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Twin screw wet granulation: Effect of powder feed rate
Advanced Powder Technology 22 (2011) 162–166
Contents lists available at ScienceDirect
Advanced Powder Technology journal homepage: www.elsevier.com/locate/apt
Original Research Paper
Twin screw wet granulation: Effect of powder feed rate Ranjit M. Dhenge a, James J. Cartwright b, David G. Doughty b, Michael J. Hounslow a, Agba D. Salman a,⇑ a b
Department of Chemical and Biological Engineering, University of Sheffield, Mappin Street, Sheffield S1 3JD, UK Pharmaceutical Development, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK
a r t i c l e
i n f o
Article history: Received 30 June 2010 Received in revised form 2 September 2010 Accepted 6 September 2010 Available online 19 September 2010 Keywords: Continuous Granulation Twin screw granulator Granule structure Strength
a b s t r a c t The twin screw extruder has recently become popular as a continuous wet granulation technique. It is logical that granulation using a twin screw granulator will depend on several process variables including powder feed rate but little is known about how these variables will affect the kinetics and mechanisms of granule growth and the eventual structure. The work focuses on understanding how granule properties like structure, surface, strength, dissolution etc., change with varying powder feed rate and attempts to develop the science behind granule formation which ultimately allows a priori process and product design. An attempt has been made to understand the steps involved in granule formation in twin screw granulator. The granules became denser and stronger with an increase in powder feed rate. Ó 2010 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.
1. Introduction Granulation is a size enlargement of particles, which is typically required to improve flow, compaction or homogeneity of a downstream blend of materials in the production of solid oral dosage forms. It can either be a dry or wet process and the granules that are formed can be categorized into either dry or wet depending on the type of bonding between primary particles. In wet granulation, granules are formed by the addition of a liquid media onto a powder bed which is under the influence of an impeller (in high shear granulator) or air (in fluidised bed granulator). The agitation imparted into the system along with the wetting of the components within the formulation results in the coalescence or consolidation of the primary powder particles to produce wet granules. The mechanism involved in the wet granulation using high shear granulator and fluidised bed has been extensively studied [1]. There are generally considered to be four main mechanisms for the production and growth of agglomerates by wet granulation. This starts off with nucleation, where a granulation liquid is added to the blended powders, the size of nuclei formed is related to the liquid droplet size [1,2]. The coating of fresh powder onto the surface of the granules is known as layering and results in both a mass and size increase. Coalescence is a main process by which the granules grow in size through sticking two or more granules to form a large one. Generally, a successful coalescence occurs at conditions where there is sufficient deformation and liquid binder on the con-
⇑ Corresponding author. Tel.: +44 1142227560. E-mail address: A.d.salman@sheffield.ac.uk (A.D. Salman).
tact surface of colliding granules so that strong enough binding forces can be generated between granules to survive in the mechanical mixing environment [3]. The final stage is attrition, where the surface of the granules is gradually worn away in an opposite process to layering [1]. However the mechanism of granulation in co-rotating twin screw granulation is still unclear in the literature. Previously empirical studies have been carried out indicating the potential of extrusion as a continuous wet granulation technique [4]. A few papers described influence of process parameters on granule properties [5–7]. However the steps involved in granulation is still not understood in detail. The research work presented here attempts to examine the steps involved in granulation using twin screw granulator and studies the influence of varying the powder feed rate on the residence time distribution and torque and their relationship with properties of granules such as size, shape, structure (porosity), strength and dissolution of the granules.
2. Materials and methods 2.1. Granulation A co-rotating twin screw granulator (Euro lab 16 TSG, Thermo Fisher Scientific, UK) was used for granulation. Its length to diameter ratio is 25:1, and has a screw configuration as shown in Fig. 1. The barrel of the granulator is divided into 5 compartments (Table 1). Compartment 1 has conveying screws to which water (granulation liquid) was injected using a peristaltic pump (Watson Marlow, U.K.). Compartment 2 and 4 have intermeshing screws,
0921-8831/$ - see front matter Ó 2010 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved. doi:10.1016/j.apt.2010.09.004
R.M. Dhenge et al. / Advanced Powder Technology 22 (2011) 162–166
163
Fig. 1. Configuration of the co-rotating screws with various compartments (C1–C5) (screw elements in Table 2).
were then collected every 10 s until the tracer disappears in the collected granules. The granules (500 mg) were then dissolved in 10 ml distilled water. The concentration of tracer in the granules was determined using a spectrophotometer (Spectronic Genesys 10, Thermo Electron corporation) at a wavelength k = 530 nm. The residence time distribution was described by differential outlet age function [E(t)] to give the variation of tracer concentration at the exit [8]. The equipment has an in-built torque measurement sensor which measures the torque and displays directly on the control panel after every 5 s. The torque was considered as an indication of extent of shear and compaction forces experienced by powder inside the barrel.
Table 1 Different compartment in the barrel of the granulator. Compartment
Screw elements in compartment
1 2 3 4 5
Conveying Intermeshing Conveying Intermeshing Conveying
Table 2 Screw elements used in Fig. 1. Screw element code
Screw element name
Ratio of length to diameter
FS LPFS F60° DFS
Feed screw Long pitch feed screw Mixing element at 60° pitch Discharge feed screw
L=D L = 2D L = D/4 L=D
while conveying screws are embedded in compartment 5. The purpose of dividing the barrel in different compartments was to study and elucidate the steps involved in granulation throughout the twin screw granulator. The formulation consisted of following excipients (brand name, particle size and content in total formulation is mentioned in brackets), a-lactose monohydrate (Pharmatose 200 M, 42 lm, 73%), microcrystalline cellulose (Avicel PH 101, 57 lm, 20%), crosscarmellose sodium (Ac-Di-Sol, 58 lm, 1.5%) hydroxypropylcellulose i.e. HPC (Klucel, 66 lm, 5%) and sodium chloride (300 lm, 0.5%). The sodium chloride was used as a non-functional active ingredient to study the dissolution characteristics of granules using conductivity measurements. Water was used as granulation liquid and was pumped into the granulator using peristaltic pump. HPC was used as binder. All the excipients were premixed in a 10 l high shear mixer (Romaco Roto Junior) before they were transferred to a gravimetric, loss-in-weight twin screw feeder (K-Tron Soder, Switzerland). During all the experiments the barrel of the granulator was set at a constant temperature of 25 °C. Granules from various compartments of the granulator were collected after 2 min once the system was allowed to equilibrate. The screw configuration was kept constant for all the experiments, as shown in Fig. 1, the elements for this configuration are listed in Table 2. Granulation was carried out at different powder feed rates (2, 3.5, 5, 6.5 kg/h) keeping liquid to solid ratio (L/S – 0.3) and screw speed (400 rpm) constant.
2.3. Size and shape analysis of granules The granules from all the experiments were oven dried at 40 °C for 24 h and their size and shape (aspect ratio) was evaluated. The aspect ratio (A) is a common shape factor which is the ratio of the length of the minor axis (X) to the length of the major axis (Y) of the granule.
A¼
X Y
ð1Þ
The aspect ratio reflects the elongation of a granule. The smaller the values of the aspect ratio indicate more elongation of granules. Samples of the granulated material were analysed using QICPIC particle size analyser with WINDOX 5.4.1.0 software (Sympatec UK). 2.4. Surface and structural characterisation of granules The granulator was stopped once it reached the equilibrium state (indicated by constant torque) and the barrel top was opened to collect granules from various compartments. The collected granules were studied for their shape and surface characteristics using a Zeiss stereo microscope (Zeiss UK). The microscope provided images that illustrated the surface characteristics of the granules that include the roughness, shape and size. The structure of the granules was studied using X-ray tomography (TOMCAT, Synchrotron Light Source, PSI, Switzerland). The structural study was used to know the change in the porosity along the length of barrel of granulator. The granules collected from various compartments had varying sizes. For this reason only the middle area of the granules was scanned to determine the porosity. The stack of 1024 images was threshold to differentiate the void and solid particle using Image J Software. The porosity of granule was determined by subtracting the area of granule from total area of the image.
2.2. Residence time distribution and torque
2.5. Determination of dissolution time of granules
The residence time distribution was determined using method (an impulse-response technique) described by Nikitine et al. [8]. The red dye, erythrosine B (acid red 51, Sigma–Aldrich) was used as a tracer. 10 mg of dye was introduced into the inlet of the extruder after stabilisation of the operating conditions. The samples
Solutions of different concentrations of sodium chloride in distilled water were prepared and the conductivities were measured at a temperature of 37 °C using a conductivity meter (Hanna 9000, Hanna Instruments, USA). This was repeated five times for each concentration to obtain a mean and standard deviation. A
R.M. Dhenge et al. / Advanced Powder Technology 22 (2011) 162–166
calibration of conductivity as a function of concentration was obtained on this basis. The dissolution of 500 mg granules in 250 ml distilled water was measured at the same temperature. The granules used in this test were in the size range 710– 1000 lm. This involved stirring with a magnetic stirrer at 250 rpm and monitoring the conductivity of the solution as a function of time. The conductivity and temperature data were recorded automatically at 3 s intervals using a computer. Five repeat measurements were made. The fraction of the non functional active ingredient dissolved, C, after a time, t, was determined as follows:
S S1 C ¼ Sx S1
sd
ð3Þ
where sd is the time taken to dissolve 63.2% of the non functional active ingredient, b is the shape factor and t0 is the lag-time, which is zero in the current work. Considering t0 = 0 and b = 1; sd was calculated for dissolving 90% of the active ingredient. 2.6. Estimation of strength of granules A known amount of granules was placed on a sieve shaker (Retsch Technology, Germany) with sieves of 710 and 1000 lm for 3 min, at constant amplitude to obtain specific size class for strength analysis. The reason behind selecting this size range was to compare the different batches of granules avoiding an effect of varying sizes of granules. The strength of granules was determined out using Zwick/Roell Z 0.5 materials testing machine with a PC for real time data logging and analysis. The granules were placed in a die with a 10 mm diameter and component height of 10 mm and compressed at a test speed of 5 mm/min, with an upper force limit of 450 N. The test was repeated 10 times in order to get accurate data from the analysis. The average strength of granules was then calculated using Adam’s equation (4) [10].
a
2 kg/h
0.05
3.5 kg/h
aen
þ aen þ lnð1 e
Þ
0.01 0
0
40
60
80
100
Fig. 2. Residence time distribution curves at different powder feed rates.
resulted in plug flow of powder. The shortest residence time was noted at powder feed rate of 6.5 kg/h. This may be due to very high throughput force which conveyed the powder quickly. Fig. 3 shows the relative torque produced during the granulation of powder material at varying powder feed rates. The torque values increased gradually (unsteady flow initially) and reached to equilibrium state (steady flow) after about 20 s. The torque values were considered as an indication of extent of compaction of powder inside the barrel. At low powder feed rate the barrel was rarely filled hence low torque was produced [5]. As the feed rate was raised to 6.5 kg/h the torque increased sharply indicating increase in conveying load on screws which further reflected the increase in packing of the powder particles over the granule surface and around each other.
40
Powder feed rate (kg/h)
35 30
2
3.5
5
6.5
25 20 15 10 5
L/S- 0.3 Screw speed- 400 rpm
0 0
20
40
60
80
Time scale (s) Fig. 3. Torque produced at powder feed rates of 2, 3.5, 5 and 6.5 kg/h.
Volume density function (1/mm)
Fig. 2 shows influence of powder feed rate on residence time distribution of the material inside the barrel during granulation. It was observed that the residence time increases with decrease in powder feed rate. At low powder feed rate there was less powder inside the barrel hence the degree of channel filling was low. This also means that there was low throughput force for powder leading to more back mixing. Hence the powder resided for longer time inside the barrel as indicated by wider residence time distribution. In contrast, the residence time was shorter for high powder feed rates. The high powder feed rate led to higher degree channel filling of screws creating high throughput force which may have
20
Time (s)
where, P is the applied pressure, s is the average agglomerate strength (also known as Adam’s strength parameter), a is a constant rated to friction and en is the natural strain. s and a were obtained by fitting the data into Eq. (4) as natural logarithms of the applied pressure and as a function of the natural strain, by non-linear regression.
3.1. Influence on residence time distribution and torque
6.5 kg/h
0.03 0.02
ð4Þ
3. Results and discussion
5 kg/h
0.04
Torque (Nm)
" # b ! t t0 100% C ¼ 1 exp
ln P ¼ ln
0.06
ð2Þ
where S is the conductivity of the solution at a time t, and S1 and Sx are the initial and final conductivities. The Weibull distribution function was used to describe the data (Eq. (3)) [9]:
hsi
0.07
E(t)
164
0.8
L/S- 0.3 Screw speed- 400 rpm
0.7 0.6 0.5
2 kg/h 3.5 kg/h 5 kg/h 6.5 kg/h
0.4 0.3 0.2 0.1 0 0
500
1000 1500 2000 2500 3000 3500 4000 4500 5000
Granule size (µm) Fig. 4. Size distributions for changing powder feed rates.
165
R.M. Dhenge et al. / Advanced Powder Technology 22 (2011) 162–166
20
0.7
2 Kg/h
18
3.5 Kg/h
0.6 0.5
2 kg/h 3.5 kg/h
0.4
L/S- 0.3 Screw speed- 400 rpm
5 Kg/h
14
Porosity (%)
Aspect ratio
16
6.5 Kg/h
12 10 8
5 kg/h
6
6.5 kg/h
4 2
0.3 0
500
1000
1500
2000
2500
3000
3500
0
Granule size (µm)
C1
C2
C3
C4
The difference in the residence time distribution and torque at varying feed rates influenced particle packing (Figs. 7 and 8), strength (Fig. 9) and dissolution time of the final granules (Fig. 10). 3.2. Influence on properties of granules The influence of varying powder feed rates on size distribution of granules has been shown in Fig. 4. The granule size decreased at high powder feed rates due to the increasing torque and decreasing residence time. This increase in torque may be attributed to higher channel filling of the screws and increased compaction; this then causes increased attrition of the wet mass between the screws and barrel wall. The size distributions for low powder feed rate was bimodal. At low powder feed rate, less channel filling; less
Fig. 8. Porosity of granules from different compartments at varying powder feed rates.
attrition, restricted packing of primary particles and the increased back mixing of wet mass resulting in the production of large and porous granules. The relative change in the elongation of the granules was determined by aspect ratio (as a shape factor). The high feed rate had no significant influence on the elongation of granules at high feed rates as indicated by the curves for aspect ratio (Fig. 5). The only small change could be observed at 2 kg/h where large, elongated agglomerates decreased the aspect ratio. The influence of powder feed rate on surface and structure has been shown in Figs. 6–8. The granules collected from various sections (C1–C5) showed change in properties like shape; surface;
Rough and loosely packed 2 kg/h
Smooth and closely packed 6.5 kg/h C1
C2
C3
C4
C5
Fig. 6. Microscopic images showing change in shape and surface of granules in various compartments.
2 kg/h
6.5 kg/h
C1
C2
C5
Compartment
Fig. 5. Aspect ratios for changing powder feed rates.
C3
C4
Fig. 7. X-ray tomographic images showing change in granule voids in various compartments.
C5
166
R.M. Dhenge et al. / Advanced Powder Technology 22 (2011) 162–166
14
(MPa)
11
8
τ 5
L/S- 0.3 Screw speed- 400 rpm 2 1
2
3
4
5
6
7
Powder feed rate (kg/h) Fig. 9. Strength of granules at different powder feed rates.
rates compact the powder inside the barrel of the granulator. When powder compaction inside the granulator is increased, the granules that form interact more with the ungranulated material in the barrel. This interaction between the powder and the surface of the granules causes the powder to efficiently pack over the granule surface and around each other (Fig. 7). The surface of the granules begin to pack the powder more effectively at higher powder feed rates, interlocking the primary particles onto the surface of the granules. The better the interlocking of the primary particles onto the structure of the granules, the stronger the granule becomes. The influence of powder feed rate on barrel filling, torque, particle packing, strength could be clearly observed on the dissolution time of the granules (Fig. 10). It may be concluded that the interparticular arrangement for the granules produced at higher feed rate was denser and hence took longer time to release the embedded salt in them and the result is more strong the granules more the dissolution time.
80
t90 (s)
4. Conclusion 60
40
L/S- 0.3 Screw speed- 400 rpm 20 1
2
3
4
5
6
7
Powder feed rate (kg/h) Fig. 10. Dissolution time of granules at different powder feed rates.
particle arrangement. Microscopic and X-ray tomographic studies (Figs. 6 and 7) showed that the structure and shape of the granule change along the length of the screw (Figs. 6 and 7 show for 2 and 6.5 kg/h). The porosity of granules decreased along the length of screw at all the four feed rates (Figs. 7 and 8). This difference in porosity may be attributed to varying barrel filling and torque at different feed rates (Fig. 3). The granules in C1 where liquid was injected on powder mass were loosely packed, porous and rough. In C2 (intermeshing screws), the granule took smoother surface and were found to be closely packed that resulted in decrease in porosity. This densification can be seen in the images from microscope and slices from X-ray tomography (Fig. 7). The granules in C3 had voids similar to granules from C2. C4 had intermeshing screws and hence the granules obtained from this section were smoother, closely packed and had small voids. The final granules were obtained from C5. Granule surface was smooth and particle packing was similar to C4. Fig. 9 shows that the strength of the final granules increased as the powder feed rate was increased. The high powder feed rates resulted in the narrow residence time distribution but increased degrees of channel filling which further increased torque and thereby the strength of the granules was high. High powder feed
The powder feed rate had significant influence on the both transition and final state granule properties. The increased powder feed rate had direct impact on residence time distribution, barrel filling and torque which monitored the changes in the size, shape, structure, porosity, strength and dissolution time of the granules. The granules collected from various compartments of barrel showed decrease in porosity along the length of screw. Also the surface of granules changed from rough to smooth along the length of screw. At high feed rate channel fill and torque increased which increased the strength of the granules. The dissolution time was found to depend on torque and the strength of the granules. References [1] B. Ennis, J. Litser, T. Allen, R.H. Snow (Eds.), Perry’s, Chemical Engineer’s Handbook Chapter 20: Size Reduction and Size Enlargement, seventh ed., McGraw Hill, New York, 1997. [2] L. Lachman, H. Sylwestrowicz, Experiences with unit-to-unit variations in tablets, Journal of Pharmaceutical Sciences 53 (1964) 1234–1242. [3] P.C. Kapur, D.W. Fuerstenau, Coalescence model for granulation, Industrial and Engineering Chemistry Process Design and Development 8 (1) (2002) 56–62. [4] E.I. Keleb, A. Vermeire, C. Vervaet, J.P. Remon, Continuous twin screw extrusion for the wet granulation of lactose, International Journal of Pharmaceutics 239 (1–2) (2002) 69–80. [5] R.M. Dhenge, R.S. Fyles, J.J. Cartwright, D.G. Doughty, M.J. Hounslow, A.D. Salman, Twin screw wet granulation: granule properties. Chemical Engineering Journal (2010), in press, doi:10.1016/j.cej.2010.05.023. [6] D. Djuric, B. Van Melkebeke, P. Kleinebudde, J.P. Remon, C. Vervaet, Comparison of two twin-screw extruders for continuous granulation, European Journal of Pharmaceutics and Biopharmaceutics 71 (1) (2009) 155–160. [7] E.I. Keleb, A. Vermeire, A. Vervaet, C. Remon, J.P. Twin, Twin screw granulation as a simple and efficient tool for continuous wet granulation, International Journal of Pharmaceutics 273 (1–2) (2004) 183–194. [8] C. Nikitine, E. Rodier, M. Sauceau, J. Fages, Residence time distribution of a pharmaceutical grade polymer melt in a single screw extrusion process, Chemical Engineering Research and Design 87 (6) (2009) 809–816. [9] F. Langenbucher, Parametric representation of dissolution-rate curves by the RRSBW distribution, Pharmaceutical Industries 38 (1976) 472–477. [10] M.J. Adams, M.A. Mullier, J.P.K. Seville, Agglomerate strength measurement using a uniaxial confined compression test, Powder Technology 78 (1) (1994) 5–13.
Contents lists available at ScienceDirect
Advanced Powder Technology journal homepage: www.elsevier.com/locate/apt
Original Research Paper
Twin screw wet granulation: Effect of powder feed rate Ranjit M. Dhenge a, James J. Cartwright b, David G. Doughty b, Michael J. Hounslow a, Agba D. Salman a,⇑ a b
Department of Chemical and Biological Engineering, University of Sheffield, Mappin Street, Sheffield S1 3JD, UK Pharmaceutical Development, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK
a r t i c l e
i n f o
Article history: Received 30 June 2010 Received in revised form 2 September 2010 Accepted 6 September 2010 Available online 19 September 2010 Keywords: Continuous Granulation Twin screw granulator Granule structure Strength
a b s t r a c t The twin screw extruder has recently become popular as a continuous wet granulation technique. It is logical that granulation using a twin screw granulator will depend on several process variables including powder feed rate but little is known about how these variables will affect the kinetics and mechanisms of granule growth and the eventual structure. The work focuses on understanding how granule properties like structure, surface, strength, dissolution etc., change with varying powder feed rate and attempts to develop the science behind granule formation which ultimately allows a priori process and product design. An attempt has been made to understand the steps involved in granule formation in twin screw granulator. The granules became denser and stronger with an increase in powder feed rate. Ó 2010 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.
1. Introduction Granulation is a size enlargement of particles, which is typically required to improve flow, compaction or homogeneity of a downstream blend of materials in the production of solid oral dosage forms. It can either be a dry or wet process and the granules that are formed can be categorized into either dry or wet depending on the type of bonding between primary particles. In wet granulation, granules are formed by the addition of a liquid media onto a powder bed which is under the influence of an impeller (in high shear granulator) or air (in fluidised bed granulator). The agitation imparted into the system along with the wetting of the components within the formulation results in the coalescence or consolidation of the primary powder particles to produce wet granules. The mechanism involved in the wet granulation using high shear granulator and fluidised bed has been extensively studied [1]. There are generally considered to be four main mechanisms for the production and growth of agglomerates by wet granulation. This starts off with nucleation, where a granulation liquid is added to the blended powders, the size of nuclei formed is related to the liquid droplet size [1,2]. The coating of fresh powder onto the surface of the granules is known as layering and results in both a mass and size increase. Coalescence is a main process by which the granules grow in size through sticking two or more granules to form a large one. Generally, a successful coalescence occurs at conditions where there is sufficient deformation and liquid binder on the con-
⇑ Corresponding author. Tel.: +44 1142227560. E-mail address: A.d.salman@sheffield.ac.uk (A.D. Salman).
tact surface of colliding granules so that strong enough binding forces can be generated between granules to survive in the mechanical mixing environment [3]. The final stage is attrition, where the surface of the granules is gradually worn away in an opposite process to layering [1]. However the mechanism of granulation in co-rotating twin screw granulation is still unclear in the literature. Previously empirical studies have been carried out indicating the potential of extrusion as a continuous wet granulation technique [4]. A few papers described influence of process parameters on granule properties [5–7]. However the steps involved in granulation is still not understood in detail. The research work presented here attempts to examine the steps involved in granulation using twin screw granulator and studies the influence of varying the powder feed rate on the residence time distribution and torque and their relationship with properties of granules such as size, shape, structure (porosity), strength and dissolution of the granules.
2. Materials and methods 2.1. Granulation A co-rotating twin screw granulator (Euro lab 16 TSG, Thermo Fisher Scientific, UK) was used for granulation. Its length to diameter ratio is 25:1, and has a screw configuration as shown in Fig. 1. The barrel of the granulator is divided into 5 compartments (Table 1). Compartment 1 has conveying screws to which water (granulation liquid) was injected using a peristaltic pump (Watson Marlow, U.K.). Compartment 2 and 4 have intermeshing screws,
0921-8831/$ - see front matter Ó 2010 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved. doi:10.1016/j.apt.2010.09.004
R.M. Dhenge et al. / Advanced Powder Technology 22 (2011) 162–166
163
Fig. 1. Configuration of the co-rotating screws with various compartments (C1–C5) (screw elements in Table 2).
were then collected every 10 s until the tracer disappears in the collected granules. The granules (500 mg) were then dissolved in 10 ml distilled water. The concentration of tracer in the granules was determined using a spectrophotometer (Spectronic Genesys 10, Thermo Electron corporation) at a wavelength k = 530 nm. The residence time distribution was described by differential outlet age function [E(t)] to give the variation of tracer concentration at the exit [8]. The equipment has an in-built torque measurement sensor which measures the torque and displays directly on the control panel after every 5 s. The torque was considered as an indication of extent of shear and compaction forces experienced by powder inside the barrel.
Table 1 Different compartment in the barrel of the granulator. Compartment
Screw elements in compartment
1 2 3 4 5
Conveying Intermeshing Conveying Intermeshing Conveying
Table 2 Screw elements used in Fig. 1. Screw element code
Screw element name
Ratio of length to diameter
FS LPFS F60° DFS
Feed screw Long pitch feed screw Mixing element at 60° pitch Discharge feed screw
L=D L = 2D L = D/4 L=D
while conveying screws are embedded in compartment 5. The purpose of dividing the barrel in different compartments was to study and elucidate the steps involved in granulation throughout the twin screw granulator. The formulation consisted of following excipients (brand name, particle size and content in total formulation is mentioned in brackets), a-lactose monohydrate (Pharmatose 200 M, 42 lm, 73%), microcrystalline cellulose (Avicel PH 101, 57 lm, 20%), crosscarmellose sodium (Ac-Di-Sol, 58 lm, 1.5%) hydroxypropylcellulose i.e. HPC (Klucel, 66 lm, 5%) and sodium chloride (300 lm, 0.5%). The sodium chloride was used as a non-functional active ingredient to study the dissolution characteristics of granules using conductivity measurements. Water was used as granulation liquid and was pumped into the granulator using peristaltic pump. HPC was used as binder. All the excipients were premixed in a 10 l high shear mixer (Romaco Roto Junior) before they were transferred to a gravimetric, loss-in-weight twin screw feeder (K-Tron Soder, Switzerland). During all the experiments the barrel of the granulator was set at a constant temperature of 25 °C. Granules from various compartments of the granulator were collected after 2 min once the system was allowed to equilibrate. The screw configuration was kept constant for all the experiments, as shown in Fig. 1, the elements for this configuration are listed in Table 2. Granulation was carried out at different powder feed rates (2, 3.5, 5, 6.5 kg/h) keeping liquid to solid ratio (L/S – 0.3) and screw speed (400 rpm) constant.
2.3. Size and shape analysis of granules The granules from all the experiments were oven dried at 40 °C for 24 h and their size and shape (aspect ratio) was evaluated. The aspect ratio (A) is a common shape factor which is the ratio of the length of the minor axis (X) to the length of the major axis (Y) of the granule.
A¼
X Y
ð1Þ
The aspect ratio reflects the elongation of a granule. The smaller the values of the aspect ratio indicate more elongation of granules. Samples of the granulated material were analysed using QICPIC particle size analyser with WINDOX 5.4.1.0 software (Sympatec UK). 2.4. Surface and structural characterisation of granules The granulator was stopped once it reached the equilibrium state (indicated by constant torque) and the barrel top was opened to collect granules from various compartments. The collected granules were studied for their shape and surface characteristics using a Zeiss stereo microscope (Zeiss UK). The microscope provided images that illustrated the surface characteristics of the granules that include the roughness, shape and size. The structure of the granules was studied using X-ray tomography (TOMCAT, Synchrotron Light Source, PSI, Switzerland). The structural study was used to know the change in the porosity along the length of barrel of granulator. The granules collected from various compartments had varying sizes. For this reason only the middle area of the granules was scanned to determine the porosity. The stack of 1024 images was threshold to differentiate the void and solid particle using Image J Software. The porosity of granule was determined by subtracting the area of granule from total area of the image.
2.2. Residence time distribution and torque
2.5. Determination of dissolution time of granules
The residence time distribution was determined using method (an impulse-response technique) described by Nikitine et al. [8]. The red dye, erythrosine B (acid red 51, Sigma–Aldrich) was used as a tracer. 10 mg of dye was introduced into the inlet of the extruder after stabilisation of the operating conditions. The samples
Solutions of different concentrations of sodium chloride in distilled water were prepared and the conductivities were measured at a temperature of 37 °C using a conductivity meter (Hanna 9000, Hanna Instruments, USA). This was repeated five times for each concentration to obtain a mean and standard deviation. A
R.M. Dhenge et al. / Advanced Powder Technology 22 (2011) 162–166
calibration of conductivity as a function of concentration was obtained on this basis. The dissolution of 500 mg granules in 250 ml distilled water was measured at the same temperature. The granules used in this test were in the size range 710– 1000 lm. This involved stirring with a magnetic stirrer at 250 rpm and monitoring the conductivity of the solution as a function of time. The conductivity and temperature data were recorded automatically at 3 s intervals using a computer. Five repeat measurements were made. The fraction of the non functional active ingredient dissolved, C, after a time, t, was determined as follows:
S S1 C ¼ Sx S1
sd
ð3Þ
where sd is the time taken to dissolve 63.2% of the non functional active ingredient, b is the shape factor and t0 is the lag-time, which is zero in the current work. Considering t0 = 0 and b = 1; sd was calculated for dissolving 90% of the active ingredient. 2.6. Estimation of strength of granules A known amount of granules was placed on a sieve shaker (Retsch Technology, Germany) with sieves of 710 and 1000 lm for 3 min, at constant amplitude to obtain specific size class for strength analysis. The reason behind selecting this size range was to compare the different batches of granules avoiding an effect of varying sizes of granules. The strength of granules was determined out using Zwick/Roell Z 0.5 materials testing machine with a PC for real time data logging and analysis. The granules were placed in a die with a 10 mm diameter and component height of 10 mm and compressed at a test speed of 5 mm/min, with an upper force limit of 450 N. The test was repeated 10 times in order to get accurate data from the analysis. The average strength of granules was then calculated using Adam’s equation (4) [10].
a
2 kg/h
0.05
3.5 kg/h
aen
þ aen þ lnð1 e
Þ
0.01 0
0
40
60
80
100
Fig. 2. Residence time distribution curves at different powder feed rates.
resulted in plug flow of powder. The shortest residence time was noted at powder feed rate of 6.5 kg/h. This may be due to very high throughput force which conveyed the powder quickly. Fig. 3 shows the relative torque produced during the granulation of powder material at varying powder feed rates. The torque values increased gradually (unsteady flow initially) and reached to equilibrium state (steady flow) after about 20 s. The torque values were considered as an indication of extent of compaction of powder inside the barrel. At low powder feed rate the barrel was rarely filled hence low torque was produced [5]. As the feed rate was raised to 6.5 kg/h the torque increased sharply indicating increase in conveying load on screws which further reflected the increase in packing of the powder particles over the granule surface and around each other.
40
Powder feed rate (kg/h)
35 30
2
3.5
5
6.5
25 20 15 10 5
L/S- 0.3 Screw speed- 400 rpm
0 0
20
40
60
80
Time scale (s) Fig. 3. Torque produced at powder feed rates of 2, 3.5, 5 and 6.5 kg/h.
Volume density function (1/mm)
Fig. 2 shows influence of powder feed rate on residence time distribution of the material inside the barrel during granulation. It was observed that the residence time increases with decrease in powder feed rate. At low powder feed rate there was less powder inside the barrel hence the degree of channel filling was low. This also means that there was low throughput force for powder leading to more back mixing. Hence the powder resided for longer time inside the barrel as indicated by wider residence time distribution. In contrast, the residence time was shorter for high powder feed rates. The high powder feed rate led to higher degree channel filling of screws creating high throughput force which may have
20
Time (s)
where, P is the applied pressure, s is the average agglomerate strength (also known as Adam’s strength parameter), a is a constant rated to friction and en is the natural strain. s and a were obtained by fitting the data into Eq. (4) as natural logarithms of the applied pressure and as a function of the natural strain, by non-linear regression.
3.1. Influence on residence time distribution and torque
6.5 kg/h
0.03 0.02
ð4Þ
3. Results and discussion
5 kg/h
0.04
Torque (Nm)
" # b ! t t0 100% C ¼ 1 exp
ln P ¼ ln
0.06
ð2Þ
where S is the conductivity of the solution at a time t, and S1 and Sx are the initial and final conductivities. The Weibull distribution function was used to describe the data (Eq. (3)) [9]:
hsi
0.07
E(t)
164
0.8
L/S- 0.3 Screw speed- 400 rpm
0.7 0.6 0.5
2 kg/h 3.5 kg/h 5 kg/h 6.5 kg/h
0.4 0.3 0.2 0.1 0 0
500
1000 1500 2000 2500 3000 3500 4000 4500 5000
Granule size (µm) Fig. 4. Size distributions for changing powder feed rates.
165
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20
0.7
2 Kg/h
18
3.5 Kg/h
0.6 0.5
2 kg/h 3.5 kg/h
0.4
L/S- 0.3 Screw speed- 400 rpm
5 Kg/h
14
Porosity (%)
Aspect ratio
16
6.5 Kg/h
12 10 8
5 kg/h
6
6.5 kg/h
4 2
0.3 0
500
1000
1500
2000
2500
3000
3500
0
Granule size (µm)
C1
C2
C3
C4
The difference in the residence time distribution and torque at varying feed rates influenced particle packing (Figs. 7 and 8), strength (Fig. 9) and dissolution time of the final granules (Fig. 10). 3.2. Influence on properties of granules The influence of varying powder feed rates on size distribution of granules has been shown in Fig. 4. The granule size decreased at high powder feed rates due to the increasing torque and decreasing residence time. This increase in torque may be attributed to higher channel filling of the screws and increased compaction; this then causes increased attrition of the wet mass between the screws and barrel wall. The size distributions for low powder feed rate was bimodal. At low powder feed rate, less channel filling; less
Fig. 8. Porosity of granules from different compartments at varying powder feed rates.
attrition, restricted packing of primary particles and the increased back mixing of wet mass resulting in the production of large and porous granules. The relative change in the elongation of the granules was determined by aspect ratio (as a shape factor). The high feed rate had no significant influence on the elongation of granules at high feed rates as indicated by the curves for aspect ratio (Fig. 5). The only small change could be observed at 2 kg/h where large, elongated agglomerates decreased the aspect ratio. The influence of powder feed rate on surface and structure has been shown in Figs. 6–8. The granules collected from various sections (C1–C5) showed change in properties like shape; surface;
Rough and loosely packed 2 kg/h
Smooth and closely packed 6.5 kg/h C1
C2
C3
C4
C5
Fig. 6. Microscopic images showing change in shape and surface of granules in various compartments.
2 kg/h
6.5 kg/h
C1
C2
C5
Compartment
Fig. 5. Aspect ratios for changing powder feed rates.
C3
C4
Fig. 7. X-ray tomographic images showing change in granule voids in various compartments.
C5
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14
(MPa)
11
8
τ 5
L/S- 0.3 Screw speed- 400 rpm 2 1
2
3
4
5
6
7
Powder feed rate (kg/h) Fig. 9. Strength of granules at different powder feed rates.
rates compact the powder inside the barrel of the granulator. When powder compaction inside the granulator is increased, the granules that form interact more with the ungranulated material in the barrel. This interaction between the powder and the surface of the granules causes the powder to efficiently pack over the granule surface and around each other (Fig. 7). The surface of the granules begin to pack the powder more effectively at higher powder feed rates, interlocking the primary particles onto the surface of the granules. The better the interlocking of the primary particles onto the structure of the granules, the stronger the granule becomes. The influence of powder feed rate on barrel filling, torque, particle packing, strength could be clearly observed on the dissolution time of the granules (Fig. 10). It may be concluded that the interparticular arrangement for the granules produced at higher feed rate was denser and hence took longer time to release the embedded salt in them and the result is more strong the granules more the dissolution time.
80
t90 (s)
4. Conclusion 60
40
L/S- 0.3 Screw speed- 400 rpm 20 1
2
3
4
5
6
7
Powder feed rate (kg/h) Fig. 10. Dissolution time of granules at different powder feed rates.
particle arrangement. Microscopic and X-ray tomographic studies (Figs. 6 and 7) showed that the structure and shape of the granule change along the length of the screw (Figs. 6 and 7 show for 2 and 6.5 kg/h). The porosity of granules decreased along the length of screw at all the four feed rates (Figs. 7 and 8). This difference in porosity may be attributed to varying barrel filling and torque at different feed rates (Fig. 3). The granules in C1 where liquid was injected on powder mass were loosely packed, porous and rough. In C2 (intermeshing screws), the granule took smoother surface and were found to be closely packed that resulted in decrease in porosity. This densification can be seen in the images from microscope and slices from X-ray tomography (Fig. 7). The granules in C3 had voids similar to granules from C2. C4 had intermeshing screws and hence the granules obtained from this section were smoother, closely packed and had small voids. The final granules were obtained from C5. Granule surface was smooth and particle packing was similar to C4. Fig. 9 shows that the strength of the final granules increased as the powder feed rate was increased. The high powder feed rates resulted in the narrow residence time distribution but increased degrees of channel filling which further increased torque and thereby the strength of the granules was high. High powder feed
The powder feed rate had significant influence on the both transition and final state granule properties. The increased powder feed rate had direct impact on residence time distribution, barrel filling and torque which monitored the changes in the size, shape, structure, porosity, strength and dissolution time of the granules. The granules collected from various compartments of barrel showed decrease in porosity along the length of screw. Also the surface of granules changed from rough to smooth along the length of screw. At high feed rate channel fill and torque increased which increased the strength of the granules. The dissolution time was found to depend on torque and the strength of the granules. References [1] B. Ennis, J. Litser, T. Allen, R.H. Snow (Eds.), Perry’s, Chemical Engineer’s Handbook Chapter 20: Size Reduction and Size Enlargement, seventh ed., McGraw Hill, New York, 1997. [2] L. Lachman, H. Sylwestrowicz, Experiences with unit-to-unit variations in tablets, Journal of Pharmaceutical Sciences 53 (1964) 1234–1242. [3] P.C. Kapur, D.W. Fuerstenau, Coalescence model for granulation, Industrial and Engineering Chemistry Process Design and Development 8 (1) (2002) 56–62. [4] E.I. Keleb, A. Vermeire, C. Vervaet, J.P. Remon, Continuous twin screw extrusion for the wet granulation of lactose, International Journal of Pharmaceutics 239 (1–2) (2002) 69–80. [5] R.M. Dhenge, R.S. Fyles, J.J. Cartwright, D.G. Doughty, M.J. Hounslow, A.D. Salman, Twin screw wet granulation: granule properties. Chemical Engineering Journal (2010), in press, doi:10.1016/j.cej.2010.05.023. [6] D. Djuric, B. Van Melkebeke, P. Kleinebudde, J.P. Remon, C. Vervaet, Comparison of two twin-screw extruders for continuous granulation, European Journal of Pharmaceutics and Biopharmaceutics 71 (1) (2009) 155–160. [7] E.I. Keleb, A. Vermeire, A. Vervaet, C. Remon, J.P. Twin, Twin screw granulation as a simple and efficient tool for continuous wet granulation, International Journal of Pharmaceutics 273 (1–2) (2004) 183–194. [8] C. Nikitine, E. Rodier, M. Sauceau, J. Fages, Residence time distribution of a pharmaceutical grade polymer melt in a single screw extrusion process, Chemical Engineering Research and Design 87 (6) (2009) 809–816. [9] F. Langenbucher, Parametric representation of dissolution-rate curves by the RRSBW distribution, Pharmaceutical Industries 38 (1976) 472–477. [10] M.J. Adams, M.A. Mullier, J.P.K. Seville, Agglomerate strength measurement using a uniaxial confined compression test, Powder Technology 78 (1) (1994) 5–13.