Powder and granule characterization

The six samples of MCC were analyzed without prior knowledge of the powder characteristics. It was only communicated that samples were produced using different wood pulps or combinations of different wood pulps as starting materials. Therefore, an extensive powder characterization study was conducted prior to the granulation experiments.

5.2.2.1. Particle size analysis of powders

The particle size distribution (PSD) of the powders was measured by laser diffraction. The wet dispersion method using the 300 RF lens (Malvern Instruments, Malvern, UK) was applied. Prior to the measurement, powder samples were dispersed in Miglyol 812 (triglyceride saturated medium, Fagron, Capelle aan den Ijssel, The Netherlands) with 0.2% Tween 80 (Polysorbate 80, BUFA, Ijsselstein, The Netherlands). PSD results were reported as d10, d50 and d90 values. Furthermore the span was calculated as a measure of distribution width. Span equals (d90-d10) / d50. Measurements were performed in triplicate.

5.2.2.2. Bulk and tapped density of powders and granules

The bulk and tapped density of powders and granules were determined according to the European Pharmacopeia 7.5. Approximately 60 mL of material was poured into a 100 ml graduated cylinder. The powder/granule weight and exact volume were used to calculate

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the bulk density (ρb). Each sample was tapped 10 times, followed by 500 and 1250 times

using an automatic tapping instrument (J. Engelsmann AG, Ludwigshafen am Rhein, Germany). When the difference between the volume after 500 taps differed more than 1 mL from the volume obtained after 1250 taps, 1250 extra taps were conducted. The volume reading was then used to determine the tapped density (ρt). All density measurements were

performed in triplicate and the average densities were calculated.

5.2.2.3. Flowability of powders and granules

The Hausner ratio (H) was used as a measure of flowability (H= ρt/ ρb). Secondly, the

flowability of the raw materials was measured using a RST-XS Schulze ring shear tester (Schulze Schüttgutmesstechnik, Wolfenbüttel, Germany) equipped with a standard 30 mL shear cell. For the powders, the applied normal load at preshear was 2000 Pa. Afterwards shear-stresses of 400, 1000, 1600 and again 400 Pa were applied. A 70 mL cell was used to measure the flowability of the granules with the ring shear tester. Herewith, a preshear of 1000 Pa was applied, followed by stresses of 250, 525, 850 and 250 Pa. The ffc, which is the

ratio of consolidation stress to unconfined yield strength, was used to evaluate the flowability. Measurements were done in triplicate.

5.2.2.4. True density of powders and granules

The true density (ρ) of the MCC samples and granules was determined by helium pycnometry (Accupyc 1330 Pycnometer, Micrometrics, Norcross, USA). A total of ten runs and ten purges was performed per experiment using a purge fill pressure of 19.5 psig.

5.2.2.5. Particle shape of powders

The shape of the powder particles was evaluated by means of scanning electron microscopy (SEM). The images were recorded on a quanta FEG FEI 200 apparatus (FEI Company, The Netherlands). Samples were put on a silicon wafer and sputtered with a thin layer of palladium/gold prior to visualization.

5.2.2.6. Moisture determination of powders

The moisture content of the starting materials was determined by means of volumetric Karl Fischer titration using a V30 volumetric Karl Fischer titrator (Mettler Toledo, USA). Methanol

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(Hydranal, Sigma Aldrich, Germany) was used as medium. The powders were stirred for five minutes prior to titration, and all measurements were done in triplicate.

5.2.2.7. Water sorption of powders

Water sorption measurements were performed using a K-12 tensiometer (Krüss, Germany), equipped with a Krüss Laboratory Desktop v2.0.0.2207. The apparatus was calibrated against double distilled water (γ=72.8 mN/m) using a platinum Wilhelmy plate. The total water sorption of the studied MCC samples was determined using the Washburn method [35], based on liquid penetration into a powder bed (recorded as mass) as a function of time. An alumina capillary (FL12 sample holder, Krüss) with a perforated bottom covered with filter paper was used. About 1.0 to 1.1 g of sample was weighted into the capillary and tapped until constant volume before closing the capillary. Measurements of water sorption were conducted in purified water as medium using a surface detection sensitivity of 0.04 g and a surface detection speed of 6 mm/min. Approximately 100 (2 points/second) of mass versus time data points were recorded during sorption until the maximum mass, which corresponds to the water binding capacity of the studied sample, was achieved (in g water/ g sample). Furthermore water binding capacity (WBC) values (in %) were obtained via FMC Health and Nutrition as such.

5.2.2.8. Degree of crystallinity of powders

X-ray diffraction (XRD) measurements were performed on a Philips X'Pert Pro powder diffractometer (model PW 3040/60). Diffractograms were recorded in the reflection mode in a 2ϑ angular range of 10–40° by steps of ca. 0.02° at room temperature. The Cu Kα radiation (λ = 1.5418 Å) generated at 45 kV and 40 mA was monochromatized using a 20 µm Ni filter. Diffractograms were recorded from rotating specimens using a position sensitive detector. Profile deconvolution was performed with a multiple peak fit tool by using Origin's Peak Analyzer (OriginPro 9, Origin Lab). The fifth-degree polynomial function was used to fit the amorphous background (baseline), and the pseudo-Voigt function was used to express each crystalline reflection [36]. Cellulose crystallinity was determined by calculating the ratio of the separated crystalline peak area to the total reflection area of all signals, including background.

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5.2.2.9. Granule size distribution

Sieve analysis was performed using a Retsch VE 1000 sieve shaker (Haan, Germany), with a series of 8 sieves (150, 250, 500, 710, 1000, 1400, 2000 and 3150 µm). Subsamples (100 g) of granules were sieved for 10 minutes with an amplitude of 2 mm. The amount of granules retained on each sieve was determined and collected. All measurements were performed in triplicate.

5.2.2.10. Friability of granules

The granule friability was determined using a friabilator (PTF E Pharma Test, Hainburg, Germany) at a speed of 25 rpm for 10 min, by subjecting 10 g (w0) of oven-dried granules

together with 200 glass beads (mean diameter = 4 mm) to falling shocks. Prior to determination, the granule fraction of less than 250 µm was removed to ensure the same starting conditions. The glass beads were then removed and the weight retained on a 250 µm sieve (w1) was determined. The friability was calculated as [(w0 – w1 )/w0] * 100.

Measurements were performed in triplicate.