- Email: [email protected]
Quantifying Effects of Particulate Properties on Powder Flow Properties Using a Ring Shear Tester
Quantifying Effects of Particulate Properties on Powder Flow Properties Using a Ring Shear Tester HAO HOU, CHANGQUAN CALVIN SUN Materials Science Laboratory, Small Molecule Pharmaceutics, Amgen, Inc., One Amgen Center Dr. 21-2-A, Thousand Oaks, California 91320-1799
Received 4 October 2007; revised 16 October 2007; accepted 9 November 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21288
ABSTRACT: Effects of particle size, morphology, particle density, and surface silicification, on powder flow properties were investigated using a ring shear tester. Flow properties were quantified by flow function (FF), that is, unconfined yield strength, fc, as a function of major principal stress. A total of 11 powders from three series of microcrystalline cellulose (MCC): Avicel (regular MCC, elongated particles), Prosolv (silicified MCC, elongated particles), and Celphere (spherical MCC), were studied. Particle size distribution in each type of MCC was systematically different. Within each series, smaller particles always led to poorer powder flow properties. The slope of FF line was correlated to degree of powder consolidation by external stress. A key mechanism of the detrimental effect of particle size reduction on flow properties was the larger powder specific surface area. Flow properties of Celphere were significantly better than Avicel of comparable particles size, suggesting spherical morphology promoted better powder flow properties. Flow properties of powders different in densities but similar in particle size, shape, and surface properties were similar. When corrected for density effect, higher particle density corresponded to better flow behavior. Surface silicification significantly improved flow properties of finer MCC, but did not improve those of coarser. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4030–4039, 2008
Keywords: powder flow properties; flow function; ring shear tester; microcrystalline cellulose; particle size; particle shape; particle density; surface silicification
INTRODUCTION It has been known that particulate properties can profoundly influence properties of bulk powders.1–6 In early days of pharmaceutical manufacturing, batch-to-batch variability of bulk excipients and active pharmaceutical ingredients (API) could be great because critical particulate properties were generally not well controlled. Variations in raw materials frequently resulted in processing difficulty and even failed commercial batches, causing
Correspondence to: Changquan Calvin Sun (Telephone: 805-313-5581; Fax: 805-447-3401; E-mail: [email protected] or [email protected]) Journal of Pharmaceutical Sciences, Vol. 97, 4030–4039 (2008) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association
4030
significant financial losses to manufacturers. Consequently, the need of more constant raw material properties, both excipients and API, has gained much attention from both the academia and the pharmaceutical industry. Variability in properties of most excipients has been substantially reduced as a result of tighter controls implemented in most manufacturing process by suppliers. On the other hand, scientists have taken advantage of the effects of particulate properties on bulk powder properties to continuously develop new grades of excipients with improved bulk properties (or functionality), such as powder flow, compaction, and dispersion properties. Reliable and consistent flow out of hoppers and feeders without excessive spillage and dust generation is of importance to pharmaceutical
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
QUANTIFYING POWDER FLOW PROPERTIES
industry.7,8 Poor powder flow properties may give rise to reduced productivity and financial losses. Sometimes, a high speed tablet press has to be operated at a suboptimum speed to accommodate the flow properties of a powder in order to meet the minimum requirements in tablet weight uniformity. One approach to improve powder flow properties is particle size enlargement (e.g., granulation). Although effective, controlling particle size alone sometimes is not sufficient to deliver adequate flow properties to accommodate APIs that are hygroscopic in nature and need to be delivered in high doses. Another approach is increasing particle density. Both intuition and experience have suggested higher particle density can improve powder flow properties of a formulation. It has been also recognized that particle morphology can affect powder compaction and flow properties.9–12 For example, more spherical particles usually result in better powder flow properties than elongated particles. Powder flow properties and compaction properties are of recognized importance to successful pharmaceutical manufacturing of solid dosage forms, that is, tablets and capsules. Effects of particulate properties on powder compaction have been extensively studied in the literature.13–17 However, similar studies on powder flow properties are scarce.18,19 Many of the instruments used to study flow properties were empirical in nature or significantly affected by the test conditions.20 Results obtained using the more empirical methods in laboratory cannot be reliably extrapolated to different powder systems or different scales. Shear cell is an instrument well established to measure powder flow properties. Flow properties characterized by shear cell have clear physical meaning and are independent of scale. Combined with some additional measurements, such as, air permeability, shear cell data obtained in a laboratory can be reliably used to design optimum equipment to handle large scale powders.21,22 The application of shear cell in pharmaceutical industry has been limited largely because previously available shear cells are the translational types that are labor intensive and poorly reproducible if a standard procedure is not carefully followed. In the recent decade, a few commercially available ring shear cells have made it possible to substantially reduce the amount of powder and labor required to characterize flow properties.23 The aim of this study was to better quantify effects of particulate properties on bulk powder flow properties using a ring shear tester. We DOI 10.1002/jps
4031
focused on effects of particle size, morphology, density, and surface modification on powder flow properties. Microcrystalline cellulose (MCC) is an important pharmaceutical excipient and is commercially available in many grades that differ in particle size, density, morphology, moisture content, and surface silicification. We therefore chose MCC as a model compound in this study.
MATERIALS AND METHODS Materials Eleven MCC powders spanning a range of particle size, morphology, density, and surface properties were used in this study. Avicel1 PH105, PH101, PH102, PH302, and PH200 were purchased from FMC BioPolymer (Philadelphia, PA). Prosolv1 SMCC50, SMCC90, and HD90 were obtained from JRS Pharma (Patterson, NY). Celphere1 SCP100, CP-102, and CP-203 were obtained from Asahi Kasei Chemicals Corporation (New York, NY). All materials were used as received. These powders are examples of regular MCC (Avicel), silicified MCC (Prosolv), and spherical MCC (Celphere).
Particle Size Distribution The volume-based particle size distribution (PSD) of dry powders was obtained using a Sympatec Helos/Rodos laser diffraction particle size analyzer (Sympatec, Inc., Princeton, NJ). The powder dispersing pressure of 2.5 bars was selected after pressure titration step and used for all PSD measurements. Three measurements were made on each powder. The resulting PSD was averaged and standard deviation was calculated. Shear Cell Test A Ring Shear Tester (RST-XS, Dietmar Schulze, Wolfenbu¨ ttel, Germany) was used for measuring the flow properties of powders following an appropriate procedure.24 Key components of the shear cell are shown in Figure 1. A powder was over-filled into the standard shear cell with a volume of 30 mL. Excess powder was scraped off with a spatula so that the powder surface was flush with the upper edge of the shear cell. The filled shear cell was weighed and then placed on the motor-driven base of the Ring Shear Tester. The lid was placed on the top surface of the powder
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
4032
HOU AND SUN
Figure 1. Photograph of the Schulze shear cell showing its key components: tie rods (A), loading rod (B), lid (C), arm of the lid (D), cell (E), rotating base (F).
approximately 2/3 of the cylinder was full. The powder was carefully leveled without compacting, and the volume (V0) and mass (M) of the bulk powder were used to calculate bulk density. The cylinder containing the powder sample was then mechanically tapped using a VanKel Tap Density Tester (Model 50–1200, Varian, Inc., Palo Alto, CA). The cylinder was tapped 500 times initially and the tapped volume of the powder was measured to the nearest graduated unit. An additional 750 taps were performed and the volume was recorded. Since the difference between the two tapped volumes was less than 2% for all powders, the second tapped volume was taken as the final tapped volume (Vf) to calculate tapped density. Carr’s compressibility index (CI) was calculated using Eq. (1) CI ¼
bed with a loading rod (for applying a normal stress to the powder bed) inserted. Two tie rods (for applying shear stress) were used to attach the lid to the two load cells. As base rotated and the lid was fixed in position by the two tie rods, shear stress was developed in the powder. The shearing procedure involved two steps: preshear and shear. The powder was first presheared under a prescribed consolidation stress until a steady-state was reached. The presheared powder was then subjected to a shear test under a normal stresses that was below the preshear consolidation stress. Failure of the powder bed was characterized by a sudden drop in shear stress. In this study, the procedure was conducted in triplicates using preshear consolidation stresses of 1, 3, 9, and 15 KPa and five normal shear stresses equally spaced between zero and the preshear consolidation stress. Because physical properties of MCC can be significantly affected by both temperature and water content,25 all experiments were performed at 20 18C and 35 5% relative humidity to minimize such effects. A prolonged application of a normal stress will cause more powder consolidation. This in turn affects measured flow properties. In this study, we tested the powder immediately after filling the shear cell. Carr’s Compressibility Index Bulk and tap densities were measured following USP guidelines.26 A powder that had been passed through a 1.00 mm (No. 18) mesh sieve screen was added into a 100 mL graduated cylinder until
100 ðV0 Vf Þ Vf
(1)
Data Analysis A yield locus is a plot of shear stress at failure as a function of the normal consolidation stress. From each yield locus, the unconfined yield strength ( fc) and the major principal stress were derived by drawing two Mohr circles. The unit of kPa was used for both stresses. Average and standard deviation were calculated based on three measurements for each set of test conditions. The strength of a powder gained after being consolidated at a certain stress is quantified by fc. To initiate a flow of the consolidated powder, external stress must exceed fc. A flow function (FF) describes fc as a function of major principal stress. Linear regression was performed for each set of data to obtain the mathematic expression of corresponding FF. Unconfined yield strength at a certain pressure could be calculated from the fitted FF line. We caution that FF line should cross origin or its vicinity. Deviations from linearity may be expected at near zero major principal stress. Thus, extrapolation to major principal stress, <1 kPa should be avoided. In order to assess the effect of density on powder flow, the density-corrected unconfined yield strength ( fc,r) was calculated according to Eq. (2) fc;r ¼
fc r
(2)
where r is the bulk density corresponding to each fc. The fc,r takes into account the effect of the bulk
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
DOI 10.1002/jps
QUANTIFYING POWDER FLOW PROPERTIES
density (g/mL) on powder flow. The correction is appropriate for accurate prediction of powder flow behavior in a process where the gravitational force plays a role, that is, when the bulk material is discharged from a hopper. The density-corrected FF is a plot of fc,r versus the major principal stress.
RESULTS AND DISCUSSION Effect of Particle Size on Powder Flow Properties Key particle properties and flow functions of the 11 powders are summarized in Tables 1 and 2. As shown in the tables, particle size of Avicel decreases in the order of Avicel PH200 > PH102 > PH101 > PH105. With decreasing particle size, flow function line rotates counterclockwise suggesting progressively worsened flow properties (Fig. 2a). Particles in Prosolv 50 are smaller than those in Prosolv 90 (Tab. 1). Similar to the Avicel series, larger particles correspond to better flow properties as shown by the lower flow function line of the Prosolv 90 powder (Fig. 2b). For the three Celphere powders, particle size decreases in the order CP-203 > CP-102 > SCP100 (Tab. 1). Consistent with the observations made on Avicel and Prosolv series, smaller particle size corresponds to worse powder flow properties (higher flow function line, Fig. 2c). To more clearly show effect of particle size, the slope of FF line is plotted against particle size, d10, d50, and d90 for each series of materials (Fig. 3). With increasing particle size, the slope of FF line decreases, suggesting better flow properties. The curves drop sharply then gradually level off. This
4033
suggests an equal reduction in particle size would result in more profound decrease in powder flow properties for finer powders. Within the particle size range studied, large particles always correspond to better powder flow properties. It holds true for the elongated MCC (Avicel) particles, nearly spherical (Celphere) particles, and surface silicified MCC (Prosolv) particles. The fc represents the strength developed within a powder when consolidated, which must be overcome to initiate the flow of a powder. The higher strength developed suggests stronger particle–particle interactions. The particle–particle interactions, including van der Waal’s force and H-bonding, are stronger as two particles get closer. An increase in the external stress in the pressure range concerning powder flow properties (<100 kPa) typically consolidates powders and brings particles closer together. The closer arrangement of particles and possibly more contact points in a powder bed can cause stronger particle– particle interactions. Consequently, the unconfined yield strength increases with increasing external stress. The stress required to induce particle–particle relative movement (shear failure in shear cell tests) is therefore higher if the powder bed is consolidated under a higher normal stress. This is analogous to the dependence of friction force on normal stress during sliding of two touching surfaces. This explains why the flow function of a powder exhibits a positive slope. The effectiveness of external stress in causing the fc to increase directly corresponds to the slope of the flow function line. If a powder does not undergo significant consolidation by external stress, the slope of its flow function line should be close to
Table 1. Key Particle Size Distribution Parameters, Densities, and Calculated Carr’s Compressibility Index for the Powders
Material Avicel PH105 Avicel PH101 Avicel PH102 Avicel PH302 Avicel PH200 Prosolv 50 Prosolv 90 Prosolv HD90 Celphere SCP-100 Celphere CP-102 Celphere CP-203
d10 (mm) 8.26 18.6 31.09 24.5 69.59 16.75 34.71 34.6 73.25 114.67 196.82
Particle Size Distribution d50 (mm) d90 (mm)
(0.14) (0.13) (0.13) (0.10) (1.15) (0.72) (0.34) (0.30) (1.35) (1.00) (1.19)
22.73 48.66 103.87 83.7 228.61 52.02 104.40 96 127.82 165.28 262.81
(0.21) (1.10) (0.52) (0.50) (2.53) (0.52) (0.76) (1.00) (2.12) (1.41) (1.68)
45.72 102.67 213.27 195.8 379.85 112.22 199.83 190.6 200.45 234.28 349.1
(1.47) (5.89) (0.45) (0.80) (8.55) (0.53) (0.41) (1.50) (2.01) (1.75) (1.69)
Bulk Density (g/cm3) 0.33 0.34 0.38 0.49 0.38 0.35 0.36 0.47 0.6 0.84 0.87
Tap Density (g/cm3) 0.53 0.51 0.55 0.7 0.45 0.49 0.47 0.58 0.73 0.99 0.99
Compressibility Index 37 33 30 31 16 28 24 19 18 15 12
Standard deviations are in parentheses (n ¼ 3). DOI 10.1002/jps
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
4034
HOU AND SUN
Table 2. Mathematic Expressions of Flow Functions of All Tested Materials Obtained by Linear Regression
Material Avicel PH105 Avicel PH101 Avicel PH102 Avicel PH302 Avicel PH200 Prosolv 50 Prosolv 90 Prosolv HD90 Celphere SCP-100 Celphere CP-102 Celphere CP-203
Mathematic Expression of Flow Function y ¼ 0.3461x þ 0.5403, y ¼ 0.2309x þ 0.1461, y ¼ 0.1266x þ 0.3427, y ¼ 0.1433x þ 0.1905, y ¼ 0.1015x þ 0.0091, y ¼ 0.1739x þ 0.2421, y ¼ 0.1359x þ 0.0702, y ¼ 0.1426x þ 0.0310, y ¼ 0.0729x þ 0.0768, y ¼ 0.0219x þ 0.1121, y ¼ 0.0180x þ 0.0400,
R2 ¼ 1.000 R2 ¼ 0.998 R2 ¼ 0.999 R2 ¼ 0.998 R2 ¼ 1.000 R2 ¼ 0.999 R2 ¼ 0.999 R2 ¼ 0.998 R2 ¼ 0.997 R2 ¼ 0.995 R2 ¼ 0.996
Variables x and y are the major principal stress and unconfined yield strength, respectively.
zero. This type of behavior is exemplified by beach sand and glass beads. The overall strength of surface interactions among particles determined mainly by three factors, (1) the total area of contact; (2) the chemical nature of the surfaces; and (3) the closeness between particles. We just discussed the third factor in the previous paragraph. The chemical nature of the surfaces is identical in each series. Thus, we shall now focus on the first factor, total area of contact, to further understand effects of particle size on powder flow properties. If everything else is the same, smaller particles correspond to larger specific surface area (m2/g). During shear cell testing, there should be a larger number of particle–particle contacts on the shear failure plane for a powder comprised of smaller particles. Consequently, the total area of contact is larger for smaller particles. If the chemical nature is identical, the interaction strength is stronger for a powder constituted of smaller particles. Thus, the detrimental effects of particle size reduction on flow properties are achieved mainly through the increased specific surface area. This mechanism is fundamentally the same as the improved tabletability of MCC by particle size reduction.27 The difference is that increased powder bed strength is detrimental to powder flow properties but beneficial to tablet. A clear understanding of flow properties of any powder requires the simultaneous considerations of all three factors. For example, some powders are much more cohesive than others due to differences in chemical nature of the surfaces. Flow functions of two different powders will be
Figure 2. Effect of particle size on powder flow properties. (a) Flow functions of Avicel PH105, PH101, PH102, and PH200; (b) flow functions of ProSolv SMCC50 and SMCC90; (c) flow functions of Celphere SCP-100, CP-102 and CP-203; n ¼ 3.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
DOI 10.1002/jps
QUANTIFYING POWDER FLOW PROPERTIES
4035
of particle size and particle morphology on flow properties. It is extremely difficult to meaningfully compare particle size when particle morphologies are very different, For example, needle versus plate. A laser scattering particle size analyzer can report size of irregular shape particles using the size of volume equivalent spheres. It can happen that two elongated particles, differing in length and thickness, may be reported to be identical in size. The dilemma is rooted in the definition of particle size and in practice unresolvable. To circumvent the difficulty, we elect to compare flow properties of powder comprised of larger but more elongated particles (Avicel PH200) with smaller but more spherical particles (Celphere SCP-100 and CP-102). Despite the fact that larger particle size would render better powder flow provided that particle morphology remains similar, Avicel PH200 exhibited poorer flow properties than Celphere SCP-100 and CP102 (Fig. 4). The results suggest that particle morphology can significantly affect powder flow properties. Spherical particles exhibit better flow than elongated particles. We only qualitatively show detrimental effect of particle elongation on flow properties. To quantitatively describe this effect, it is required to have access to a series of powders comprised of progressively elongated particles while surface chemistry remains constant. It is also necessary to quantify particle morphology through parameters such as aspect ratio, shape factor, and sphericity. Effect of Particle Density on Powder Flow Properties For regular MCC, Avicel PH302 is of a higher density than PH102. For silicified MCC, Prosolv
Figure 3. Plots of the slope of flow function versus particle size. (a) Avicel powders; (b) Prosolv powders; (c) Celphere powders.
different even if particle size and shape are identical.
Effect of Particle Morphology on Powder Flow Properties The inherent challenge in quantifying effect of morphology is the difficulty in separating effects DOI 10.1002/jps
Figure 4. Flow functions of Avicel PH200, Celphere SCP-100 and CP-102 (n ¼ 3).
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
4036
HOU AND SUN
HD90 is of a higher density than Prosolv 90. PSDs between two powders in each pair are nearly identical (Tab. 1). Particle morphology is also nearly identical, all are slightly elongated. Thus, effects of PSD and morphology on powder flow properties may be ignored. When packing patterns are similar, the powder of higher particle density will exhibit proportionally higher bulk density. Flow functions of Avicel PH102 and PH302 are overall similar, suggesting comparable flow properties (Fig. 5a). Similarly, Prosolv 90 and HD90 exhibited similar flow properties (Fig. 5b). The results suggest density only has limited effect on powder flow properties measured by the ring shear tester. This is understandable based on the physical principles in shear cell measurements.
During the shear cell measurement, applied normal load significantly exceeds the gravitational force of powder bed and remains a major source for powder consolidation. Gravity is negligible compared to the applied normal load. Consequently, the regular flow function does not reflect on the density effects. If particle size, shape, and surface properties are essentially constant between two powders constituted of particles of different densities, flow functions within each pair are expected to be similar. Flow function describes powder flow properties that are material properties inherent to a powder. Powder flow properties affect how the powder flows under a given set of conditions and are equipment independent. Flow properties are affected by surface interactions among particles (e.g., van der Waals, electrostatic, surface tension, interlocking, and friction). Flow behavior, however, depends on both the powder flow properties and equipment used to handle, store, or process the material.28 Therefore, to more accurately predict flow behavior, both the material characteristics and the equipment should be considered. For example, a material may exhibit mass flow in one hopper but funnel flow in another when the design or the construction materials of the hoppers are different. As powder flow behavior is taken into consideration, powder bulk density has to be incorporated into the flow function. Based on this consideration, density-corrected flow function should be used to quantify flow behavior. The density-corrected flow function of Avicel PH302 is significantly below that of Avicel PH102 (Fig. 6a), suggesting that Avicel PH302 flows better than PH102 when identical hopper is used. The same trend holds true for Prosolv 90 and HD90 (Fig. 6b).
Effect of Surface Silicification on Powder Flow Properties
Figure 5. Effect of particle density on powder flow properties. (a) Avicel PH102 and PH302; (b) Prosolv SMCC90 and HD90; n ¼ 3.
Each pair of regular and silicified MCC exhibited similar powder bulk density and PSD (Tab. 1). Thus surface silicification does not significantly affect particle packing in the powders. Flow properties of Prosolv 50 are significantly better than those of Avicel PH101 (Fig. 7a). Since Avicel PH101 and Prosolv 50 have nearly identical PSD and shape, we may attribute the improved flow properties to the surface silicification. However, flow properties of the other two pairs of
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
DOI 10.1002/jps
QUANTIFYING POWDER FLOW PROPERTIES
4037
Figure 6. Effect of particle density on powder flow behavior. (a) Avicel PH102 and PH302; (b) Prosolv 90 and HD90; n ¼ 3.
powders, Avicel PH102 versus Prosolv 90 and Avicel PH302 versus Prosolv HD90, are similar (Fig. 7b and c), suggesting that surface silicification is not effective in improving flow properties of Avicel PH102 and PH302. It is unclear why effects of silicification depend on particle size. Since substituting Avicel PH102 and PH302 with corresponding grades of Prosolv does sometimes profoundly improve flow properties of mixtures containing hygroscopic components, there must be certain interactions between Prosolv and other constituting components responsible to the improved flow properties. Further investigations are needed to better understand the unknown interactions with silicified surfaces in order to achieve rational uses of Prosolv in future formulation development. DOI 10.1002/jps
Figure 7. Effect of surface silicification on powder flow properties. (a) Flow functions of Avicel PH101 and Prosolv 50. (b) Flow functions of Avicel PH102 and Prosolv 90. (c) Flow functions of Avicel PH 302 and Prosolv HD90; n ¼ 3.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
4038
HOU AND SUN
Correlation Between fc and CI Carr’s CI is widely used to characterize powder flow properties. However, it has not been always reliable in predicting powder flow properties. In this study, the rank of powder flow properties based on CI and flow function is the same within each series of materials. Higher CI always corresponds to higher fc within each series of powders (Fig. 8) both suggesting poorer flow properties. However, when powders from different series are compared, higher CI does not necessarily correspond to higher fc, that is, Avicel PH200 versus Celphere SCP-100 (Fig. 8). Therefore, CI is not a reliable universal measurement of powder flow properties. Here we provide some insights on the origin of this problem. CI considers the consolidation of a powder (change in powder volume) by gravity in the process of tapping. Because of different bulk densities, the actual consolidation stress a powder experiences during the course of tapping is not the same for various powders even though a standard test method, that is, USP method, is used. Due to the lack of control on the external stress during tapping, it is not surprising that CI sometimes fails to successfully rank order powder flow properties. In summary, CI is an over-simplified and imperfect representation of the powder consolidation property, which does influence powder flow properties.
CONCLUSIONS Results from this study support the following conclusions. (1) Smaller particles result in poorer powder flow properties provided chemical nature on the surfaces and particle morphology are the same. These effects are in turn caused by the increased total contact surface area. (2) MCC powders constituted of more spherical particles exhibit better flow properties than elongated particles when particle size is comparable. Effects of both particle size and morphology support the practice of improving flow properties by granulation. (3) Higher particle density does not significantly change the powder flow properties but can improve powder flow behavior. (4) Surface silicification significantly improves flow properties of finer MCC (e.g., Avicel PH101) but not coarser MCC (e.g., Avicel PH102 and PH302). (5) The sensitivity of fc on external stress, that is, the slope of flow function, may be correlated to the sensitivity of powder densification to external stress. (6) Because of the inconsistent consolidation stress powders experience during the process tapping, CI is not a reliable measurement of powder flow properties.
REFERENCES
Figure 8. Correlation between the Carr compressibility index (CI) and fc at the major principal stress of 5 KPa. (1 ¼ Avicel PH105; 2 ¼ Avicel PH101; 3 ¼ Avicel PH102; 4 ¼ Avicel PH302; 5 ¼ Avicel PH200; 6 ¼ Prosolv SMCC50; 7 ¼ Prosolv SMCC90; 8 ¼ Prosolv HD90; 9 ¼ Celphere SCP-100; 10 ¼ Celphere CP-102; 11 ¼ Celphere CP-203). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
1. Lam CC, Nakagawa M. 1994. Packing of particles. J Ceram Soc Jpn 102:133–138. 2. Podczeck F, Mia Y. 1996. The influence of particle size and shape on the angle of internal friction and the flow factor of unlubricated and lubricated powders. Int J Pharm 144:187–194. 3. Ridgway K, Morland I. 1977. The bulk density of mixtures of particles of different shape. J Pharm Pharmacol 29:58P. 4. Shotten E, Obiorah BA. 1973. The effect of particle shape and crystal habit on properties of sodium chloride. J Pharm Pharmacol 25:37P–43P. 5. Kaerger JS, Edge S, Price R. 2004. Influence of particle size and shape on flowability and compactibility of binary mixtures of paracetamol and microcrystalline cellulose. Eur J Pharm Sci 22:173–179. 6. Podczeck F, Re´ ve´ sz P. 1993. Evaluation of the properties of microcrystalline and microfine cellulose powders. Int J Pharm 91:183–193. 7. Faqih AM, Chaudhuri B, Alexander AW, Davies C, Muzzio FJ, Tomassone MS. 2006. An experimental/ computational approach for examining unconfined cohesive powder flow. Int J Pharm 324:116–127. 8. Crowder TM, Hickey AJ. 2000. The physics of powder flow applied to pharmaceutical solids. Pharm Technol 24:50–58. DOI 10.1002/jps
QUANTIFYING POWDER FLOW PROPERTIES
9. Danjo K, Kinoshita K, Kitagawa K, Lida K, Sunada H, Otsuka A. 1989. Effect of particle shape on the compaction and flow properties of powders. Chem Pharm Bulletin 37:3070–3073. 10. Popov KI, Pavlovic MG, Pavlovic LJ, Ivanovic ER, Krstic SB, Obradovic MC. 2003. The effect of the particle shape and structure on the flowability of electrolytic copper powder. II. The experimental verification of the model of the representative powder particle. J Serbian Chem Soc 68:779–783. 11. Rasenack N, Muller BW. 2002. Ibuprofen crystals with optimized properties. Int J Pharm 245:9–24. 12. Stanford MK, DellaCorte C, Eylon D. 2004. Effect of particle morphology on flow characteristics of a composite plasma spray powder. J Therm Spray Technol 13:586–592. 13. Alderborn G, Nystro¨ m C. 1985. Studies on direct compression of tablets. XIV. The effect of powder fineness on the relation between tablet permeametry surface area and compaction pressure. Powder Technol 44:37–42. 14. Bassam F, York P, Row RC, Roberts RJ. 1988. Effect of particle size and source on variability of Young’s modulus of microcrystalline cellulose powders. J Pharm Pharmacol 40:68P. 15. Sun CC, Grant DJW. 2001. Effects of initial particle size on the tableting properties of L-lysine monohydrochloride dihydrate powder. Int J Pharm 215: 221–228. 16. Sun CC, Grant DJW. 2001. Influence of crystal shape on the tableting performance of L-lysine monohydrochloride dihydrate. J Pharm Sci 90: 567–577. 17. York P. 1992. Crystal engineering and particle design for the powder compaction process. Drug Dev Ind Pharm 18:677–721.
DOI 10.1002/jps
4039
18. Fitzpatrick JJ, Barringer SA, Iqbal T. 2004. Flow property measurement of food powders and sensitivity of Jenike’s hopper design methodology to the measured values. J Food Eng 61:399–405. 19. Stasiak M, Molenda M. 2004. Direct shear testing of flowability of food powders. Res Agric Eng 50: 6–10. 20. Gold G, Duvall RN, Palermo BT, Slater JG. 1968. Powder flow studies III-factors affecting the flow of lactose granules. J Pharm Sci 57:667–671. 21. Carson JW, Wilms H. 2006. Development of an international standard for shear testing. Powder Technol 167:1–9. 22. Behera S, Das S, Hatvani Z, Pahl MH. 2002. Flowability studies of bulk materials for design of hopper using a Jenike shear cell. Powder Hand Proc 14: 96–101. 23. Schulze D. 1996. Flowability and time consolidation measurements using a ring shear tester. Powder Hand Proc 3:221–226. 24. Subcommittee D18.24. 2002. Standard shear test method for bulk solids using the Schulze ring shear tester, ASTM Standard D6773-02. American Society for Testing and Materials. 25. Sun CC. 2008. Mechanism of moisture induced variations in true density and compaction properties of microcrystalline cellulose. Int J Pharm 346: 93–101. 26. USP<616>. United States Pharmacopoeia Method 616-Bulk and tapped density. 27. Sun CC, Himmelspach MW. 2006. Reduced tabletability of roller compacted granules as a result of granule size enlargement. J Pharm Sci 95: 200–206. 28. Prescott JK, Barnum RA. 2000. On powder flowability. Pharm Technol 24: 60–84.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
Received 4 October 2007; revised 16 October 2007; accepted 9 November 2007 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21288
ABSTRACT: Effects of particle size, morphology, particle density, and surface silicification, on powder flow properties were investigated using a ring shear tester. Flow properties were quantified by flow function (FF), that is, unconfined yield strength, fc, as a function of major principal stress. A total of 11 powders from three series of microcrystalline cellulose (MCC): Avicel (regular MCC, elongated particles), Prosolv (silicified MCC, elongated particles), and Celphere (spherical MCC), were studied. Particle size distribution in each type of MCC was systematically different. Within each series, smaller particles always led to poorer powder flow properties. The slope of FF line was correlated to degree of powder consolidation by external stress. A key mechanism of the detrimental effect of particle size reduction on flow properties was the larger powder specific surface area. Flow properties of Celphere were significantly better than Avicel of comparable particles size, suggesting spherical morphology promoted better powder flow properties. Flow properties of powders different in densities but similar in particle size, shape, and surface properties were similar. When corrected for density effect, higher particle density corresponded to better flow behavior. Surface silicification significantly improved flow properties of finer MCC, but did not improve those of coarser. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:4030–4039, 2008
Keywords: powder flow properties; flow function; ring shear tester; microcrystalline cellulose; particle size; particle shape; particle density; surface silicification
INTRODUCTION It has been known that particulate properties can profoundly influence properties of bulk powders.1–6 In early days of pharmaceutical manufacturing, batch-to-batch variability of bulk excipients and active pharmaceutical ingredients (API) could be great because critical particulate properties were generally not well controlled. Variations in raw materials frequently resulted in processing difficulty and even failed commercial batches, causing
Correspondence to: Changquan Calvin Sun (Telephone: 805-313-5581; Fax: 805-447-3401; E-mail: [email protected] or [email protected]) Journal of Pharmaceutical Sciences, Vol. 97, 4030–4039 (2008) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association
4030
significant financial losses to manufacturers. Consequently, the need of more constant raw material properties, both excipients and API, has gained much attention from both the academia and the pharmaceutical industry. Variability in properties of most excipients has been substantially reduced as a result of tighter controls implemented in most manufacturing process by suppliers. On the other hand, scientists have taken advantage of the effects of particulate properties on bulk powder properties to continuously develop new grades of excipients with improved bulk properties (or functionality), such as powder flow, compaction, and dispersion properties. Reliable and consistent flow out of hoppers and feeders without excessive spillage and dust generation is of importance to pharmaceutical
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
QUANTIFYING POWDER FLOW PROPERTIES
industry.7,8 Poor powder flow properties may give rise to reduced productivity and financial losses. Sometimes, a high speed tablet press has to be operated at a suboptimum speed to accommodate the flow properties of a powder in order to meet the minimum requirements in tablet weight uniformity. One approach to improve powder flow properties is particle size enlargement (e.g., granulation). Although effective, controlling particle size alone sometimes is not sufficient to deliver adequate flow properties to accommodate APIs that are hygroscopic in nature and need to be delivered in high doses. Another approach is increasing particle density. Both intuition and experience have suggested higher particle density can improve powder flow properties of a formulation. It has been also recognized that particle morphology can affect powder compaction and flow properties.9–12 For example, more spherical particles usually result in better powder flow properties than elongated particles. Powder flow properties and compaction properties are of recognized importance to successful pharmaceutical manufacturing of solid dosage forms, that is, tablets and capsules. Effects of particulate properties on powder compaction have been extensively studied in the literature.13–17 However, similar studies on powder flow properties are scarce.18,19 Many of the instruments used to study flow properties were empirical in nature or significantly affected by the test conditions.20 Results obtained using the more empirical methods in laboratory cannot be reliably extrapolated to different powder systems or different scales. Shear cell is an instrument well established to measure powder flow properties. Flow properties characterized by shear cell have clear physical meaning and are independent of scale. Combined with some additional measurements, such as, air permeability, shear cell data obtained in a laboratory can be reliably used to design optimum equipment to handle large scale powders.21,22 The application of shear cell in pharmaceutical industry has been limited largely because previously available shear cells are the translational types that are labor intensive and poorly reproducible if a standard procedure is not carefully followed. In the recent decade, a few commercially available ring shear cells have made it possible to substantially reduce the amount of powder and labor required to characterize flow properties.23 The aim of this study was to better quantify effects of particulate properties on bulk powder flow properties using a ring shear tester. We DOI 10.1002/jps
4031
focused on effects of particle size, morphology, density, and surface modification on powder flow properties. Microcrystalline cellulose (MCC) is an important pharmaceutical excipient and is commercially available in many grades that differ in particle size, density, morphology, moisture content, and surface silicification. We therefore chose MCC as a model compound in this study.
MATERIALS AND METHODS Materials Eleven MCC powders spanning a range of particle size, morphology, density, and surface properties were used in this study. Avicel1 PH105, PH101, PH102, PH302, and PH200 were purchased from FMC BioPolymer (Philadelphia, PA). Prosolv1 SMCC50, SMCC90, and HD90 were obtained from JRS Pharma (Patterson, NY). Celphere1 SCP100, CP-102, and CP-203 were obtained from Asahi Kasei Chemicals Corporation (New York, NY). All materials were used as received. These powders are examples of regular MCC (Avicel), silicified MCC (Prosolv), and spherical MCC (Celphere).
Particle Size Distribution The volume-based particle size distribution (PSD) of dry powders was obtained using a Sympatec Helos/Rodos laser diffraction particle size analyzer (Sympatec, Inc., Princeton, NJ). The powder dispersing pressure of 2.5 bars was selected after pressure titration step and used for all PSD measurements. Three measurements were made on each powder. The resulting PSD was averaged and standard deviation was calculated. Shear Cell Test A Ring Shear Tester (RST-XS, Dietmar Schulze, Wolfenbu¨ ttel, Germany) was used for measuring the flow properties of powders following an appropriate procedure.24 Key components of the shear cell are shown in Figure 1. A powder was over-filled into the standard shear cell with a volume of 30 mL. Excess powder was scraped off with a spatula so that the powder surface was flush with the upper edge of the shear cell. The filled shear cell was weighed and then placed on the motor-driven base of the Ring Shear Tester. The lid was placed on the top surface of the powder
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
4032
HOU AND SUN
Figure 1. Photograph of the Schulze shear cell showing its key components: tie rods (A), loading rod (B), lid (C), arm of the lid (D), cell (E), rotating base (F).
approximately 2/3 of the cylinder was full. The powder was carefully leveled without compacting, and the volume (V0) and mass (M) of the bulk powder were used to calculate bulk density. The cylinder containing the powder sample was then mechanically tapped using a VanKel Tap Density Tester (Model 50–1200, Varian, Inc., Palo Alto, CA). The cylinder was tapped 500 times initially and the tapped volume of the powder was measured to the nearest graduated unit. An additional 750 taps were performed and the volume was recorded. Since the difference between the two tapped volumes was less than 2% for all powders, the second tapped volume was taken as the final tapped volume (Vf) to calculate tapped density. Carr’s compressibility index (CI) was calculated using Eq. (1) CI ¼
bed with a loading rod (for applying a normal stress to the powder bed) inserted. Two tie rods (for applying shear stress) were used to attach the lid to the two load cells. As base rotated and the lid was fixed in position by the two tie rods, shear stress was developed in the powder. The shearing procedure involved two steps: preshear and shear. The powder was first presheared under a prescribed consolidation stress until a steady-state was reached. The presheared powder was then subjected to a shear test under a normal stresses that was below the preshear consolidation stress. Failure of the powder bed was characterized by a sudden drop in shear stress. In this study, the procedure was conducted in triplicates using preshear consolidation stresses of 1, 3, 9, and 15 KPa and five normal shear stresses equally spaced between zero and the preshear consolidation stress. Because physical properties of MCC can be significantly affected by both temperature and water content,25 all experiments were performed at 20 18C and 35 5% relative humidity to minimize such effects. A prolonged application of a normal stress will cause more powder consolidation. This in turn affects measured flow properties. In this study, we tested the powder immediately after filling the shear cell. Carr’s Compressibility Index Bulk and tap densities were measured following USP guidelines.26 A powder that had been passed through a 1.00 mm (No. 18) mesh sieve screen was added into a 100 mL graduated cylinder until
100 ðV0 Vf Þ Vf
(1)
Data Analysis A yield locus is a plot of shear stress at failure as a function of the normal consolidation stress. From each yield locus, the unconfined yield strength ( fc) and the major principal stress were derived by drawing two Mohr circles. The unit of kPa was used for both stresses. Average and standard deviation were calculated based on three measurements for each set of test conditions. The strength of a powder gained after being consolidated at a certain stress is quantified by fc. To initiate a flow of the consolidated powder, external stress must exceed fc. A flow function (FF) describes fc as a function of major principal stress. Linear regression was performed for each set of data to obtain the mathematic expression of corresponding FF. Unconfined yield strength at a certain pressure could be calculated from the fitted FF line. We caution that FF line should cross origin or its vicinity. Deviations from linearity may be expected at near zero major principal stress. Thus, extrapolation to major principal stress, <1 kPa should be avoided. In order to assess the effect of density on powder flow, the density-corrected unconfined yield strength ( fc,r) was calculated according to Eq. (2) fc;r ¼
fc r
(2)
where r is the bulk density corresponding to each fc. The fc,r takes into account the effect of the bulk
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
DOI 10.1002/jps
QUANTIFYING POWDER FLOW PROPERTIES
density (g/mL) on powder flow. The correction is appropriate for accurate prediction of powder flow behavior in a process where the gravitational force plays a role, that is, when the bulk material is discharged from a hopper. The density-corrected FF is a plot of fc,r versus the major principal stress.
RESULTS AND DISCUSSION Effect of Particle Size on Powder Flow Properties Key particle properties and flow functions of the 11 powders are summarized in Tables 1 and 2. As shown in the tables, particle size of Avicel decreases in the order of Avicel PH200 > PH102 > PH101 > PH105. With decreasing particle size, flow function line rotates counterclockwise suggesting progressively worsened flow properties (Fig. 2a). Particles in Prosolv 50 are smaller than those in Prosolv 90 (Tab. 1). Similar to the Avicel series, larger particles correspond to better flow properties as shown by the lower flow function line of the Prosolv 90 powder (Fig. 2b). For the three Celphere powders, particle size decreases in the order CP-203 > CP-102 > SCP100 (Tab. 1). Consistent with the observations made on Avicel and Prosolv series, smaller particle size corresponds to worse powder flow properties (higher flow function line, Fig. 2c). To more clearly show effect of particle size, the slope of FF line is plotted against particle size, d10, d50, and d90 for each series of materials (Fig. 3). With increasing particle size, the slope of FF line decreases, suggesting better flow properties. The curves drop sharply then gradually level off. This
4033
suggests an equal reduction in particle size would result in more profound decrease in powder flow properties for finer powders. Within the particle size range studied, large particles always correspond to better powder flow properties. It holds true for the elongated MCC (Avicel) particles, nearly spherical (Celphere) particles, and surface silicified MCC (Prosolv) particles. The fc represents the strength developed within a powder when consolidated, which must be overcome to initiate the flow of a powder. The higher strength developed suggests stronger particle–particle interactions. The particle–particle interactions, including van der Waal’s force and H-bonding, are stronger as two particles get closer. An increase in the external stress in the pressure range concerning powder flow properties (<100 kPa) typically consolidates powders and brings particles closer together. The closer arrangement of particles and possibly more contact points in a powder bed can cause stronger particle– particle interactions. Consequently, the unconfined yield strength increases with increasing external stress. The stress required to induce particle–particle relative movement (shear failure in shear cell tests) is therefore higher if the powder bed is consolidated under a higher normal stress. This is analogous to the dependence of friction force on normal stress during sliding of two touching surfaces. This explains why the flow function of a powder exhibits a positive slope. The effectiveness of external stress in causing the fc to increase directly corresponds to the slope of the flow function line. If a powder does not undergo significant consolidation by external stress, the slope of its flow function line should be close to
Table 1. Key Particle Size Distribution Parameters, Densities, and Calculated Carr’s Compressibility Index for the Powders
Material Avicel PH105 Avicel PH101 Avicel PH102 Avicel PH302 Avicel PH200 Prosolv 50 Prosolv 90 Prosolv HD90 Celphere SCP-100 Celphere CP-102 Celphere CP-203
d10 (mm) 8.26 18.6 31.09 24.5 69.59 16.75 34.71 34.6 73.25 114.67 196.82
Particle Size Distribution d50 (mm) d90 (mm)
(0.14) (0.13) (0.13) (0.10) (1.15) (0.72) (0.34) (0.30) (1.35) (1.00) (1.19)
22.73 48.66 103.87 83.7 228.61 52.02 104.40 96 127.82 165.28 262.81
(0.21) (1.10) (0.52) (0.50) (2.53) (0.52) (0.76) (1.00) (2.12) (1.41) (1.68)
45.72 102.67 213.27 195.8 379.85 112.22 199.83 190.6 200.45 234.28 349.1
(1.47) (5.89) (0.45) (0.80) (8.55) (0.53) (0.41) (1.50) (2.01) (1.75) (1.69)
Bulk Density (g/cm3) 0.33 0.34 0.38 0.49 0.38 0.35 0.36 0.47 0.6 0.84 0.87
Tap Density (g/cm3) 0.53 0.51 0.55 0.7 0.45 0.49 0.47 0.58 0.73 0.99 0.99
Compressibility Index 37 33 30 31 16 28 24 19 18 15 12
Standard deviations are in parentheses (n ¼ 3). DOI 10.1002/jps
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
4034
HOU AND SUN
Table 2. Mathematic Expressions of Flow Functions of All Tested Materials Obtained by Linear Regression
Material Avicel PH105 Avicel PH101 Avicel PH102 Avicel PH302 Avicel PH200 Prosolv 50 Prosolv 90 Prosolv HD90 Celphere SCP-100 Celphere CP-102 Celphere CP-203
Mathematic Expression of Flow Function y ¼ 0.3461x þ 0.5403, y ¼ 0.2309x þ 0.1461, y ¼ 0.1266x þ 0.3427, y ¼ 0.1433x þ 0.1905, y ¼ 0.1015x þ 0.0091, y ¼ 0.1739x þ 0.2421, y ¼ 0.1359x þ 0.0702, y ¼ 0.1426x þ 0.0310, y ¼ 0.0729x þ 0.0768, y ¼ 0.0219x þ 0.1121, y ¼ 0.0180x þ 0.0400,
R2 ¼ 1.000 R2 ¼ 0.998 R2 ¼ 0.999 R2 ¼ 0.998 R2 ¼ 1.000 R2 ¼ 0.999 R2 ¼ 0.999 R2 ¼ 0.998 R2 ¼ 0.997 R2 ¼ 0.995 R2 ¼ 0.996
Variables x and y are the major principal stress and unconfined yield strength, respectively.
zero. This type of behavior is exemplified by beach sand and glass beads. The overall strength of surface interactions among particles determined mainly by three factors, (1) the total area of contact; (2) the chemical nature of the surfaces; and (3) the closeness between particles. We just discussed the third factor in the previous paragraph. The chemical nature of the surfaces is identical in each series. Thus, we shall now focus on the first factor, total area of contact, to further understand effects of particle size on powder flow properties. If everything else is the same, smaller particles correspond to larger specific surface area (m2/g). During shear cell testing, there should be a larger number of particle–particle contacts on the shear failure plane for a powder comprised of smaller particles. Consequently, the total area of contact is larger for smaller particles. If the chemical nature is identical, the interaction strength is stronger for a powder constituted of smaller particles. Thus, the detrimental effects of particle size reduction on flow properties are achieved mainly through the increased specific surface area. This mechanism is fundamentally the same as the improved tabletability of MCC by particle size reduction.27 The difference is that increased powder bed strength is detrimental to powder flow properties but beneficial to tablet. A clear understanding of flow properties of any powder requires the simultaneous considerations of all three factors. For example, some powders are much more cohesive than others due to differences in chemical nature of the surfaces. Flow functions of two different powders will be
Figure 2. Effect of particle size on powder flow properties. (a) Flow functions of Avicel PH105, PH101, PH102, and PH200; (b) flow functions of ProSolv SMCC50 and SMCC90; (c) flow functions of Celphere SCP-100, CP-102 and CP-203; n ¼ 3.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
DOI 10.1002/jps
QUANTIFYING POWDER FLOW PROPERTIES
4035
of particle size and particle morphology on flow properties. It is extremely difficult to meaningfully compare particle size when particle morphologies are very different, For example, needle versus plate. A laser scattering particle size analyzer can report size of irregular shape particles using the size of volume equivalent spheres. It can happen that two elongated particles, differing in length and thickness, may be reported to be identical in size. The dilemma is rooted in the definition of particle size and in practice unresolvable. To circumvent the difficulty, we elect to compare flow properties of powder comprised of larger but more elongated particles (Avicel PH200) with smaller but more spherical particles (Celphere SCP-100 and CP-102). Despite the fact that larger particle size would render better powder flow provided that particle morphology remains similar, Avicel PH200 exhibited poorer flow properties than Celphere SCP-100 and CP102 (Fig. 4). The results suggest that particle morphology can significantly affect powder flow properties. Spherical particles exhibit better flow than elongated particles. We only qualitatively show detrimental effect of particle elongation on flow properties. To quantitatively describe this effect, it is required to have access to a series of powders comprised of progressively elongated particles while surface chemistry remains constant. It is also necessary to quantify particle morphology through parameters such as aspect ratio, shape factor, and sphericity. Effect of Particle Density on Powder Flow Properties For regular MCC, Avicel PH302 is of a higher density than PH102. For silicified MCC, Prosolv
Figure 3. Plots of the slope of flow function versus particle size. (a) Avicel powders; (b) Prosolv powders; (c) Celphere powders.
different even if particle size and shape are identical.
Effect of Particle Morphology on Powder Flow Properties The inherent challenge in quantifying effect of morphology is the difficulty in separating effects DOI 10.1002/jps
Figure 4. Flow functions of Avicel PH200, Celphere SCP-100 and CP-102 (n ¼ 3).
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
4036
HOU AND SUN
HD90 is of a higher density than Prosolv 90. PSDs between two powders in each pair are nearly identical (Tab. 1). Particle morphology is also nearly identical, all are slightly elongated. Thus, effects of PSD and morphology on powder flow properties may be ignored. When packing patterns are similar, the powder of higher particle density will exhibit proportionally higher bulk density. Flow functions of Avicel PH102 and PH302 are overall similar, suggesting comparable flow properties (Fig. 5a). Similarly, Prosolv 90 and HD90 exhibited similar flow properties (Fig. 5b). The results suggest density only has limited effect on powder flow properties measured by the ring shear tester. This is understandable based on the physical principles in shear cell measurements.
During the shear cell measurement, applied normal load significantly exceeds the gravitational force of powder bed and remains a major source for powder consolidation. Gravity is negligible compared to the applied normal load. Consequently, the regular flow function does not reflect on the density effects. If particle size, shape, and surface properties are essentially constant between two powders constituted of particles of different densities, flow functions within each pair are expected to be similar. Flow function describes powder flow properties that are material properties inherent to a powder. Powder flow properties affect how the powder flows under a given set of conditions and are equipment independent. Flow properties are affected by surface interactions among particles (e.g., van der Waals, electrostatic, surface tension, interlocking, and friction). Flow behavior, however, depends on both the powder flow properties and equipment used to handle, store, or process the material.28 Therefore, to more accurately predict flow behavior, both the material characteristics and the equipment should be considered. For example, a material may exhibit mass flow in one hopper but funnel flow in another when the design or the construction materials of the hoppers are different. As powder flow behavior is taken into consideration, powder bulk density has to be incorporated into the flow function. Based on this consideration, density-corrected flow function should be used to quantify flow behavior. The density-corrected flow function of Avicel PH302 is significantly below that of Avicel PH102 (Fig. 6a), suggesting that Avicel PH302 flows better than PH102 when identical hopper is used. The same trend holds true for Prosolv 90 and HD90 (Fig. 6b).
Effect of Surface Silicification on Powder Flow Properties
Figure 5. Effect of particle density on powder flow properties. (a) Avicel PH102 and PH302; (b) Prosolv SMCC90 and HD90; n ¼ 3.
Each pair of regular and silicified MCC exhibited similar powder bulk density and PSD (Tab. 1). Thus surface silicification does not significantly affect particle packing in the powders. Flow properties of Prosolv 50 are significantly better than those of Avicel PH101 (Fig. 7a). Since Avicel PH101 and Prosolv 50 have nearly identical PSD and shape, we may attribute the improved flow properties to the surface silicification. However, flow properties of the other two pairs of
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
DOI 10.1002/jps
QUANTIFYING POWDER FLOW PROPERTIES
4037
Figure 6. Effect of particle density on powder flow behavior. (a) Avicel PH102 and PH302; (b) Prosolv 90 and HD90; n ¼ 3.
powders, Avicel PH102 versus Prosolv 90 and Avicel PH302 versus Prosolv HD90, are similar (Fig. 7b and c), suggesting that surface silicification is not effective in improving flow properties of Avicel PH102 and PH302. It is unclear why effects of silicification depend on particle size. Since substituting Avicel PH102 and PH302 with corresponding grades of Prosolv does sometimes profoundly improve flow properties of mixtures containing hygroscopic components, there must be certain interactions between Prosolv and other constituting components responsible to the improved flow properties. Further investigations are needed to better understand the unknown interactions with silicified surfaces in order to achieve rational uses of Prosolv in future formulation development. DOI 10.1002/jps
Figure 7. Effect of surface silicification on powder flow properties. (a) Flow functions of Avicel PH101 and Prosolv 50. (b) Flow functions of Avicel PH102 and Prosolv 90. (c) Flow functions of Avicel PH 302 and Prosolv HD90; n ¼ 3.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
4038
HOU AND SUN
Correlation Between fc and CI Carr’s CI is widely used to characterize powder flow properties. However, it has not been always reliable in predicting powder flow properties. In this study, the rank of powder flow properties based on CI and flow function is the same within each series of materials. Higher CI always corresponds to higher fc within each series of powders (Fig. 8) both suggesting poorer flow properties. However, when powders from different series are compared, higher CI does not necessarily correspond to higher fc, that is, Avicel PH200 versus Celphere SCP-100 (Fig. 8). Therefore, CI is not a reliable universal measurement of powder flow properties. Here we provide some insights on the origin of this problem. CI considers the consolidation of a powder (change in powder volume) by gravity in the process of tapping. Because of different bulk densities, the actual consolidation stress a powder experiences during the course of tapping is not the same for various powders even though a standard test method, that is, USP method, is used. Due to the lack of control on the external stress during tapping, it is not surprising that CI sometimes fails to successfully rank order powder flow properties. In summary, CI is an over-simplified and imperfect representation of the powder consolidation property, which does influence powder flow properties.
CONCLUSIONS Results from this study support the following conclusions. (1) Smaller particles result in poorer powder flow properties provided chemical nature on the surfaces and particle morphology are the same. These effects are in turn caused by the increased total contact surface area. (2) MCC powders constituted of more spherical particles exhibit better flow properties than elongated particles when particle size is comparable. Effects of both particle size and morphology support the practice of improving flow properties by granulation. (3) Higher particle density does not significantly change the powder flow properties but can improve powder flow behavior. (4) Surface silicification significantly improves flow properties of finer MCC (e.g., Avicel PH101) but not coarser MCC (e.g., Avicel PH102 and PH302). (5) The sensitivity of fc on external stress, that is, the slope of flow function, may be correlated to the sensitivity of powder densification to external stress. (6) Because of the inconsistent consolidation stress powders experience during the process tapping, CI is not a reliable measurement of powder flow properties.
REFERENCES
Figure 8. Correlation between the Carr compressibility index (CI) and fc at the major principal stress of 5 KPa. (1 ¼ Avicel PH105; 2 ¼ Avicel PH101; 3 ¼ Avicel PH102; 4 ¼ Avicel PH302; 5 ¼ Avicel PH200; 6 ¼ Prosolv SMCC50; 7 ¼ Prosolv SMCC90; 8 ¼ Prosolv HD90; 9 ¼ Celphere SCP-100; 10 ¼ Celphere CP-102; 11 ¼ Celphere CP-203). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008
1. Lam CC, Nakagawa M. 1994. Packing of particles. J Ceram Soc Jpn 102:133–138. 2. Podczeck F, Mia Y. 1996. The influence of particle size and shape on the angle of internal friction and the flow factor of unlubricated and lubricated powders. Int J Pharm 144:187–194. 3. Ridgway K, Morland I. 1977. The bulk density of mixtures of particles of different shape. J Pharm Pharmacol 29:58P. 4. Shotten E, Obiorah BA. 1973. The effect of particle shape and crystal habit on properties of sodium chloride. J Pharm Pharmacol 25:37P–43P. 5. Kaerger JS, Edge S, Price R. 2004. Influence of particle size and shape on flowability and compactibility of binary mixtures of paracetamol and microcrystalline cellulose. Eur J Pharm Sci 22:173–179. 6. Podczeck F, Re´ ve´ sz P. 1993. Evaluation of the properties of microcrystalline and microfine cellulose powders. Int J Pharm 91:183–193. 7. Faqih AM, Chaudhuri B, Alexander AW, Davies C, Muzzio FJ, Tomassone MS. 2006. An experimental/ computational approach for examining unconfined cohesive powder flow. Int J Pharm 324:116–127. 8. Crowder TM, Hickey AJ. 2000. The physics of powder flow applied to pharmaceutical solids. Pharm Technol 24:50–58. DOI 10.1002/jps
QUANTIFYING POWDER FLOW PROPERTIES
9. Danjo K, Kinoshita K, Kitagawa K, Lida K, Sunada H, Otsuka A. 1989. Effect of particle shape on the compaction and flow properties of powders. Chem Pharm Bulletin 37:3070–3073. 10. Popov KI, Pavlovic MG, Pavlovic LJ, Ivanovic ER, Krstic SB, Obradovic MC. 2003. The effect of the particle shape and structure on the flowability of electrolytic copper powder. II. The experimental verification of the model of the representative powder particle. J Serbian Chem Soc 68:779–783. 11. Rasenack N, Muller BW. 2002. Ibuprofen crystals with optimized properties. Int J Pharm 245:9–24. 12. Stanford MK, DellaCorte C, Eylon D. 2004. Effect of particle morphology on flow characteristics of a composite plasma spray powder. J Therm Spray Technol 13:586–592. 13. Alderborn G, Nystro¨ m C. 1985. Studies on direct compression of tablets. XIV. The effect of powder fineness on the relation between tablet permeametry surface area and compaction pressure. Powder Technol 44:37–42. 14. Bassam F, York P, Row RC, Roberts RJ. 1988. Effect of particle size and source on variability of Young’s modulus of microcrystalline cellulose powders. J Pharm Pharmacol 40:68P. 15. Sun CC, Grant DJW. 2001. Effects of initial particle size on the tableting properties of L-lysine monohydrochloride dihydrate powder. Int J Pharm 215: 221–228. 16. Sun CC, Grant DJW. 2001. Influence of crystal shape on the tableting performance of L-lysine monohydrochloride dihydrate. J Pharm Sci 90: 567–577. 17. York P. 1992. Crystal engineering and particle design for the powder compaction process. Drug Dev Ind Pharm 18:677–721.
DOI 10.1002/jps
4039
18. Fitzpatrick JJ, Barringer SA, Iqbal T. 2004. Flow property measurement of food powders and sensitivity of Jenike’s hopper design methodology to the measured values. J Food Eng 61:399–405. 19. Stasiak M, Molenda M. 2004. Direct shear testing of flowability of food powders. Res Agric Eng 50: 6–10. 20. Gold G, Duvall RN, Palermo BT, Slater JG. 1968. Powder flow studies III-factors affecting the flow of lactose granules. J Pharm Sci 57:667–671. 21. Carson JW, Wilms H. 2006. Development of an international standard for shear testing. Powder Technol 167:1–9. 22. Behera S, Das S, Hatvani Z, Pahl MH. 2002. Flowability studies of bulk materials for design of hopper using a Jenike shear cell. Powder Hand Proc 14: 96–101. 23. Schulze D. 1996. Flowability and time consolidation measurements using a ring shear tester. Powder Hand Proc 3:221–226. 24. Subcommittee D18.24. 2002. Standard shear test method for bulk solids using the Schulze ring shear tester, ASTM Standard D6773-02. American Society for Testing and Materials. 25. Sun CC. 2008. Mechanism of moisture induced variations in true density and compaction properties of microcrystalline cellulose. Int J Pharm 346: 93–101. 26. USP<616>. United States Pharmacopoeia Method 616-Bulk and tapped density. 27. Sun CC, Himmelspach MW. 2006. Reduced tabletability of roller compacted granules as a result of granule size enlargement. J Pharm Sci 95: 200–206. 28. Prescott JK, Barnum RA. 2000. On powder flowability. Pharm Technol 24: 60–84.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 9, SEPTEMBER 2008