both single- and multi-nuclei microstructures were observed, as shown in Fig. 5b–d. The effect of fluid level and wet massing time on the external morphology of 300–500 µm granules is shown in Fig. 6. At 1 min of wet massing, the morphology did not change appreciably between 70 and 78% fluid level. Wet massing for 7 min at 70% water did not change the appearance of the granule surface appreciably, however the granules are generally more deformed. The external surfaces of the granules in all of
these cases are comprised of small particles, suggesting that they were produced by layering of fines. At 78% water and 7 min of wet massing, however, the external microstructure changed significantly; these granules clearly are comprised of smaller granules rather than primary particles. These observations are consistent with the evolution of the granule size distributions, especially the absence of fines in the granulation produced at 78% water and 7 min of wet massing. Milling of the tray-dried granulations produced only a modest change in the granule size distribution, as shown in Fig. 7. Milling eliminated granules larger than mill screen opening of 1.2 mm, however
Fig. 4. Micrographs of micronised API (left) and particles in pan after granulation (same magnification).
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Fig. 5. X-ray tomographs of granules in different mesh cuts: (a) −105 + 150 mm; (b), (c) and (d) −180 + 300 mm; e) −500 + 1000 mm. (a–d: left-hand image and (e) top image: transmission shadow X-ray image; right hand on (a)–(d) and bottom images on (e) are reconstructed cross-sections. Dotted line on side view images indicate the position of the reconstructed cross-section. Arrow points to a embedded small nuclei which are comparable in size with the nuclei in (a).
qualitatively the distribution was unchanged. In particular, the fines fraction did not increase significantly. This indicates that the smaller granules largely survived milling, and the large granules broke into fragments rather than disintegrating into primary particles. 4. Discussion 4.1. Granule formation The granulation experiments demonstrated that stable hollow granules were successfully formed in the granulator from the formulation A. This is consistent with granule nucleus formation by spreading of micronized powder around water droplets, as observed
in formation of liquid marbles [14,15] However, stable liquid marbles could not be formed in the single drop experiments from this formulation. Even after removing the SLS surfactant from the system entirely, liquid marbles formed but collapsed after 10–20 s. This apparent contradiction in nucleus stability can be rationalized by comparing the drop sizes in the granulation and single drop experiments to the average distance between particles of the hydrophilic excipients dispersed in the hydrophobic powder. A simple model can be derived from first principles to estimate the average distance between hydrophilic particles. In order to penetrate into the powder matrix, the drop diameter must be larger than this average distance. Since approximately 70% (by weight) of the formulation is a hydrophobic powder of very low bulk density, we assume that the
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Fig. 6. Electron micrographs of granules produced at 70 and 78% fluid level and 1 and 7 min of wet massing. (granules from −300 + 500 µm mesh cut).
hydrophilic excipients are uniformly distributed within a low density matrix of the hydrophobic drug. The hydrophilic particles are assumed to be spherical and are arranged uniformly on a simple cubic lattice with a unit cell dimension of a. The total number of excipient particles Nex in the blend is given by the total volume of the excipient divided by the volume occupied by each individual excipient particle:
Nex ¼
mex 6 2mex ≈ ρex πd3 ρex d3ex
ð1Þ
where mex is weight fractions of the excipient in the powder matrix, ρex is the true density of the excipient, and dex is the average diameter of an excipient particle. The bulk density of the hydrophobic powder was ρm = 0.2 g/cc and we use a typical true density for the excipients of ρex = 1.5 g/cc. Since the total volume occupied by the excipient particles Vex is negligible compared to the bulk volume of the hydrophobic drug Vm, the total
volume occupied by the powder matrix (Vm Vm+ VexVex) can be approximated by VmVm. Dividing the total volume of the hydrophobic matrix VmVm by the number of excipient particles NexNex gives an estimate of the total volume occupied per excipient particle vexvex: vex ¼
Vm mm ρex d3ex ¼ Nex ρm 2mex
ð2Þ
where mm is weight fraction of the hydrophobic powder and ρm is the bulk density of the hydrophobic matrix powder. Since we have assumed a simple cubic lattice structure, the length of the cube side a is [17]: a¼
ffiffiffiffiffiffiffi p 3 vex ¼ dex
mm ρex 2mex ρm
1=3 ¼ dex K1=3
ð3Þ
where K¼
mm ρex 2mex ρm
1=3 ð4Þ
This procedure is similar to estimating the crystal lattice spacing given the density of a simple cubic crystal (e.g. [17]. Under these conditions, the maximum water droplet diameter D that can be placed in the crystal lattice cube without touching a hydrophilic excipient particle is given by the length of the lattice cube diagonal, (√3a from geometry) minus the diameter of the excipient particles dexdex: D¼
Fig. 7. Particle size distributions of unmilled and milled dry granulation produced at 74% fluid level and 4 min of wet massing.
pffiffiffi pffiffiffi 3dex K−dex ¼ dex 3K−1
ð5Þ
The estimated maximum droplet diameters that can be contained within the hydrophobic matrix without touching any hydrophilic components are summarized in Table 2. The results in Table 2 show that the maximum drop diameters are between 300 and 1000 µm, bracketing the 300–500 µm hollow granule size observed in the granulation experiments. Drops added to the formulation that are larger than the sizes shown in Table 2 may
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initially form a liquid marble, but they will interact with other formulation components to produce a hydrophilic drainage path through the powder shell. Thus, the large (~5 mm) drops used in the single drop experiments initially form a liquid marble, but this quickly collapses as liquid drains from the core. In contrast, the atomised drops used in the granulation experiments were approximately 100– 300 µm in diameter, small enough to interact predominantly with the hydrophobic powder to form stable liquid-marble nuclei. The largest droplets in the spray formed unstable nuclei which produced granules with holes or large depressions that were observed in the larger sieve fractions of the dried granulation. This is a highly simplified description of the structure of powder mixtures, which supports our hypothesis that drop size differences are at least partially responsible for the difference in lifetime of liquid–marble nuclei in the single drop nucleation and the small scale granulation experiments. This is clearly an area that requires further investigation, including experimental work where the excipient concentrations and particle sizes are varied. The liquid–marble nuclei are clearly strong enough to survive extended agitation during high-shear granulation. This is consistent with studies showing that the shear strength of liquid marbles is dominated by the properties of the fluid and that they maintain their integrity during collisions, allowing measurement of a coefficient of restitution [15]. Since the nuclei persist, trapping the progenitor water droplets, granulation occurs primarily by drop-controlled granulation [18]. At the lower fluid levels studied, no significant granule growth occurs during wet massing; the main impact of extended mixing is elongation of the hollow granules. Growth by layering of fines does not appear to be significant. In this granulation regime, increasing the fluid level increases the number of granule nuclei with a corresponding reduction in the fraction of ungranulated fines, and the granule size distribution is directly related to the droplet size distribution [1]. At the highest fluid level investigated, the same behaviour is exhibited at short wet massing times. However, a qualitative change in growth mechanism occurs at larger mixing times, shown by the rapid consumption of remaining fines, consolidation of granule nuclei into larger conglomerate granules, and a rapid increase in main impeller power draw. The reason for this change in mechanism is not clear, however we speculate that it is due to the increased probability that granulating fluid contacts and dissolves the SLS in the formulation. This would lower surface tension and allow it to wet and penetrate the powder shell. Ultimately, this would lead to shell collapse, releasing the trapped granulating fluid, and promoting rapid granulation consolidation. 4.2. Dry granule strength After tray drying, the hollow granules had sufficient mechanical strength to withstand milling. This implies that the shell contained HPC (the only binder in the dry mix) and that water permeated into the shell and dissolved the HPC during processing. On drying, this created solid bridges between particles in the shell which cemented the shell together [19]. 5. Conclusions A highly hydrophobic pharmaceutical formulation was granulated in a high-shear granulator via a solid spreading nucleation mechanism to produce granules comprised of a shell of fine powder surrounding individual water droplets. These “green” granules were strong enough to withstand extended wet massing. When tray-dried, they retained their shape and were sufficiently strong to withstand milling, and thus were suitable for further pharmaceutical processing. The formation of hollow granules was confirmed by X-ray tomography of dried granule samples.
Formation of the hollow granule structure via solid spreading nucleation opens a unique approach to granulation of hydrophobic materials. The approach can be used to manufacture “designer granules” with a number of advantageous attributes: 1. Controlled granule size by manipulating the size distribution of the spray drop “templates” at low spray flux conditions (i.e. dropcontrolled nucleation regime). 2. Controlled granule structure which produces spherical, highly porous granules with excellent flow and compression properties. 3. Very high content of hydrophobic component (e.g. drug). Formulations that nucleate via solid spreading also offer a unique experimental insight into the growth of granules. Granulation of such systems may be useful as a model system for population balance studies. Further research into the solid spreading mechanism and the dominant controlling groups is ongoing, with the ultimate aim of extending granulation theory to include non-wetting systems. Acknowledgements Thanks for Bevan Bautista for the assistance with the single drop experiments and Michael Pignatiello for assistance with the granulation experiments. References [1] K.P. Hapgood, J.D. Litster, R. Smith, Nucleation regime map for liquid bound granules, AIChE Journal 49 (2003) 350–360. [2] S.M. Iveson, J.D. Litster, K.P. Hapgood, Nucleation, growth and breakage phenomena in agitated wet granulation processes: a review, Powder Technology 117 (2001) 3–39. [3] S.M. Iveson, P.A.L. Wauters, S. Forrest, J.D. Litster, G.M.H. Meesters, B. Scarlett, Growth regime map for liquid-bound granules: further development and experimental validation, Powder Technology 117 (2001) 83–97. [4] G.I. Tardos, M.I. Khan, P.R. Mort, Critical parameters and limiting conditions in binder granulation of fine powders, Powder Technology 94 (1997) 245–258. [5] S.J.R. Simons, R.J. Fairbrother, Direct observations of liquid binder particle interactions: the role of wetting behaviour in agglomerate growth, Powder Technology 110 (2000) 44–58. [6] K.P. Hapgood, (2000). Nucleation and Binder Dispersion in Wet Granulation, PhD thesis, University of Queensland. [7] S. Wu, Polar and non polar interactions in adhesion, Journal of Adhesion 5 (1973) 39–55. [8] R.C. Rowe, Binder–substrate interactions in granulation, a theoretical approach based on surface free energy and polarity, International Journal of Pharmaceutics 52 (1989) 149–154. [9] R.C. Rowe, Surface free energy and polarity effects in the granulation of a model system, International Journal of Pharmaceutics 53 (1989) 75–78. [10] O. Planinsek, R. Pisek, A. Trojak, S. Srcic, The utilization of surface free-energy parameters for the selection of a suitable binder in fluidized bed granulation, International Journal of Pharmaceutics 207 (2000) 77–88. [11] I. Krycer, D.G. Pope, “An evaluation of tablet binding agents. Part I. Solution binders”, Powder Technology 34 (1983) 39–51. [12] L. Zajic, G. Buckton, The use of surface energy values to predict optimum binder selection for granulations, International Journal of Pharmaceutics 59 (1990) 155–164. [13] R.C. Rowe, Correlation between predicted binder spreading coefficients and measured granule and tablet properties in the granulation of paracetamol, International Journal of Pharmaceutics 58 (1990) 209–213. [14] P. Aussillous, D. Quere, Liquid marbles, Nature 411 (6840) (2001) 924–927. [15] P.J. Aussillous, D. Quere, Properties of liquid marbles, Proceedings Royal Society A 462 (2067) (2006) 973–999, doi:10.1098/rspa.2005.1581. [16] L. Forny, I. Pezron, K. Saleh, et al., Storing water in powder form by self-assembling hydrophobic silica nanoparticles, Powder Technology 171 (1) (2007) 15–24. [17] R.J. Tilley, Crystals and Crystal Structures, John Wiley & Sons, 2006. [18] J.D. Litster, K.P. Hapgood, J.N. Michaels, et al., “Liquid distribution in wet granulation. Dimensionless spray flux.”, Powder Technology 114 (2001) 32–39. [19] L. Farber, G. Tardos, J.N. Michaels, Micro-mechanical properties of drying material bridges of pharmaceutical excipients, International Journal of Pharmaceutics 306 (2005) 41–55. [20] T. Schæfer, C. Mathiesen, Melt pelletization in a high shear mixer IX. Effects of binder particle size, International Journal of Pharmaceutics 139 (1996) 139–148.