The role of the screw profile on granular structure and mixing efficiency of a high-dose hydrophobic drug formulation during twin screw wet granulation

Journal Pre-proofs The role of the screw profile on granular structure and mixing efficiency of a high-dose hydrophobic drug formulation during twin screw wet granulation Shahab Kashani Rahimi, Shubhajit Paul, Changquan Calvin Sun, Feng Zhang PII: DOI: Reference:

S0378-5173(19)31003-8 https://doi.org/10.1016/j.ijpharm.2019.118958 IJP 118958

To appear in:

International Journal of Pharmaceutics

Received Date: Revised Date: Accepted Date:

8 October 2019 10 December 2019 12 December 2019

Please cite this article as: S.K. Rahimi, S. Paul, C.C. Sun, F. Zhang, The role of the screw profile on granular structure and mixing efficiency of a high-dose hydrophobic drug formulation during twin screw wet granulation, International Journal of Pharmaceutics (2019), doi: https://doi.org/10.1016/j.ijpharm.2019.118958

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© 2019 Published by Elsevier B.V.

The role of the screw profile on granular structure and mixing efficiency of a high-dose hydrophobic drug formulation during twin screw wet granulation

Shahab Kashani Rahimia, Shubhajit Paulb, Changquan Calvin Sunb and Feng Zhang,a,*

(a) College of Pharmacy, Department of Molecular Pharmaceutics and Drug delivery, University of Texas at Austin, 2409 University Ave, Austin TX 78712 (b) College of Pharmacy, Department of Pharmaceutics, University of Minnesota, 308 SE Harvard St, Minneapolis, MN 55455

* Corresponding Author: Email address: [email protected] Phone: (512) 471-0942, Fax: (512) 471-7474

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Abstract This study aimed at systematically investigating the role of distributive comb mixing element (GLC) and neutral dispersive mixing kneading block element (K90) on the structure and physical properties of granules containing high-dose of poorly water-soluble drug. Albendazole was used as the model drug at 50 wt% drug loading. Lactose monohydrate and microcrystalline cellulose were used as diluent, and 3 w/v% hydroxypropyl cellulose aqueous solution was used as binder liquid. It was found that the use of GLC element resulted in formation of granules with higher internal porosity, more homogeneous binder distribution, smaller particle size, superior compaction properties and tabletability while K90 kneading element produced relatively larger and denser granules with less homogeneous binder distribution where binder was mainly concentrated in larger granules. The use of downstream GLC element was shown to result in an approximately 8% and 57% reduction in the D50 for 0.2 and 0.3 liquid-to-solid ratios, demonstrating a significantly higher sensitivity of granule size to screw profile at higher liquidto-solid ratios. The axial mixing efficiency was assessed by measuring the residence time distribution of the granulation process with screw profiles containing K90 and GLC elements. It was found that granules had longer mean residence time and broader residence time distribution within GLC element due to enhanced backmixing and axial dispersion processes. The continuous “fragmentation-reagglomeration” cycle was proposed to be the main advantage of distributive GLC element in granulation of hydrophobic powders. Keywords: Twin screw wet granulation, screw profile, screw design, hydrophobic powder, kneading element, granulation residence time

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LIST OF ABBREVIATIONS

API

Active Pharmaceutical Ingredient

BCS

Biopharmaceutics Classification System

FHD

Full High Definition

GFA

Conveying element

GLC

Comb-shaped distributive mixing element

HPC

Hydroxypropyl Cellulose

K90

Kneading element with 90⁰ advance angle

L/S

Liquid to solid ratio

MCC

Microcrystalline cellulose

PAT

Process Analytical technology

RGB

Red Green Blue

RTD

Residence Time Distribution

TSWG

Twin Screw Wet Granulation

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1. Introduction Wet granulation is a process of particle size enlargement based on formation of larger aggregates of fine primary powder particles and is one of the key unit operations in pharmaceutical industry 1. The main purpose of wet granulation process is to improve the materials properties such as powder compressibility, flowability and product content uniformity by preventing particle segregation during mixing, handling and down-stream processing 2-4. Traditionally, pharmaceutical wet granulation was based on batch processing techniques utilizing fluidization in the case of fluid bed granulator or mechanical agitation in high/low shear granulation processes 5, 6. However, continuous processes and, in particular, twin screw wet granulation (TSWG) process is an attractive alternative to traditional wet granulation process. The early usage of extruders in granulation was in the spheronization process which was mainly accomplished with single screw extruders 7 while the first use of extruder in pharmaceutical industry was in the manufacturing of paracetamol extrudates in a work done by Gamlen et al 8. The pioneering works of Keleb and co-workers 9 on twin screw granulation process showed that granules produced by twin screw granulation exhibited improved tensile strength, disintegration, and friability when compared to those produced by high shear wet granulation, highlighting the enhanced benefits of twin screw extruder as an alternative to batch high shear granulators. Moreover, the twin screw extruder offer additional advantageous over high shear batch granulation such as shorter residence time (typically less than a minutes as opposed to several minutes in batch processes), process design flexibility, efficient mixing of formulation ingredients, and applicability to a range of throughputs and production volume 10. In addition, granulation in extruder is more adaptable with in-line process analytical technology (PAT) and controlling strategies. The “self-wiping” property of intermeshing twin screw extruder ensures minimal material accumulation during the process, resulting in a less labor intensive process and lower manufacturing costs 11. From a mechanistic point of view, there are three stages involved in a wet granulation process 12. It starts with wetting the powder through incorporation of granulating liquid and formation of granule nuclei through liquid bridges by either immersion or flocculation mechanisms 13 (depending on the mode of liquid addition). Then follows a transition step where 4

an equilibrium between particle attrition and agglomeration results in creation of larger clusters. In the second phase, growth occurs through random layering of particles and small clusters on other agglomerate species. The layering phase is governed by the transport of binder to the surface of clusters and densification of granules 14. Eventually, as the number of smaller particles decrease, the third phase proceeds via coalescences of clusters and agglomerates to form coarse and larger granules. Within high shear granulation process, all the steps involved in granulation, such as nucleating by wetting, particle agglomeration, attrition and coalescence can coexist simultaneously 14, 15 however, in a twin screw extruder, the structure development is more complex as the granules travel along the various zones of the screw, and is largely dependent on the screw profile and mixing elements 16. It is worthy to note that the structure development along the screw axis does not necessarily follow the sequential manner as in high shear batch process. For example, in a number of previous studies 17, 18 on progression of granule formation along the screw length, it has been shown that nucleation is typically achieved by droplet immersion mechanism at the point of liquid injection. As the wet mass reaches the kneading block (or a similar non-conveying equivalent) along the screw, it undergoes simultaneous compaction (consolidation) and fragmentation while further downstream kneading block are more influential in reshaping the granules rather than affecting their sizes 18. In a twin-screw wet granulation process, the structure and properties of the granules are largely governed by a number of different formulation and process variables. These include the particle size distribution of primary powders 19, binder type and viscosity 20, 21, liquid to solid (L/S) ratio 22, 23, screw speed and feed rate 23, 24 as well as the degree of fill 25, 26 and residence time 27. It was reported that the granulation behavior of powder is predominantly determined by their internal porosity, compressibility and structure 21, 28, 29. Lute et al 19 reported that processed powders, such as spray-dried and granulated lactose and mannitol are preferred over crystalline excipients, especially when formulating with highly cohesive API powders. Studies on the effect of L/S ratio 23 have shown that a higher L/S ratio typically results in formation of denser granules with less porosity depending on the screw profile and feed rate 30. Analysis of the effect of binder viscosity 31 showed that increasing the viscosity resulted in formation of denser granules and less fines and transformed the particle size distribution toward mono-modality, although granules of larger sizes are rarely used for direct tableting and require further downstream processing 23, 32. Investigation of the effect of barrel fill level 25 on granulation of microcrystalline cellulose 5

showed that, at high degrees of fill, due to limited solid-liquid interaction, granule size and tablet tensile strength decreased. However, similar conditions showed no noticeable change in the case of lactose 25. This was attributed to the solubility of lactose over MCC in granulation liquid which facilitates the dissolution of smaller particles 25, 33. Moreover, the role of the screw profile on granular structure evolution and properties have been studied. Djuric and co-workers 34 reported that while conveying elements produced high friable and porous granules of lactose, use of kneading blocks resulted in complete agglomeration and formation of dense granules. Increasing the stagger angle in the kneading blocks from 30⁰ to 60⁰ and 90⁰ or increasing the number of kneading blocks have been shown to increase the particle packing and formation of coarse granules 35, 36 although this effect is more prominent at high degrees of fill. However, Thompson et al 30 reported that the offset angle of the kneading blocks had minimal effect on particle development while the intermeshing region had most significant effect in compressive forces build-up and granular densification. In addition, they reported that the conveying elements had no considerable effect on granule shape and structure although in a number of other studies 37, the downstream conveying elements after kneading blocks have been reported to decrease the granule size especially those with smallpitched flights. Despite the progress on twin-screw wet granulation process of hydrophilic and water soluble compounds, wet granulation of hydrophobic compounds becomes challenging due to a number of factors, mainly the difficulty in wetting and nucleation, leading to poor liquid distribution and granule content uniformity. Some of the earlier studies 38 looked at the granulation of mixtures of hydrophobic and hydrophilic compounds and found a decreasing granule size trend with increasing hydrophobic content which was primarily attributed to the compromised hydration of outer layers of clusters resulting in slow granular growth rate. In addition, the effect of hydrophobic powders with low wettability has been studied 39, 40 with respect to the nucleation phase through the analysis of drop penetration time. A higher amount of the hydrophobic component in the mixture increases the water contact angle that significantly reduces the penetration time of the droplet in the powder bed. This effect would delay the formation of agglomerate nucleus.

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Yu et al 41 reported on the effect of various process parameters on twin screw wet granulation of increasingly hydrophobic formulations of lactose (as hydrophilic) and di-calcium phosphate anhydrate (as hydrophobic) components. Their observation was consistent with previous studies showing a high content of un-wetted fine particles with increasing level of the hydrophobic component. They found that while the feed rate and hydroxypropyl cellulose (HPC) concentration in the binder solution did not have any significant effect on particle size distribution, increasing the number of kneading elements and liquid to solid ratio considerably increased the D50 value of particle size distribution. The distribution of lactose in a highly hydrophobic formulation was used as a measure of content uniformity although even with twelve kneading elements, the distribution remained heterogeneous. In a recent study by Mundozah et al 42, twin-screw wet granulation of a mixture of lactose monohydrate (hydrophilic part) and magnesium stearate (hydrophobic part) was investigated by analyzing the effect of hydrophobic content of the mixture as well as variation in a single mixing zone screw element. They found that when hydrophilic phase was dominant, the mixing did not show strong dependency on screw fill levels. Additionally, they reported that tooth mixing elements (TME-type) provided more efficient distributive and dispersive mixing. Increasing the width of TME elements resulted in further densification of granules and increasing their size in addition to slight increase in the residence time. The importance of understanding the granulation behavior of hydrophobic compounds is due to the fact that more than 60% of newly discovered drugs belong to BCS class II or VI with poor water insolubility 43 (typically <1µg/ml). An example of such compounds is Albendazole, a broad spectrum anthelmintic drug with extremely low water solubility (log P = 13.94), poor powder flowability and poor compressibility 44-46. Therefore, it is of great interest to develop twin screw wet granulation process to manufacture high dose Albendazole granules with improved critical quality attributes. Current work extends the understanding of the role of the screw profile on twin screw wet granulation of high dose highly hydrophobic drugs using Albendazole-based formulations. Particularly, the role of kneading and GLC (comb) mixing elements and their arrangements along the screw profile on the structure development of the granules as well as binder uniformity and mixing efficiency is investigated. 7

2. Experimental

2.1 Materials Microcrystalline cellulose (Pharmacel 102) with D50 of 90 μm and lactose monohydrate (Pharmatose 200M) with D50 of 40 μm were obtained from DFE pharma (Paramus, NJ, USA). Albendazole was purchased from Shenzhen Nexconn Pharmatechs (Shenzhen, China) with a D50 of 13 μm. Hydroxypropyl cellulose (KlucelTM, EXF grade) with Mw= 80 kDa was supplied by Ashland (Wilmington, DE, USA). Silicon dioxide Aerosil 200 Pharma was supplied by Evonik (Piscataway, NJ, USA). Sulforhodamine B (75% dye content) with 𝜆𝑚𝑎𝑥 = 554 nm was purchased from Sigma Aldrich (Milwaukee, WI, USA). All chemicals were used as received.

2.2 Twin-screw wet granulation process All the materials were first dried in vacuum oven overnight at 60⁰C and then sieved over a 600 μm mesh (#30) to remove agglomerates. Feed powder mixture was prepared by blending 50 wt% of Albendazole, 35 wt% lactose monohydrate and 15 wt% microcrystalline cellulose (MCC) with 0.2 wt% of SiO2 (to improve the flow) in a V-blender (MAXIBLEND, GlobePharma) for 10 minutes at 25 rpm. Binder solution was prepared by dissolving 3 w/v% HPC in DI water. Granulation was performed on a Leistritz Micro 18 (D=18 mm, L/D: 25/1) twin screw extruder operating at the feed rate of 0.7 kg/h and screw speed of 100 rpm and temperature of 25 ⁰C. The powder blend was fed into the extruder using a MT-1 Brabender® screw feeder with consistency of ±4%. The liquid binder (3 w/v% HPC solution) was fed into the second barrel zone (C1) of the extruder using a Waters® HPLC pump (model 510). The liquid to solid ratio was set to 0.2, 0.3 and 0.4 (w/w). The screw design was primarily based on a combination of conveying elements for powder transport as well as 900 kneading element (K90) and comb mixing element (GLC) with various configurations as shown in Figure 1. No die was used at the end of the extruder while the screw shaft was fixed to the gearbox (motor) through connector pins to ensure no axial movement of the screws during the process. The port on C3 zone was kept closed in the process and was opened only when samples were needed to be taken from C3 zone. After the start of the 8

feed, extruder ran for at least five minutes to reach steady state. Samples were collected from the discharge zone and then dried at 35 ⁰C in a convection oven for 24 hours. Granules were then kept in desiccator until characterized. Samples are coded based on the screw profile arrangement followed by the liquid to solid ratio. For example, GLC0.3 refers to the samples prepared with a single GLC element at the L/S ratio of 0.3. 2.3 Particle size and shape analysis Size fractioning of the granules was conducted using an Advantech® L3P sonic sifter with a stack of precision mesh sizes of 1180, 850, 600, 425, 250 and 125 μm and the fines are the particles collected bellow the smallest mesh47 (<125μm). Sonic sifter was operated at an amplitude where the particle arc above the mesh was limited to about 1/4" and the sieve time was set to 180 seconds (minimum time to observe no more weight change on the screens). About 1215 grams of sample was sieved in every run and for each sample at least 3 replicate runs were performed. Measurement of the D50 of the granules were performed using a QICPIC/RODOS L with a vibratory feeder VIBRI/L (Sympatec GmbH System, Clausthal-Zellerfeld, Germany) operating with 0.3 bar in the pressure dispersion module. The obtained data is the logarithmic plot of volume cumulative distribution versus particle size. In addition to particle size distribution, this techniques provided information about the particle convexity, which is the ratio of the projection area to the area of the convex hull (value between 0 and 1). It represents the extent of “irregularity” of the perimeter of the particles. 2.4 Contact angle measurement The wetting behavior of a compact bed of formulation components were studied using water contact angle measurements. For this purpose, the effect of variation of both the Albendazole and MCC content on the dynamic drop penetration time was studied. The effect of Albendaozle variation was studied using a 1:1 ratio of MCC and lactose with 0-100 wt% of Albendazole. For MCC content variation study, the Albendazole content was fixed at 50 wt% and MCC content was set to 7.5, 15, 25 and 37.5 wt%. After blending the mixtures at 25 rpm for 10 minutes, the compact bed was prepared by compressing the powder blend at 2000 psi using a Carver® laboratory press. The water contact angle of compacted powder bed was measured using

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a FTA200 contact angle goniometer. A 1 ml syringe was used to dispense the droplet (4-5 μL) and the variation of the contact angle with time was recorded. 2.5 Morphology, microstructure and specific surface area The morphology and structure of the granules were studied by FEI Quanta® 650 Scanning Electron Microscope (SEM) operated at 10kV. The samples were sputter coated with silver using an ESM 550 sputter coater. The internal porosity and structure of the granules were studied using X-ray CT scans on a Xradia microXCT 400 Scanner. Granules of above 1.18 mm were randomly selected and scanned to a resolution of 4.5 μm pixel size with scanning angles of ±180⁰ at 70 kV and 3 s acquisition time. Specific surface area was measured by the BrunauerEmmett-Teller (BET) method using a MonosorbTM Quantachrome (Quantachrome Instruments, Boynton, Florida) gas adsorption analyzer. Samples were degassed by purging with helium for 24 hours at 65⁰C on the Thermoflow Degasser (Quantachrome Instruments, Boynton, Florida) prior to analysis. A mixture containing Nitrogen gas (30 mol%) and helium (70 mol%) was used as the adsorbate. A total of 5 adsorption-desorption cycle experiments were performed on each sample and the average and standard deviation are reported. Experiments were performed on 300-320 mg of samples. 2.6 Liquid binder distribution To investigate the distribution of liquid binder within the granules, the amount of a trace dye was measured across a range of different particle sizes. For this purpose, a red dye, sulforhodamine B was dissolved in the binder solution. Once the samples were fractionated on shaking sieves, samples from the fractions of <125μm, 250-425μm, 600-850μ and >1180μm were taken and dissolved at the concentration of 3 wt% in an 80/20 (v/v %) of water/acetonitrile mixture by mixing for a minimum of 2 hours and sonicated in a ultrasonic bath for 10 minutes. 2 ml of the supernatant solution was taken and centrifuged at 10,000 rcf for 5 minutes. The final supernatant was used for analysis of dye absorbance at the wavelength of 565 nm on an Agilent® 8453 UV/Vis spectrophotometer to measure the concentration of dye in each size fraction. 2.7 Measurement of granulation residence time The residence time distribution (RTD) of a twin screw wet granulation process was measured by analyzing the color intensity changes of a pulsed tracer dye (Brilliant Blue, Aldrich) during the process as follows: certain amount of tracer was introduced into the feed of the 10

extruder. A Nikkon D3400 camera was used to capture a video of the material exiting the extruder from the open die plate. Video was recorded with a resolution of 1920 x 1080 pixels (Full High Definition, FHD) at 60 frames per second recording frequency. A white paper was used as a reference background in order to eliminate the color intensity changes due to change in environmental lightning. Video recording was started immediately after addition of the die to the feed zone and continued until no color change in the discharged granules was observed. The video was processed to a stack of photos with the resolution of 10 frames per second (0.1 s resolving accuracy). The stack of images were analyzed using a program written in MATLAB® software in order to measure the red-green-blue (RGB) channel of each image in the stack. The final RGB value of each image was an average of the pixels in the whole frame. The variation of color intensity versus time was used to construct the residence time distribution.

2.8 Granule compaction and compressibility The true density (ρt) of the granule samples was determined using a helium pycnometer (Quantachrome Instruments, Ultrapycnometer 1000e, Byonton Beach, FL).

An accurately

weighed sample (1-2 g) was placed into the sample cell. The volume measurement was allowed to repeat for a maximum of 100 iterations. When the coefficient of variation of five consecutive measurements was below 0.005%, the experiment was terminated and the mean and standard deviation of the last five measurements were considered for analysis. For the compaction studies, approximately 300 mg of the powder from 250-425µm sieve cut was manually filled into the die and compressed with 10 mm diameter flat-faced round tooling over the range of 25-300 MPa compaction pressure (P). Tablets were prepared (10ms dwell time, corresponding to a tablet production rate of 103,000 tablets/h) on a compaction simulator (Presster, Metropolitan Computing Corporation, NJ), simulating Korsch XL400 (29 stations) tableting press. After ejection, tablets were allowed to relax for two hours in a sealed container before they were diametrically broken on a texture analyzer (Texture Technologies Corp., Surrey, UK) at a speed of 0.01 mm/s. Radial tensile strength of tablets (TS) was obtained from Equation (1) 48. 2𝐹

TS = π.D.h 11

(1)

where F, D, and h are the breaking force, tablet diameter, and tablet thickness, respectively.

3. Results and Discussion 3.1 Wetting behavior of the powder beds The water contact angle and drop penetration times are shown in Figure 2. When the API content is increased from 0 to 80 wt%, the initial contact angle gradually increases. In powder beds containing up to 20 wt% API, the initial contact angle is 75⁰ and the droplet penetrates the powder bed over the following period of 1 minute and eventually completely wets the surface. As the API content of the powder bed is increased to 40 wt%, the initial contact angle increases to 94⁰, while the drop penetration time significantly decreases with the final contact angle of 86⁰ (after 1 min). Further increasing the API content renders the surface completely hydrophobic with contact angles above 90⁰. Two factors contribute to such observation. Hapgood and coworkers 39 introduced the concept of the effective powder bed porosity during the penetration of water inside a porous powder bed through the “wicking” effect. However, for a mixture of hydrophilic and hydrophobic powders, some of the available capillaries (if the powder bed was totally hydrophilic) would be obstructed and inaccessible for the penetrant to flow into. Therefore, the fractional “accessible” area for the liquid would decrease. Taking this into consideration together with the role of the macrovoids (εmacrovoid), the following expression was suggested 40 for calculating the effective porosity of the powder bed: 𝜀𝑒𝑓𝑓 = 𝜀𝑡𝑎𝑝 (1 ― 𝜀𝑚𝑎𝑐𝑟𝑜𝑣𝑜𝑖𝑑𝑠 ―𝜀.

𝑆ℎ𝑦𝑑𝑟𝑜𝑝ℎ𝑜𝑏𝑖𝑐 𝑆𝑡𝑜𝑡𝑎𝑙

)

(2)

Where εtap is the tap voidage, ε is the bed voidage (=εtap*Hausner ratio), Shydrophobic and Stotal are the cross sectional surface area of hydrophobic fraction and total area of the powder bed, respectively. Integration of effective porosity into the drop penetration model developed by Middleman 49 results in the following expression that correlates the drop penetration time to the effective porosity of the powder bed: 𝜏𝑃 =

𝑘3 𝑉2𝑜

𝜇 1 𝑅𝑒𝑓𝑓 .𝛾𝐿𝑉.𝐶𝑜𝑠𝜃.(1 ― 𝜉). 𝜀2𝑒𝑓𝑓

12

(3)

Where k is an integer equals to 1.37, Reff is the effective pore radius, µ is the penetrant viscosity, γLV is the surface tension of the penetrant liquid, θ is the dynamic contact angle of the liquid on the solid capillary, Vo is the drop volume and ξ is the hydrophobic fraction of the powder bed. As can be seen from this equation, with increasing the API content the Cos θ value decreases due to the increase in the contact angle (shown in Figure 2), in addition, with increasing the API, due to the smaller particle size of the API compared to excipients (as discussed in the experimental section) and the poor compressibility and packing of the drug particles, the fraction of macrovoids increases within the powder bed that results in decrease in the effective porosity of the compact. The reduction of Cosθ and εeff and increase of the hydrophobic fraction (ξ) will result in increasing drop penetration time according to equation 3. Figure 2(c) shows the effect of the variation of the MCC content with constant portion of hydrophobic fraction. With increasing the MCC concentration (and decrease in the lactose portion), the initial contact angle decreases while the drop penetration time increases. The surface energy of the lactose 50 and MCC (Avicel PH101) 51 have been reported to be 43±1 mN/m and 37.7 ±0.9 mN/m. Based on these values, it is proposed that the overall surface energy of the powder bed will decrease by increasing the MCC content which is the reason of the initial decrease in the contact angle with increasing MCC content. On other hand, due to the abundance and close proximity of surface hydroxyl groups, MCC has exceptional compaction properties (compressibility) as it plastically deforms under compressive forces and significantly increases the inter-particle bonding area 52-54. As a result, with increasing the MCC content, the overall compressibility of the powder bed increases and under similar compressive force, it forms stronger/more tightly packed compacts. This would eventually delay the penetration of water droplet during the wetting process (Figure 2). Therefore in our formulation we considered a fixed MCC content of 15 wt% in samples with 50 wt% API. (Similar proportion of MCC: lactose was used for samples with higher API content).

3.2 Granule microstructure and particle size distribution Based on the observations of the wetting behavior of the powder bed, screw profile was designed accordingly. In the zone 2, where the binder solution is injected in to the extruder, a 13

large-pitched conveying element was used (GFA-30) in order to minimize the powder packing and allow for wetting of the powder bed with the binder solution. Subsequently, a mediumpitched conveying element was used to provide some packing prior to powder entrance in the mixing elements. In addition, since we are interested in studying the effect of mixing elements on granule properties, the final conveying zone (in both the single and double mixing element designs) was based on using large-pitched conveying elements 37 since small-pitched conveying elements exert considerable particle attrition and breakage as well as particle re-growth that changes the structure and shape of the granules exiting the mixing element. The particle size distribution, particle shape and particle morphology were studied to get a better understanding of the role of screw elements on the size, shape and structure development of the granules. A representative sieve fractionation data for granules granulated with all conveying elements, K90 and GLC element as a function of L/S ratio is shown in Figure 3(a-c). The granules prepared by all conveying element at L/S=0.2 represent a large fraction of undergranulated or fine particles (<125µm). Increasing the L/S ratio to 0.3 slightly increase the granules in the larger fractions while further increase of L/S to 0.4 generates a distinct bimodal distribution where a large fraction of fines (around 20%) and larger fraction of overgranulated particles (>1180µm) are formed. Conveying elements with large pitch (as those used in this study) have high powder transportation capability. However, due to large channel volume and less mixing capability, only very weak agglomerates of particles (through layering mechanism) are formed and majority of the particles remain undergranulated due to lack of sufficient mechanical mixing. This scenario is aggravated due to the fact that the binder was added to the barrel through droplet addition resulting in immersion nucleation mechanism. In this dropcontrolled nucleation system, the granulation follows through mechanical dispersion regime where liquid distribution and subsequent granular growth is essentially dependent on shear forces and mechanical agitation exerted by the extruder 55. In the case of K90 and GLC a similar observation with regard to the effect of liquid to solid ratio is seen. With increasing L/S ratio, the proportion of granules in larger size fractions increases. Interestingly, the granules produced by the single GLC mixing element show a relatively narrower size distribution at higher L/S ratios whereas the K90 element produces relatively broader size distribution (especially at L/S=0.3). In addition, at L/S=0.4, the K90 14

element produces a higher fraction of overgrnulated particles above 1180 µm whereas for the GLC element, a higher population of granules in the 850-1180µm is developed. This is consistent with the geometry of the GLC element that promotes higher extent of axial breakage and particle attrition that consequently decreases the particle size and narrows the particle size distribution through continuous mixing /reagglomeration and particle attrition through the cutting action of the slotted flights. In the case of K90 element, due to the minimum transport capacity of this element, the granules are subjected to significant shear and compressive forces. This will create a dense and compacted granular structure which has higher structural strength to withstand the fragmentation process (unlike those prepared through GLC element) resulting in less particle attrition. This is evident by considering the D50 and D90 values obtained from the cumulative size distribution curves (shown in Figures 3(d-f)) of K90 to be 994 and 2090 µm whereas the particles resulted from single GLC element had sizes of 820 and 1497µm respectively. In the case of L/S=0.3, it is very important to consider the hydrophobicity of the formulation. In a previous study by Thompson et al 30 on granulation of hydrophilic lactose powder , it was reported that granules made by kneading blocks had consistently larger particle size compared to other screw elements due to continuous compaction of lumps and formation of new layers though re-wetting of the compacts. However, there is a different behavior in the current granulation system. Once the hydrophobic powder mixture (with saturated core) gets compacted in the K90 overflights, the binder solution that is “squeezed out” to the surface, is less likely to promote new layer formation due to the difficulty of wetting the compacted surface (as shown in the contact angle study) which slows down the granular re-growth process. Thus, we see a relatively broad size distribution for the granules made by K90 element (compared to those made by GLC) at L/S=0.3 It should be noted that in the case of hydrophobic powders, a significant fraction of fines was reported in a number of previous studies 40, 56. This observation is primarily due to the change in granule nucleation mechanism and structural properties. First of all, a smaller nuclei are formed in presence of highly hydrophobic powders in the immersion nucleation mechanism due to formation of saturated core, but relatively a dry shell or outer layer that halts the formation of larger nuclei. In addition, since the powder bed is a mixture of hydrophilic and hydrophobic powders, upon formation of nuclei, there are less available thermodynamically favorable 15

surfaces for further wetting. This will prevent the formation of strong inter-particle bridges by the binder solution resulting in structurally weak granules. These granules will be more susceptible to fragmentation along the screw that will eventually result in formation of a relatively large fraction of fines. The cumulative particle size distribution of granules granulated via two mixing elements are also shown in Figure 3(d-f). It is evident that placing a second GLC element after K90 results in a considerable decrease in the particle size especially at higher L/S ratios. The D50 value decreases from 994 and 791µm to 545 and 335µm at L/S ratios of 0.4 and 0.3 respectively. This is consistent with the role of GLC element in cutting down the granule size through fragmentation due to the slotted screw geometry. Moreover, a screw profile consisting of two GLC elements, leads to smallest particle size (D50 values of 342 and 240µm at L/S ratios of 0.4 and 0.3 respectively) and a relatively narrow particle size distribution. This is an important finding with considerable implications on wet granulation as a narrow particle size distribution ensures homogeneous drying and less segregation during the downstream processing of granules. The morphology of the granules are shown in SEM images of Figure 4. It is seen that the granules formed by using all conveying elements are highly porous and resemble a loosely packed agglomerates of particles. The granules granulated by K90 kneading blocks show an elongated and compacted structure with low intra-granular porosity. On the other hand, when using single and double GLC elements, the porosity of the granules significantly increases, granules are less compacted and the shape of the granules becomes more rounded. A typical granule made via K90 and GLC elements are shown in Figure 4. It is also interesting to note the difference in the morphology of the granules that were extracted at the vent port in the K90-GLC design (before the granules move through downstream GLC element) and compare with the final morphology of the granules after discharging from the extruder. It is clearly seen that granules taken from the vent still hold their elongated shape as they compressed through the overflight of the kneading block discs. This compacted structure has sufficient mechanical integrity to hold the shape and resist significant fragmentation. Once passed through the downstream GLC element, these compacted elongated granules are fragmented and re-agglomerated into more rounded/porous structures.

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In order to assess the porosity of the granules, X-ray tomographic images of two representative granules granulated through single K90 and single GLC element (of the largest size fraction >1180µm) are shown in Figure 5. In addition, the specific surface area of the granules measured by BET at various L/S ratios are shown in Table 1. It is evident in the X-ray CT images that the granule produced by the GLC element has significantly higher porosity compared to that made by K90. The total void volume accounts for 32.3 % in the granule granulated by GLC while for the granule made by K90 total porosity drops to 3.2%. In addition, the 3D images extracted from the CT scans show that the pores form an interconnected structure within the granule made by GLC while for the K90, the majority of voids appear around/near surface and the core of the granule is a dense compact. The BET specific surface areas of granules made by GLC, K90 and GLC-GLC (Table 1) show that with increasing the liquid to solid ratio, the overall surface areas decreases for all the samples which is consistent with the fact that increasing the L/S ratio results in more efficient mixing and formation of compacted granules due to the increase in binder inter- and intraparticulate bridges. By comparing the values of specific surface areas, we see that granules prepared through two GLC elements have slightly higher surface area compared to those made by single GLC while both single and double GLC elements produce granules with considerably higher surface area compared to those made by K90. As for the single and double GLC element designs, there are two competing factors that determine the overall porosity. In the case of double GLC, although the granules experience larger number of perpendicular cutting and relayering steps, which should technically increase their porosity, the granules undergo an additional packing and compression in the second element as well. The combination of these two phenomenon are seemed to be resulting in only a slight increase in the overall surface area. It should also be mentioned that there could be a contribution of smaller particle size in the case of double GLC however, by choosing a narrow sieve cut, we attempted to minimize this effect. In addition, it should be noted that the internal closed pores are not accessible in the gas adsorption experiment, it is proposed that the interconnectivity of the pores in the samples made by GLC element (as shown in CT images) provide access to the majority of porous surfaces that could be confidently used as an evidence of overall porosity. Based on the X-ray CT images and

17

BET surface area measurement results, it is clear that K90 element forms granules that are highly compacted and less porous while GLC element promotes formation of highly porous granules. In order to further study the role of screw profile on the shape of the granules, the convexity values of granules prepared by K90 and GLC elements are shown in Figure 3(g). As can be seen, the granules made by GLC element show lower convexity values which correlates to more surface irregularities, grooves and pores. These “concave” regions reduce the overall convexity of the particles. The presence of surface roughness and pores will have considerable effects on compaction behavior of the granules as will be discussed in compressibility section. 3.3 Binder distribution and residence time Uniform distribution of binder in the granules produced with twin screw wet granulation process could become a challenge especially in the case of hydrophobic formulations due to the relatively short residence of the TSWG process. While in traditional high shear granulators 57, the initial heterogeneous binder dispersion becomes homogeneous over time with mixing, such condition is not readily achievable in extruder and the presence of distributive and dispersive mixing elements is critical to achieve content uniformity. In fact, as shown in Figure 6, it is evident that binder distribution is extremely heterogeneous in the case of a screw profile with only conveying elements. This is primarily due to the dominated layering mechanism of granule growth in an “all-conveying” screw profile which lacks sufficient dispersive/distributive mixing and as a result, binder is predominantly accumulated in lager size fractions while the smaller size granules and ungranulated fines receive significantly less binder content. Increasing the L/S ratio is found to have no effect on the binder distribution within granule size fraction in the case of all conveying elements. As for the K90, it is seen that at L/S ratio of 0.2, the larger granules (>850µm) have higher binder content compared to smaller sized granules. With increasing the L/S ratio, the binder distribution becomes more homogeneous. In the case of GLC element, the binder distribution is considerably more homogeneous across the entire size fractions studied. It is believed that the enhanced binder distribution in GLC element (even at relatively lower L/S ratio), is due to the continuous “fragmentation-reagglomeration” cycle within the GLC grooved

18

channels, that results in more homogeneous distribution of binder among various granular size fractions. It is imperative to note that the wetting characteristics (hydrophobicity/hydrophilicity) of the powder bed plays a key role in determining the granulation mechanism within different types of mixing elements. In the case of K90, as discussed before, the significant compressive force exerted in the intermeshing region, forms a dense and highly compacted granule, and subsequently squeezes the liquid out of the granule bulk. However, due to poor wetting of the compacted hydrophobic powder bed, it is difficult for the binder to re-disperse within the compacted granules. Since these hard and dense granules are less susceptible to fragmentation, it is also less likely for the binder to redistribute through dispersive cycles. Therefore, the key difference between the K90 and GLC is that the repetitive “fragmentation-reagglomeration dispersive cycle” is absent in K90 as opposed to the GLC element. In the case of GLC-GLC and K90-GLC screw profiles, it is evident from the Figure 6 that two GLC elements produce an exceptionally homogeneous distribution of binder in the granules. The K90-GLC profile is found to follow the trend of K90 although a unique feature in this arrangement is that with increasing the L/S ratio, there seems to be a slight accumulation of binder in smaller granules. We believe this is primarily due to the cutting action of the downstream GLC element. In fact, the binder-rich smaller granules are proposed to have some of the fragments of the originally larger granules (that were passed through the upstream K90) that were chopped into smaller size by the downstream GLC element. In order to further assess the mixing efficiency of these screw profiles, the residence time distribution of the materials during the granulation was measured by using a colored tracer and tracking the color intensity changes. The measured values of the color intensity versus time (as the raw data) was fitted with Zusatz function 58: 𝐸(𝑡) = 𝑎𝑡 ―(𝑐 + 1)𝑏𝑐 + 1exp [

𝑏𝑐 𝑡

(

)(

―1

― (𝑐 + 1) 𝑐

)]

Where a and b correspond to peak height and residence time at peak height and c correlates with peak width but with no direct physical meaning. The residence time function is calculated as 59: 19

(4)

𝑒(𝑡) =

𝑐(𝑡)

(5)

∞ ∫0 𝑐(𝑡)𝑑𝑡

Where c(t) is the dye concentration (intensity in this case) in the outlet with an interval of dt. The mean residence time is then calculated using 59: ∞

𝑡𝑚 =

∫0 𝑡.𝑒(𝑡)𝑑𝑡

(6)

∞

∫0 𝑒(𝑡)𝑑𝑡

Another important characteristic parameter for residence time distribution (RTD) curve is the width of the curve that correlates with the extent of axial mixing. The width of the RTD curve is assessed through the distribution mean centered variance as follows 59: ∞

𝜎2𝑡𝑚

=

∫0 (𝑡 ― 𝑡𝑚)2.𝑒(𝑡)𝑑𝑡 ∞

∫0 𝑒(𝑡)𝑑𝑡

(7)

In order to assess the axial mixing within the extruder, the dimensionless Pécelt number (Pe) is used. Pe number denotes the ratio of the convective over diffusive transport. In the current case, it correlates the convective axial material transport to axial transport via diffusion/dispersion. A mathematical term has been derived by considering the extruder as a closed system (with respect to boundary condition) with no radial variation in the concentration as follows 59: 𝜎𝑡𝑚 2

( 𝑡𝑚 ) ≈

2(𝑃𝑒 + 𝑒 ―𝑃𝑒 ― 1) 𝑃𝑒2

(8)

As the width of the RTD curve decreases and the mean centered variance approaches zero, the Pe number approaches infinity. Technically, this is a characteristic of a plug flow reactor (PFR). In the case of granulation process, it is desirable to increase the extent of axial mixing which would be correlated with lower Pe numbers (characteristic of continuous stirred tank reactor) therefore, Pe number can be used as a measure of quality of axial mixing along the extruder. A typical fit of Zusats function on the raw data and the RTD curve of samples processed with GLC at 0.2, 0.3 and 0.4 as well as K90 at L/S=0.3 are shown in Figure 7. The mean residence time and Pe numbers obtained from the RTD curves are shown in Table 2. First of all, 20

it is evident that with increasing the L/S ratio, the mean residence time of the wet mass increases while the Pe number decreases. This is consistent with a previous report showing that higher L/S ratio prolong the residence time of the granules in the extruder 58. With increasing the L/S ratio the rheological behavior of the powder-liquid mixture is modified as the formation of higher number of liquid bridges and the higher content of HPC in the formulation increases the flow resistance of the mixture and the resulting pasty material takes longer time to flow along the barrel length which consequently, increase the residence time of the process. In addition, increasing the L/S ratio is shown to prolong the tail of the RTD curve suggesting a higher level of axial mixing and dispersive transport compared to the conditions with lower L/S ratio. Now considering the role of the element geometry, it is evident that at the similar L/S ratio, there is a significant difference between the obtained RTD curves. At L/S ratio of 0.3, the mean residence time in a single GLC element screw profile is 39.6 s which is higher than that of K90 at 25.2 s. The Pe number is lower for single GLC compared to single K90 profile (21.5 versus 25.6). It is therefore clear that the extent of axial mixing is considerably higher in the case of GLC element. The critical factor that governs such observation is the geometry of the GLC element. The open channels of the slotted flights on the GLC, guarantees a “backmixing” where the wet mass particles and fragments flow backward to mix with the incoming material in the screw channel. Since the current formulation is highly hydrophobic, the concept of the Capillary number 60 ( =

ℎ𝑦𝑑𝑟𝑜𝑑𝑦𝑛𝑎𝑚𝑖𝑐 𝑠𝑡𝑟𝑒𝑠𝑠 𝑖𝑛𝑡𝑒𝑟𝑓𝑎𝑐𝑖𝑎𝑙 𝑠𝑡𝑟𝑒𝑠𝑠 )

can be considered where a competition between the shear forces

(hydrodynamic stress) and the interfacial tension determines the extent of mixing. The incompatibility between the hydrophilic aqueous binder and hydrophobic powder bed increases the interfacial tension which is associated with the thermodynamic driving force towards phase separation (minimization of interfacial area). However, the shear forces exerted by the screw in addition to the shear field within the flow of the wet mass in the channels of the GLC element (through backmixing with the incoming material) In the GLC element, provide a considerable hydrodynamic stress contribution to overcome the unfavorable interfacial tension resulting in an enhanced mixing or “dispersion”. In fact, as the results of the dye distribution and binder uniformity showed, use of GLC elements resulted in most homogeneous distribution of binders across the particle sizes studied. The higher mean residence time and the RTD tail (higher mean centered variance), in combination with the results of the particle size distribution (which 21

showed formation of smaller granules in GLC elements) confirm the mechanism of “fragmentation-layering cycles” to be the dominating process within GLC elements. In contrast, with the K90 element, due to its low conveying capacity, it operates in a “fuller” state that significantly compacts and densifies the granules. At the same time, the back mixing and wall slippage is lower compared to GLC which results in compacts being pushed out in a plug-flow manner. Another important aspect to consider between GLC and K90 elements is the free volume within the elements. The GLC element with the same length as K90 (20 mm in our case) has an occupied volume which is 16.8% less than K90 which results in an extra free volume of 16.8% within the 20 mm length of the elements. Assuming that the volumetric flow rate within the extruder is governed by drag flow (due to absence of back pressure flow as no die is used at the extruder discharge) and considering the constant screw speed and feed rate of material, similar volumetric flow rate exist for the powder/granule that enters both K90 and GLC element. However, compared to the K90, the material that enters the GLC has 16.8% higher free volume within the mixing zone (element) that not only undergoes significantly less compaction but also provides more free volume for backmixing through the dispersive recycle flow within the GLC channels that significantly increases mixing efficiency, residence time and considerably higher fragmentation/breakup steps. In the case of K90, the granules are compacted in the overflight of the kneading discs and jammed into a mass by the pressure of incoming material and pushed forward.

3.4 Granule compaction and properties The compactibility and compressibility of the granules of samples made by single K90, single GLC, GLC- GLC and K90-GLC profiles at L/S ratios of 0.3 and 0.4 are shown in Figure 8. The compactiblity of the granules is presented as the tablet tensile strength versus tablet porosity 61. The compactibility is correlated with the ability of the material to form strong interparticulate bonds by powder compression. It is evident that the sample granulated with K90 has a relatively poorer compaction property than other samples at both L/S ratios which is attributed to the lower internal porosity of the sample. The K90 element forms very hard and densified 22

granules (as shown before). In addition, based on the SEM images and particle convexity data, the K90 granules have a relatively smooth outer surface that further limits the inter-particle bond forming capability of the granules. On the other hand, the sample granulated with two GLC elements shows the highest tensile strength as a function of porosity. This superior compactibility of this sample is attributed to its porous structure (as shown in the BET specific surface area and X-ray CT images), the surface irregularities and low convexity which is the characteristic of the samples granulated by GLC element. This surface roughness facilitates the inter-particle bond formation through effective mechanical interlocking mechanism that contributes to formation of stronger tablets. It is worthy to note that compactibility worsened for L/S=0.4 (due to reduction of granule porosity) especially in the case of K90 samples. The compressibility, the variation of porosity of the tablet as a function of compression pressure, represents the granules’ ability to undergo reduction of volume under pressure. Although all the granules show rather similar compressibility, the sample granulated with two GLC element presents a slightly higher compressibility. This could be attributed to the internal porous structure of the granule as well as its higher population of smaller sized granules in the same size fraction (250-425µm) that facilitates easier particle rearrangement and reduction of volume under pressure. Comparing the compactiblity (Figure 8(e)) and compressibility (Figure 8(f)) of the physical mixture with those of the granules, clearly shows that there is a significant improvement in compactibility upon granulation as evident from the low tensile strength plateau observed in the physical mixture which is due to the poor compaction behavior of the ungranulated Albendazole blend. The improved compactibility of granules may be attributed to the presence of a thin layer of HPC on their surface as a result of granulation. Such polymer coating has been shown to be an extremely effective strategy to improve powder tabletability 62. In addition, the variation of compact porosity as a function of compaction pressure (compressibility) shows a minimum plateau above 0.1 porosity which is almost twice as high as that of the granules. This shows that the physical mixture is no longer undergoing volume reduction even under high pressures (300 MPa) due to formation of macrovoids in the powder bed.

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4. Conclusion This study investigated the role of different mixing screw elements and their arrangements in the screw profile on twin screw wet granulation of a formulation containing high dose (50 wt%) of Albendazole as a hydrophobic model drug. It was shown that granulation with GLC element produces granules with relatively smaller size, narrower size distribution and a typical porous microstructure and round shape with rough surface, while the use of K90 kneading element produces elongated granules that are highly densified with relatively larger sizes, broader size distribution and smoother surface. In addition, it was found that the use of GLC elements enhances the distribution of granulating liquid binder within various size fractions of the granules while the granules granulated with conveying and K90 elements have an accumulation of binder in larger size fractions. Higher mixing efficiency of the GLC was further evidenced by analysis of residence time where it was shown that the backmixig and axial dispersion is significantly improved in GLC elements due to its higher free volume and the special geometrical features of this element that allows backward flow (backmixing) through the slotted channels. On the other hand, the use of K90 element resulted in less axial dispersion and shorter residence time and it showed characteristics of a plug flow RTD curve. Finally, the results of the compaction tests revealed that the granules granulated with double GLC element had superior compaction properties due to its porous structure and presence of surface roughness and irregularities while granules densified by K90 (with relatively smoother surface) found to be less compactible.

Acknowledgment This work was supported by PhRMA Foundation. We are thankful to Leistritz Extrusion for their technical support. We would also like to thank DFE Pharma for their kind supply of MCC and lactose monohydrate for this study.

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Graphical abstract

(c)

GLC element

K90 element

Distributive mixing

Dispersive mixing

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(d)

( 3)

( 4)

( 1) ( 2)

Figure 1: (a) the screw profiles used in this study and (b) typical screw element used, (1) 20mm GLC, (2) 20mm K90, (3) 90mm GFA30 (30mm pitch) and (4) 60mm GFA 20 (20mm pitch)

Figure 2: (a) the screw profiles used in this study and (b) typical screw element of the following types: (1) 20mm GLC, (2) 20mm K90, (3) 90mm GFA30 (30mm pitch) and (4) 60mm GFA 20 (20mm pitch)

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Figure 2: (a) Drop penetration into the powder bed as a function of Albendazole content and water contact angle as a function of (b) Albendazole and (c) MCC content

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Figure 3: Particle size fractions of granules extruded with (a) all conveying, (b) K90 and (c) GLC elements and cumulative size distribution for granules extruded with L/S ratio of (d) 0.2, (e) 0.3, (f) 0.4 and (g) convexity of the granules extruded with K90 and GLC at L/S = 0.3

(b)

(a)

500µm

(c)

500µm

500µm

(d)

(

(e)

400µm

1mm

f)

(f)

C0

C1

(g)

C2

C3

C4

*

* 0d

2d

4d

6d

8d

10d

12d

14d

16d

18d

20d

22d

24d

Figure 4: SEM images of granules extruded with (a) K90, (b) GLC, (c) GLC-GLC, (d) all conveying, (e) K90-GLC and (f) SEM images of samples taken from the vent (before the GLC) and (g) after the GLC element in K90-GLC profile

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1mm

1mm

1mm

1mm

Figure 5: Cross section X-ray CT images of granules extruded with (a) GLC and (b) K90 elements. 3D void distribution sideways images of granules extruded with (c) GLC and (d) K90 elements. (The red and green colors show the voids).

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Figure 6: Distribution of dye (binder) for all conveying, K90 and GLC at L/S ratios (a) 0.2, (b) 0.3, (c) 0.4, and for (d) GLC-GLC and (e) K90-GLC screw profiles

Figure 7: (a) a typical distribution of the tracer concentration and the Zusatz function fit on the data, (b) Residence time distribution curve for GLC with L/S ratio of 0.2, 0.3 and 0.4 and K90 at L/S of 0.3

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Figure 8: Compaction (tablet tensile strength versus porosity) properties of granules prepared at liquid to solid ratios of (a) 0.3, (b) 0.4 and compressibility (porosity versus compaction pressure) properties of granules at liquid to solid ratios of (c) 0.3 and (d) 0.4, (e) compactibility and (f) compressibility of physical mixture.

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Table 1: BET specific surface areas of granules produced with K90, GLC and GLC-GLC elements at different L/S ratios.

L/S ratio (w/w) 0.2 0.3 0.4

Specific surface area (m2/g) K90 GLC GLC-GLC 3.203 ± 0.015 4.638 ± 0.016 4.717 ± 0.023 3.086 ± 0.014 4.109 ± 0.010 4.187 ± 0.008 2.743 ± 0.036 3.686 ± 0.025 3.716 ± 0.017

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Table 2: Residence time and Peclet number of granules processed with single GLC and K90 elements.

Element type L/S ratio (w/w) Peclet number Mean residence time(s)

K90 0.3 25.6 25.17

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0.2 27.5 27.53

GLC 0.3 21.5 39.6

0.4 17.1 52.43

Author contribution section Shahab Kashani Rahimi: conceptualization, methodology, validation, formal analysis, investigation, writing-original draft, writing-review & editing, visualization Shubhajit Paul: methodology, investigation, formal analysis, writing-review & editing Changquan Calvin Sun: Resources, writing-review & editing, project administration Feng Zhang: conceptualization, resources, writing-review & editing, supervision, project administration, funding acquisition

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Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

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