Investigation of the effects of particle size on fragmentation during tableting

Journal Pre-proofs Investigation of the effects of particle size on fragmentation during tableting Anne Linnet Skelbæk-Pedersen, Thomas Kvistgaard Vilhelmsen, Vibeke Wallaert, Jukka Rantanen PII: DOI: Reference:

S0378-5173(19)31046-4 https://doi.org/10.1016/j.ijpharm.2019.118985 IJP 118985

To appear in:

International Journal of Pharmaceutics

Received Date: Revised Date: Accepted Date:

7 October 2019 10 December 2019 19 December 2019

Please cite this article as: A. Linnet Skelbæk-Pedersen, T. Kvistgaard Vilhelmsen, V. Wallaert, J. Rantanen, Investigation of the effects of particle size on fragmentation during tableting, International Journal of Pharmaceutics (2019), doi: https://doi.org/10.1016/j.ijpharm.2019.118985

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© 2019 Published by Elsevier B.V.

Investigation of the effects of particle size on fragmentation during tableting 1,2

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Anne Linnet Skelbæk-Pedersen , Thomas Kvistgaard Vilhelmsen , Vibeke Wallaert , Jukka 2 Rantanen 1 Oral Pilot & Process Development Department, Novo Nordisk A/S, Måløv, Denmark. 2 Department of Pharmacy, University of Copenhagen, Denmark. ABSTRACT

Particle size is a critical parameter during tablet production as it can impact tabletability, flowability, and dissolution rate of the final product. The purpose of this study was to investigate the effect of initial particle size on fragmentation of pharmaceutical materials during tableting. Initial particle size fractions ranging from 0-125 to 355-500 µm of dibasic calcium phosphate (DCP), lactose monohydrate, and agglomerated and non-agglomerated microcrystalline cellulose (MCC) were blended with magnesium stearate and compressed into tablets. Larger initial particle sizes were found to fragment more extensively than smaller initial particle sizes for all materials based on the particle size distributions determined by laser diffraction. DCP was found to fragment most extensively followed by lactose and both MCCs. The fragmentation degrees of DCP, lactose, agglomerated and non-agglomerated MCC reached 95, 81, 32, and 29 %, respectively. These findings were further supported by an increase in specific surface area with increasing compression pressure of compressed particles. The NIR spectral baseline offset from tablets was found to increase with increasing compression pressure up to 50 MPa for all materials, which was the same compression pressure range where fragmentation was observed. The NIR spectral slope from tablets as a function of compression pressure furthermore showed a similar trend as the tabletability profiles. NIR spectroscopy can thereby potentially be used as a surrogate control strategy for assessing compression related particle size changes and possibly tablet density and deformation behavior during tablet production. 1. INTRODUCTION

Tablets are the most widespread solid dosage form in the pharmaceutical industry and are typically manufactured by compression of a powder blend into compacts. During compression a material will undergo deformation, which is a critical part of the tablet formation process (Roberts, 2011). Materials are often classified by their predominant deformation mechanism. Brittle materials such as dibasic calcium phosphate (DCP) deform predominantly by fragmentation during compression, whereas ductile materials such as microcrystalline cellulose (MCC) deform predominantly by plastic deformation (Roberts, 2011). Finally, some materials (e.g. lactose) undergo a non-predominantly combination of fragmentation and plastic deformation (Roberts, 2011). The effect of particle size has been investigated previously and it has been found to impact tabletability, compressibility, dissolution rate, and particle flowability (Roberts, 2011; Sun and Grant, 2001; McKenna and McCafferty, 1982; Tuladhar et al., 1983, Leuenberger et al., 1989, Eriksson and Alderborn, 1995). Larger particles possess better flow properties and are therefore often preferred over smaller particles, as adequate flowability is required to obtain low tablet mass variation during tablet production. Oppositely, smaller particles have been found to decrease fragmentation tendency, increase tabletability, and increase dissolution rate

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(Sun and Grant, 2001, Roberts and Rowe, 2000; Alderborn and Nyström, 1985). The lowered fragmentation tendency of smaller particles is termed the brittle-ductile transition and characterizes the critical size below which fragmenting materials starts to deform predominantly plastically (Sun and Grant, 2001, Roberts and Rowe, 2000, Patel and Kaushal, 2006; Narayan and Hancock, 2005). Furthermore, smaller particles have been found to increase tabletability of plastic deforming materials due to larger specific surface area (SSA) (Sun, 2017; Sun, 2011). Since fragmentation during compression results in smaller particles and thereby larger SSA, the effect of initial particle size on tabletability will be lowered or even eliminated for fragmenting materials (Sun, 2011; Nyström et al., 1993). The Heckel equation is commonly used for assessing the predominant irreversible deformation mechanism of pharmaceutical materials (Heckel, 1961a; Heckel, 1961b). Furthermore, the Hiestand tableting indices, hereunder the brittle fracture index, have been used to describe the deformation properties of materials during tableting (Hiestand and Smith, 1984). The Kuentz Leuenberger equation was later introduced in an effort to improve the ability to describe material compressibility (Kuentz and Leuenberger, 1999). SSA measurements have furthermore been used to determine the predominant irreversible deformation mechanism of pharmaceutical materials after tableting (Cabiscol et al., 2018; Busignies et al., 2011; Masteau and Thomas, 1999). Increase in the SSA was attributed to fragmentation due to generation of smaller particles, whereas decrease in the SSA was attributed to plastic deformation due to reduction and closing of interstitial pores (Cabiscol et al., 2018; Busignies et al., 2011; Masteau and Thomas, 1999). However, SSA analysis for determining deformation of pharmaceutical materials is difficult as it depends not only on changes in particle size but also on particle morphology and surface roughness and may be biased by inaccessible voids inside particles. Computer modeling and related simulations are emerging approaches for evaluating e.g. the density distribution in tablets and deformation properties of pharmaceutical materials (Sun, 2017; Loidolt et al., 2019; Nordström et al., 2018). However, brittle materials make simulation more complex as fragmentation result in new geometries and surfaces, which can be difficult to simulate. Fracture mechanics therefore have to be considered, leading to more complex analysis (Loidolt et al., 2019). Different pharmaceutical materials possess different fragmentation tendencies further complicating this task. Experimental analysis investigating fragmentation behavior of different pharmaceutical materials is therefore required to aid modelling and simulation attempts. This would furthermore allow for fewer experiments and thereby lowering of cost (Loidolt et al., 2019). Near-infrared (NIR) spectroscopy is sensitive to both particle size and tablet density and/or hardness (Pasikatan et al., 2001; Kirsch and Drennen, 1999; Pasquini, 2018). Diffuse reflectance of a powder is dependent on light scattering, which is related to its particle size (Pasikatan et al., 2001). Larger particles allow for deeper penetration of NIR radiation causing an apparent increase in absorption and thereby a decrease in the level of diffuse reflectance, whereas smaller particles will result in an increase in diffuse reflectance (Pasikatan et al., 2001; Kubelka and Munk, 1931). The sensitivity of NIR spectroscopy on particle size

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changes makes it suitable for in-line particle size monitoring in addition to their well-known ability to provide chemical information (Pasikatan et al., 2001). NIR spectroscopy is thus a fast and non-destructive technique that allows for both chemical and physical analysis in-line. Still, one should be cautious when applying NIR spectroscopy for quantitative physical measures, as the technique is more suitable for investigating chemical changes. Khorasani et al. also used NIR chemical imaging to visualize and predict porosity distribution of ribbons at different pressures during roller compaction (2015). While Rantanen et al. (2005) investigated the use of in-line NIR spectroscopy in combination with chemometrics to improve understanding of granule growth during high shear granulation. Morisseau and Rhodes (1997) and Kirsch and Drennen (1999) were the first to investigate the applicability of NIR spectroscopy as a nondestructive technique to determine tablet hardness. Kirsch and Drennen used linear best-fit through each NIR spectrum (1999). The advantages being use of the whole spectrum and thereby averaging out the unduly influence of singular absorbance peaks or bands, and thereby reducing spectral variations to slope and intercept values. The spectral baseline slope was found to evaluate changes in tablet hardness, as harder tablets resulted in higher slope values (Kirsch and Drennen, 1999; Morisseau and Rhodes, 1997). Tanabe et al. (2007) evaluated tablet hardness using chemometrics and found that the loading vector of the first principal component (PC1) reached a plateau and therefore explained a spectral baseline shift. The second principal component was found to explain the slope of the baseline. PC1 and PC2 were therefore attributed to physical changes related to particle size and/or pore volume (Tanabe et al., 2007). A new method for quantification of fragmentation after tableting was recently introduced based on particle size distributions (PSDs) of compressed particles determined by laser diffraction. Here, the effect of compression pressure on PSDs of compressed particles was determined. The fragmentation degrees of one size fraction of DCP, lactose, and MCC were found to be 80, 81, and 15 %, respectively (Skelbæk et al., 2019). However, as particle size previously have been found to impact the fragmentation tendency of pharmaceutical materials (Sun and Grant, 2001), a study determining the fragmentation degree as a function of particle size is required. The purpose of this study was therefore to quantify fragmentation of different initial particle sizes of different deforming materials based on PSDs of compressed particles. In addition, the purpose was to evaluate the applicability of NIR spectroscopy as a surrogate method for investigating fragmentation. 2. MATERIALS

Calcium hydrogen phosphate dihydrate (DCP) (Emcompress®, JRS Pharma, Germany), agglomerated microcrystalline cellulose (MCC200) (Avicel® PH 200, FMC, USA), α-lactose monohydrate (lactose) (Pharmatose 100M, DFE Pharma, Germany), non-agglomerated microcrystalline cellulose (MCC101) (Avicel® PH 101, FMC, USA), and magnesium stearate (MgSt) (Peter Greven GmbH, Germany). 3. METHODS

3.1 Fractionation and blending

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All materials were manually fractionated using Retsch® sieves (Retsch®, Germany). MCC200 and DCP were fractionated to size fractions of 0-125, 125-180, 180-250, 250-355, and 355500 µm, lactose to 0-125, 125-180, and 180-250 µm, MCC101 to 0-90 and >90 µm, and MgSt to 0-90 µm. The various size fractions of DCP and lactose were blended with 5 % w/w MgSt and the size fractions of MCC200 and MCC101 were blended with 10 % w/w MgSt, using a Turbula® mixer (Turbula® T2F, Switzerland) at 25 rpm for 30 min. 3.2 Tableting and grinding All blends were compressed using 10 mm round flat-faced tooling on a Fette 102i instrumented rotary tableting press as in Skelbæk et al. (2019). The blend for each tablet was individually weighed, manually filled into the die and compressed. Tensile strength was determined within 24 hours post compression (Fell and Newton, 1970). Two tablets at a time were manually ground to recover compressed particles as previously described (Skelbæk et al., 2019). Compressed particles were subjected to PSD analysis, NIR spectroscopy, X-ray powder diffraction (XRPD), SSA analysis, and scanning electron microscopy (SEM). 3.3 Particle size distribution (PSD) analysis The PSDs (n=2) of all blends and compressed particles were determined by laser diffraction (Malvern Mastersizer 3000, Malvern Instruments, UK). The particle size from inflection point (PSIP), i.e. the intercept of the tangent at the inflection point with the x-axis on the left side of the main peak of the PSD, was derived for data analysis (Skelbæk et al., 2019). PSIP was subsequently expressed as a function of compression pressure to present the fragmentation profiles. One phase decay was applied for data modeling using GraphPad Prism version 8.0.2 with equations 1 and 2: (1) (2) where Y0 is the initial PSIP before compression, YP is the PSIP at the plateau at infinite pressure and k is the fragmentation rate constant. Furthermore, equation 3 was used to calculate the fragmentation degree (relative YΔ). (3) Analysis of variance (ANOVA) was applied for data analysis using SAS JMP version 12.2. The fragmentation rate constant (k), the plateau (YP), and the fragmentation degree (relative YΔ) were used for statistical evaluations. 3.4 Near-infrared (NIR) spectroscopy of tablets Reflectance NIR spectroscopy was performed on tablets using a Bruker Multi-Purpose Analyzer (MPA, Bruker Optics, USA) and a FT-NIR spectrometer with a spectral range of 833-2630 nm. The spectral resolution was set to 0.3 nm and 32 scans were taken per spectrum. All spectra were measured in duplicate and tablets were rotated between scans. The duplicate scans were averaged and used for data analysis (Kirsch and Drennen, 1999). The NIR spectra analysis was performed in MATLAB (Matlab v. 2016b, Mathworks, Massachusetts, USA) using in-house developed codes. All size fractions of each material were included in a principal component analysis (PCA) model and mean centering was

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performed as pre-processing with a variable selection from 1100-2200 nm (Kirsch and Drennen, 1999). 3.5 Near-infrared (NIR) spectroscopy of compressed particles Reflectance NIR spectroscopy (n=1) was applied on blends and compressed particles. The compressed particles were placed in mini-vials and placed in an auto-sampler. The same equipment, settings and data analysis as listed for the tablets above were used for the compressed particles. 3.6 Specific surface area (SSA) analysis SSAs (n=3) of raw unfractionated materials, blends, and compressed particles were determined by nitrogen adsorption using a Micromeritics ASAP 2020 (Micromeritics®, Norcross, USA). Samples were outgassed under vacuum at 30 ℃ and the outgassing was stopped when the pressure reached 0.05 mmHg. The amount of nitrogen resulting in an adsorbed monolayer was measured at -196 ℃ at ten relative nitrogen pressures (P/P0) from 0.035 to 0.200 (Busignies et al., 2011). The Brunauer, Emmet and Teller (BET) equation was applied for data analysis (Brunauer et al., 1938). 3.7 X-Ray powder diffraction (XRPD) XRPD (n=1) was recorded using an Empyrean X-ray diffractometer (PANalytical, The Netherlands) at 45 kV, 20 mA, and a scanning rate of 0.06° min−1 over a range of 2 – 40 2θ, using CuKα1 radiation of wavelength λ = 1.5405 Å. The full width at half max (FWHM) of the most predominant peaks were calculated by the equipment software. 3.8 Scanning electron microscopy (SEM) SEM analysis was performed on a Hitachi TM3030 Tabletop. The samples were sputter coated with gold (E5200 Auto Sputter Coater, BioRad, UK) for 20 s before microscopy. 4. RESULTS AND DISCUSSIONS 4.1 Changes in particle size after compression The initial PSDs of all materials can be found in the supporting information (Figure S1). Changes in PSDs after compression of the different size fractions blended with MgSt can be seen in Figure 1, 2, 4 and 5 for all materials. The extent of fragmentation was found to increase with increasing initial particle size for all materials and almost all fragmentation happened below 50 MPa regardless of the initial particle size. Compression pressure was therefore limited to around 100 MPa to reduce the force needed for particle recovery although this is lower than what typically is used during tablet production. The high amount of MgSt could possibly lead to different results compared to studies on raw materials but given the very low compression pressures required for fragmentation to occur, MgSt is not expected to have a cushioning effect. DCP was found to fragment extensively (Figure 1), which is in agreement with DCP being a highly fragmenting material (Roberts, 2011). Lactose fragmented to a large extent, but not as much as DCP (Figure 2), which agreed with lactose deforming by a non-predominant

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combination of fragmentation and plastic deformation (Roberts, 2011). A large extent of fragmentation was observed already at 5 MPa for the three largest initial size fractions of DCP (Figure 1). This has earlier been explained by DCP consisting of agglomerates of small primary particles (Bolhuis and Waard, 2016). These were reported to project outward from the center of the agglomerate, and can be expected to break off at the center at low pressures. This explained the extensive fragmentation of DCP occurring already at 5 MPa for the large initial size fractions based on SEM pictures (Figure 3). Unlike DCP, lactose does not consist of agglomerate-like structures likely leading to less fragmentation of lactose at low pressures, and that higher pressure was required to fragment the more isotropic particles of lactose (Figure 3). To investigate the impact of compression on crystallinity, XRPDs were recorded of the crystalline materials DCP and lactose. The full width at half max (FWHM) of the most predominant peak of DCP was found to increase slightly (up to 0.06° 2) with increasing compression pressure (0 to around 100 MPa), thus indicating that some crystallite size reduction occurred upon compression. Oppositely, no changes in FWHM were observed upon compression of lactose. Blend 4 MPa 11 MPa 19 MPa 34 MPa 55 MPa 69 MPa 87 MPa 98 MPa

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Figure 2. PSDs of compressed lactose particles from different compression pressures for three size fractions. SD is shown in error bars.

SEM images of the smallest and largest initial size fraction of DCP and lactose are provided in Figure 3. Fragmentation was observed with increasing compression pressures for both materials, in agreement with the findings from the PSD analysis (Figure 1 and 2). This was furthermore in agreement with previous results (Skelbæk et al., 2019). The particle size of the largest and smallest initial particle sizes of DCP upon compression at around 100 MPa were

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visually comparable (Figure 3). In case of lactose, the particle size was still larger upon compression at around 100 MPa for the largest initial particles than for the smallest initial particles (Figure 3). This reconfirmed that DCP fragmented more extensively compared to lactose. In addition, DCP fragmented to the same minimum particle size regardless of initial particle size in the applied compression setup whereas lactose did not.

Figure 3. SEM images of the smallest and largest initial size fractions of DCP and lactose. The blends and compressed particles are displayed from left to right with increasing compression pressures.

The PSDs of both the agglomerated and non-agglomerated MCC grades were found to shift towards reduced particle size with increasing compression pressure (Figure 4 and 5). A larger shift towards reduced particle size was observed with increasing initial particle size for both MCC grades (Figure 4 and 5). Finally, fragmentation was found to be considerably lower for both MCCs compared to DCP and lactose, as would be expected.

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Based on the SEM images of MCC200 and MCC101, a small decrease in particle size was observed upon compression of the largest size fraction indicating some fragmentation during compression (Figure 6). Furthermore, densification appeared to have occurred above 40 MPa of the largest initial size fraction of MCC200, as the surface seemed denser in terms of a surface smoothening after compression as evident at a magnification of 600 (Figure 6). The SEM images therefore indicated that both fragmentation and densification occurred during compression of MCC200.

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Figure 6. SEM images of the smallest and largest initial size fractions of MCC200 and MCC101. The blends and compressed particles are displayed from left to right with increasing compression pressures.

4.2 Impact of compression on specific surface area (SSA) SSAs of raw materials, blends, and compressed particles as a function of compression pressure are presented in Figure 7. SSAs of blends were found to be higher than their corresponding raw material (Figure 7) due to the presence of MgSt, which had a SSA of 7.6 m²/g (Table S1). Nevertheless, SSA increased with increasing compression pressure for all materials indicating fragmentation to some extent (Figure 7). The relative increase in SSA was larger for DCP and lactose compared to the MCC grades, as would be expected based on the PSDs (Figure 1, 2, 4, 5, and 7). However, as the majority of fragmentation was found to occur below 50 MPa in the PSDs, it was unexpected to observe a further increase in SSA above 50 MPa. This indicated that SSA analysis may not only be sensitive to particle size reductions but also to changes in morphology, surface roughness and access to previously inaccessible voids inside the particles. Furthermore, as most of the investigated materials are porous, the pores and voids inside the particles will potentially have a big impact on the SSA measurements. This was supported by the different initial particle size fractions not being distinguishable by SSA indicating that the SSA was impacted by other parameters than just particle size alone. Still, other researchers have used SSA measurements to investigate fragmentation and the predominant deformation mechanism (Vromans et al., 1987,

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Westermarck et al., 1998). Here, the ratio between tablet pore surface area and the initial powder surface area was used to determine the degree of fragmentation.

Figure 7. SSA as a function of compression pressure of compressed particles of DCP, MCC200, lactose, and MCC101. SSA: specific surface area.

The increase in SSA cannot solely be attributed to fragmentation of the materials under investigation as MgSt alone was found to increase from 7.6 to 13.5 m²/g after compression at 100 MPa (Table S1). MgSt has been stated to consist of plate-like crystals, which are stacked together (Shadangi et al., 2012). These plates have been found to shear off during blending and were therefore also found to do so during tableting and/or particle recovery in this study. However, taking the amount of MgSt in each blend into account the increase in SSA could not be explained by the presence of MgSt alone (Table S1). This was evident, as all SSA measurements of blends compressed at 100 MPa, resulted in larger SSA compared to the calculated SSA (Table S1). These calculations were based on the SSA of raw MgSt after compression at 100 MPa and the relative amount of MgSt and the material under investigation in each blend (Table S1). All the investigated materials were therefore fragmenting. The SSA of the large size fractions of MCC200 leveled off above 50 MPa (Figure 7). This can be explained by densification becoming more pronounced than fragmentation above 50 MPa. This is in agreement with the observations from the SEM images (Figure 6). Furthermore, a systematic effect of particle size on the degree of densification was seen for MCC200, as larger initial size fractions compressed around 100 MPa resulted in more densification (Figure 7). 4.3 Quantification of fragmentation The fragmentation profiles of all the materials can be found in Figure 8 and an overview of the fragmentation rate constants (k), plateaus (YP), and fragmentation degrees (relative YΔ) (eq. 1-3) can be found in the supporting information (Table S2). Almost all fragmentation was found to occur at pressures below 50 MPa for all materials based on the fragmentation profiles (Figure 8). The initial particle size was furthermore found to have a systematic effect

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on the fragmentation rate constants (k) and the fragmentation degree (relative YΔ) as larger initial particles resulted in both faster and more extensive fragmentation. The impact of the initial particle size on the fragmentation degree was, however, found to be different depending on the material (Figure 8, Table S2). This is in good agreement with other researchers investigating the fracture resistance of single particles of different sized paracetamol (Patel et al., 2007). Here, it was found that the resistance to fracture increased with smaller particles, meaning that the pressure required for particle fragmentation was higher the smaller the particles. Hence, larger particles are more likely to fragment when studied as single particles, which is in agreement with the results of this study using many particles recovered after compression. 5 % MgSt/DCP

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DCP fragmented to a constant minimum particle size of 11-14 µm (YP) regardless of the initial particle size (p > 0.05) (Table S2, Figure 8), which was in agreement with the observation from the SEM images (Figure 3). Consequently, fragmentation rates (k) and fragmentation degree (relative YΔ) increased with increasing initial particle size (p < 0.001) (Table S2). The initial particle size of lactose was found to impact the plateau (YP , as larger initial particles resulted in larger YP (p < 0.001) (Table S2, Figure 8). This agreed with the observations from the SEM images (Figure 3). The fragmentation degree (relative YΔ) was not dependent on initial particle size for the two large size fractions (p > 0.05) as it plateaued around 80 %. Finally, larger particles of lactose resulted in faster initial fragmentation rates (k) compared to smaller particles (p < 0.05). Based on these results, the fragmentation patterns of lactose and DCP can be differentiated, as DCP has a minimum particle size which it fragmented to and that was not the case for lactose. The fragmentation degree (relative YΔ) was furthermore found to reach 95 % for DCP, whereas lactose reached a maximum fragmentation degree of 80 %. DCP can therefore be concluded to fragment more extensively than lactose. This differentiation was not possible with the previous use of only one size fraction from 125-180 µm (Skelbæk et al., 2019).

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MCC200 and MCC101 fragmented to much lower degrees than both DCP and lactose, as would be expected due to MCC’s well-known plastic deforming properties (Roberts, 2011). For both grades, larger size fractions increased both the fragmentation rate (k) and the plateau (YP) (p < 0.05). The increase in the plateau can be explained by the low fragmentation degree (relative YΔ), which ranged from 15 to 32 % (Table S2). The PSIP of the smallest initial size fraction of both MCC grades remained constant with increasing compression pressure indicating that no fragmentation occurred below a certain particle size for both MCC grades. In previous work, it was argued that the decrease in PSIP for MCC200 was due to granule rather than particle fragmentation due to fragmentation occurring at compression pressures below 50 MPa (Skelbæk et al., 2019). As fragmentation was observed in this study for MCC101, a non-granulated species of MCC, it can now be concluded that it was not only granule fragmentation occurring. The PSIP approach was thus found applicable for differentiating between rather narrow particle size fractions of the starting materials and further allowed for differentiation of the four investigated materials (Figure 8). However, the method was not able to detect the small decrease in particle size of the smallest initial size fractions of both MCC grades based on the PSIP approach (Figure 4, 5, and 8). This highlights a drawback of the PSIP approach, as it does not consider the observed increase in volume of the main peak with increasing compression pressure. This increase in volume increased the slope at the inflection point meaning that the PSIP remained constant with increasing compression pressure, regardless of the small shift towards smaller particles. The fragmentation profiles should consequently always be co-evaluated with the corresponding PSDs when quantifying fragmentation. The best approach for quantification of fragmentation using PSIP was discussed previously (Skelbæk et al., 2019). Based on this study, the fragmentation degree (relative YΔ) was found to be most suitable for quantifying fragmentation. This was due to it allowing for a comparison between different materials and different initial particle sizes. Furthermore, that it covered the whole pressure range. The limitation of the plateau (Yp) being that it did not highlight the impact of initial particle size of DCP as it fragmented to a constant plateau regardless of initial particles size. Furthermore, it did not include the change in particle size with increasing pressure. Finally, the fragmentation rate constant (k) was highly impacted by fragmentation at low compression pressure rather than the extent of fragmentation. MCC101 above 90 µm was thus found to result in a higher fragmentation rate than any fractions of MCC200 and lactose as MCC101 only fragmented below 20 MPa, regardless of the limited degree of fragmentation of MCC101. 4.4 Effect of initial particle size on resulting particle size The plateau (YP) plotted as a function of the median particle size (D50) of the fractionated raw materials (Figure S1) before blending can be found in Figure 9. Here, a clear distinction was found between the predominantly plastic and fragmenting materials. The plateau of the predominantly plastic deforming MCC grades decreased linearly with decreasing median particle size. It was furthermore interesting to note that the non-agglomerated MCC101 was in

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extension of the agglomerated MCC200. On the other hand, for the highly fragmenting DCP no decrease in plateau was observed. A minor decrease was observed from the largest to the mid-size fraction of lactose. This reaffirmed that lactose deforms by a combination of plastic deformation and fragmentation. Figure 9 can thereby be used to distinguish between different deforming materials.

Figure 9. Plateau (YP) as a function of median particle size (D50) of DCP, MCC200, lactose, and MCC101.

Alderborn (1996) showed that materials have a critical particle size (d crit) from where they start to deform predominantly by plastic deformation when below d crit. MCC and lactose have been reported to have a d crit of 1949 and 45 µm, respectively (Alderborn, 1996). As MCC grades in general have a diameter below this value, MCC is termed a plastic deforming material. The results of this study showed that MCC still fragmented all the way down to a size fraction of 125-180 µm for MCC200 and >90 µm for MCC101 (section 4.1 and 4.3). However, all size fractions of MCCs deformed by less fragmentation compared to the brittle materials. The smallest initial size fraction of lactose was found to fragment slightly during tableting in this study, which agreed with the dcrit of 45 µm found previously (Alderborn, 1996). 4.5 Tablet formation: When PSIP was plotted as a function of tensile strength, it was observed that almost all fragmentation (decrease in PSIP) occurred before the interparticulate bonding and thereby tensile strength started to increase (Figure 10). This is in accordance with earlier results (Khan and Rhodes, 1975; Roberts and Rowe, 1987; Skelbæk et al., 2019). It was argued that irreversible deformation happens almost sequentially, meaning that fragmentation primarily occurred before plastic deformation and thus before bond formation happens (Skelbæk et al., 2019), which previously was termed the brittle-ductile transition (Roberts and Rowe, 1987). This was especially the case for DCP, as the PSIP was nearly constant with increasing tensile strength (Figure 10). Oppositely, for lactose and the largest initial particle size fraction of both MCC grades a further decrease in PSIP was found with increasing tensile strength. Reaffirming that the deformation mechanism of lactose can be defined to be between the highly fragmenting DCP and the highly plastic MCC grades, which correlated with the findings in the fragmentation profiles (Figure 8). Still, one needs to be cautious about the effect of the high amount of MgSt used in this study on tensile strength.

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5 % MgSt/DCP

10 % MgSt/MCC200

250

300

PSIP (µm)

PSIP (µm)

200 150 100

200

100

0-90/125 µm

50 0

0 0.0

0.5

1.0

0.0

Tensile strength (MPa)

5 % MgSt/lactose

1.0

PSIP (µm)

100

50

>90/ 125-180 µm 180-250 µm

10 % MgSt/MCC101 150

150

PSIP (µm)

0.5

Tensile strength (MPa)

250-355 µm 355-500 µm

100

50

0

0 0.0

0.5

Tensile strength (MPa)

1.0

0.0

0.5

1.0

1.5

2.0

Tensile strength (MPa)

Figure 10. PSIP as a function of tensile strength for DCP, MCC200, lactose, and MCC101. SD is shown in error bars. PSIP: particle size from inflection point.

4.6 NIR spectroscopy of tablets The NIR spectra and PCA of tablets of all materials can be seen in Figure 11-14. Tablets compressed below 10 MPa were too fragile to be tested and MCC200 tablets compressed at 100 MPa laminated and were therefore excluded. NIR spectral baseline offset and slope were found to explain the spectral variations in PC1 and PC2, respectively (Figure 11-14), which was in agreement with previously reported results (Tanabe et al., 2007). Based on the PC1 score plots, it was found that PC1 increased with increasing compression pressure for all materials up to 50 MPa after which it leveled off for the brittle materials but decreased for the ductile MCCs (Figure 11-14). The PC1 loading plots were close to constant over the wavelength range and therefore explained the NIR spectral baseline offset. As the formulation remained the same, tabletability profiles showed a different trend and fragmentation happened below 50 MPa in the PSDs, it could be speculated that the change in NIR spectral baseline below 50 MPa was due to fragmentation. Laser diffraction is often used as a reference method to NIR spectroscopy for investigating changes in particle size and could thereby potentially also be used in this study to evaluate the changes in spectral baseline (Pasikatan et al., 2001). Furthermore, the decrease in PC1 above 50 MPa of the ductile MCCs could indicate densification of the plastically deforming particles, which was also observed in the SEM images and SSA analysis (Figure 13, 14, 6, and 7). PC2 for the brittle materials was found to first decrease with increasing compression pressure below 50 MPa from where PC2 started to increase, based on the PC2 score plots (Figure 11 and 12). This decrease in PC2 below 50 MPa was more pronounced for larger initial particle sizes of both brittle materials (Figure 11 and 12). This might be due to the extensive fragmentation observed in the PSDs of the larger initial particle sizes of DCP and lactose (Figure 1 and 2). PC2 of the smallest initial particle size of lactose increased throughout the compression range (Figure 12).

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PC2 of the ductile MCCs was found to increase with increasing compression pressure throughout the compression range (Figure 13 and 14). The differences between the brittle and ductile materials in PC2 below 50 MPa, therefore seemed to match with the predominant deformation mechanisms of the different materials. Based on the loading plots, PC2 was explained by changes in the spectral baseline slope (Figure 11-14), which previously have been correlated to tablet hardness (Kirsch and Drennen, 1999). The increase in PC2 and thereby spectral baseline slope of the ductile materials could therefore potentially be explained by an increase in tensile strength throughout the compression range, whereas the tensile strength of the brittle materials did not start to increase before 30-40 MPa (Figure 1114). These findings showed a similar trend as the results of the tabletability profiles (Figure S2). NIR spectroscopy could thereby potentially serve as a surrogate method during tablet production for investigating tablet hardness and possibly deformation behavior.

Figure 11. NIR spectra (left), score plots (upper right) and loading plot (lower right) of five size fractions of DCP tablets. NIR spectra are colored according to particle size and shaded after compression pressure, darker colors indicate lower pressures. The spectra of the different initial particle size fractions have been offset for visual purposes.

Figure 12. NIR spectra (left), score plots (upper right) and loading plot (lower right) of three size fractions of lactose tablets. NIR spectra are colored according to particle size and shaded after compression pressure, darker colors indicate lower pressures. The spectra of the different initial particle size fractions have been offset for visual purposes.

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Figure 13. NIR spectra (left), score plots (upper right) and loading plot (lower right) of five size fractions of MCC200 tablets. NIR spectra are colored according to particle size and shaded after compression pressure, darker colors indicate lower pressures. The spectra of the different initial particle size fractions have been offset for visual purposes.

Figure 14. NIR spectra (left), score plots (upper right) and loading plot (lower right) of two size fractions of MCC101 tablets. NIR spectra are colored according to particle size and shaded after compression pressure, darker colors indicate lower pressures. The spectra of the different initial particle size fractions have been offset for visual purposes.

4.7 NIR spectroscopy of compressed particles The NIR spectroscopy results of tablets were further supported by the NIR spectra and PCA of compressed particles of all materials (Figure S3, S4, S5, and S6). PC1 was found to decrease with increasing compression pressure for DCP and lactose. This was in accordance with the lower diffuse reflectance of larger particles as described in the Kubelka-Munk theory (1931). Oppositely, increase with increasing compression pressure for MCC200 (Figure S3, S4, and S5). Based on the loading plots it was seen that PC1 was close to constant over the wavelength range for the compressed particles, which again supported that the changes in spectra were due to spectral baseline offset and thereby physical rather than chemical changes (Figure S3, S4, S5, and S6). The water present in the samples was visible at approximately 1940 nm and was explained in PC2 (Figure S3, S4, S5, and S6). Furthermore, for DCP and lactose the spectral baseline offsets were more evident for larger initial particles (Figure S3 and S4), which was in accordance with the results from the PSDs where larger particles were

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found to fragment more extensively than smaller particles (Figure 1 and Figure 2). No or only smaller differences in spectral baseline offset for different sized MCC200 particles were observed (Figure S5). NIR spectroscopy thereby showed promising results as a tool to investigate relatively small particle size changes in rather narrow PSDs and to assess deformation behavior of compressed particles. Initial particle sizes could not be differentiated in the score plot of the compressed particles above 50 MPa for DCP (Figure S3), which resembled the fragmentation profile of DCP (Figure 8) and could again be explained by the extensive fragmentation of DCP observed in the PSDs (Figure 1). This was not the case for MCC200 and lactose, where the initial particle size could be distinguished at all pressures, which again was in good agreement with the fragmentation profiles (Figure 8). MCC101 differed from MCC200 as no clear trends were observed in the NIR spectra and PCA for the compressed particles of MCC101 (Figure S6). The trend observed in the NIR spectra of the tablets (Figure 11-14) appeared to be more stringent compared to the compressed particles, which were more randomly distributed (Figure S3-S6). This can be explained by difficulties in placing the material reproducibly in the mini vial and/or risk of stamping and thereby reducing powder density before testing. Investigating NIR spectroscopy on tablets instead of compressed particles eliminate these risks. 6. CONCLUSIONS The degree of fragmentation was found to increase during compression with increasing initial particle size. The maximum fragmentation degree was 95 % for DCP, 81 % for lactose, and 32 and 29 % for agglomerated and non-agglomerated MCC, respectively, based on the fragmentation profiles. Furthermore, the NIR spectral baseline for tablets of all materials was found to increase with increasing compression pressure up to 50 MPa, which was in agreement with where fragmentation was observed in the PSDs. NIR spectroscopy could thereby possibly be used as a surrogate method to investigate deformation properties and tablet density during tableting. As fragmentation expectedly was found to increase SSA, it would be interesting to investigate the effect of initial particle size and fragmentation degree on dissolution rates of compressed particles of active pharmaceutical ingredients. Finally, the results of this study could be used to verify computer simulations and thereby validate simulation models. ACKNOWLEDGEMENT/CONFLICT OF INTERESTS Novo Nordisk A/S (Bagsværd, Denmark) has financed the PhD project of Anne Linnet Skelbæk-Pedersen (STAR program). Erik Skibsted and Jian Xiong Wu (Novo Nordisk A/S) are acknowledged for valuable insights into NIR experimental setup and NIR data treatment. Thomas Vilhelmsen and Vibeke Wallaert are employed at Novo Nordisk A/S. Jukka Rantanen has not received any consulting fees from Novo Nordisk A/S. ABBREVIATIONS D50

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Median particle size

DCP Dcrit FWHM k MCC101 MCC200 MgSt NIR PCA PSD PSIP Relative YΔ SEM SSA XRPD Y0 YP

Calcium hydrogen phosphate dihydrate Critical particle size Full width at half max Fragmentation rate constant Non-agglomerated microcrystalline cellulose Agglomerated microcrystalline cellulose Magnesium stearate Near-infrared Principal component analysis Particle size distribution Particle size from inflection point Fragmentation degree Scanning electron microscopy Specific surface area X-ray powder diffraction Initial PSIP before compression PSIP at the plateau at infinite pressure

REFERENCES Alderborn, G., 1996. Particle dimensions. In: Alderborn G, Nyström C, eds. Pharmaceutical Powder Compaction Technology. New York, Marcel Dekker. 252-255. Alderborn, G., Nyström, C., 1985. Studies on direct compression of tablets XIV. The effect of powder fineness on the relation between tablet permeametry surface area and compaction pressure. Powder Technol. 44(1), 37-42. https://doi.org/10.1016/00325910(85)85018-X Bolhuis G, Waard H. Compaction properties of directly compressible materials. In: M. Celik, eds. Pharmaceutical Powder Compaction Technology, 2nd ed., United Kingdom: Informa Healthcare 2016. Brunauer, S., Emmett, P.H., Teller, E., 1938. Adsorption of gases in multimolecular layers. J Am Chem Soc. 60(2), 309-319. https://doi.org/10.1021/ja01269a023 Busignies, V., Leclerc, B., Truchon, S., Tchoreloff, P., 2011. Changes in the specific surface area of tablets composed of pharmaceutical materials with various deformation behaviors. Drug Dev Ind Pharm. 37(2), 225-233. https://doi.org/10.3109/03639045.2010.504925 Cabiscol, R., Finke, J., Zetzener, H., Kwade, S., 2018. Characterization of Mechanical Property Distributions on Tablet Surfaces. Pharmaceutics. 10(4), 184. https://doi.org/10.3390/pharmaceutics10040184 Eriksson, M., Alderborn, G., 1995. The effect of particle fragmentation and deformation on the interparticulate bond formation process during powder compaction. Pharm Res 12(7), 1031-1039. https://doi.org/10.1023/a:1016214616042

18 of 29

Fell, J., Newton, J., 1970. Determination of tablet strength by the diametral-compression test. J Pharm Sci. 59(5), 688-691. https://doi.org/10.1002/jpS2600590523 Heckel R.W., 1961a. An analysis of powder compaction phenomena. Trans. Metall. Soc. AIME. 221: 1001–1008. Heckel R.W., 1961b. Density-pressure relationships in powder compaction. Trans. Metall. Soc. AIME. 221(4):671-675. Hiestand, H.E.N., Smith, D.P., 1984. Indices of tableting performance. Powder Technol, 38(2), 145-159. https://doi.org/10.1016/0032-5910(84)80043-1 Jain, S., 1999. Mechanical properties of powders for compaction and tableting: an overview. Pharm Sci Tech Today. 2(1), 20-31. https://doi.org/10.1016/S14615347(98)00111-4 Jonsson, H., Frenning, G., 2016. Investigations of single microcrystalline cellulose-based granules subjected to confined triaxial compression. Powder Technol. 289, 79-87. https://doi.org/10.1016/j.powtec.2015.11.051. Khan, K.A., Rhodes, C.T., 1975. Effect of compaction on particle size. J Pharm Sci. 64(3):444-447. https://doi.org/10.1002/jps.2600640320 Khorasani, M., Amigo, J.M., Sonnergaard, J., Olsen, P., Bertelsen, P., Rantanen, J., 2015. Visualization and prediction of porosity in roller compacted ribbons with near-infrared chemical imaging (NIR-CI). J Pharm Biomed Anal. 109, 11-17. https://doi.org/10.1016/j.jpbS2015.02.008 Kirsch, J.D., Drennen, J.K., 1999. Nondestructive tablet hardness testing by near-infrared spectroscopy: a new and robust spectral best-fit algorithm. J Pharm Biomed Anal. 19(34), 351-362. https://doi.org/10.1016/S0731-7085(98)00132-0 Kubelka, P., Munk, F., 1931. An Article on Optics of Paint Layers. Tech. Physik. 12, 593. Kuentz, M., Leuenberger, H., 1999. Pressure susceptibility of polymer tablets as a critical property: a modified Heckel equation. J Pharm Sci. 88(2), 174-179. https://doi.org/10.1021/js980369a Leuenberger, H., Bonny, J.D., Lerk, C.F., and Vromans, H., 1989. Relation between crushing strength and internal specific surface area of lactose compacts. Int J Pharm, 52(2), 91-100. https://doi.org/10.1016/0378-5173(89)90282-2

19 of 29

Loidolt, P., Ulz, M.H., Khinast, J., 2019. Prediction of the anisotropic mechanical properties of compacted powders. Powder Technol. 345, 589-600. https://doi.org/10.1016/j.powtec.2019.01.048 Masteau, J.C., Thomas, G., 1999. Modelling to understand porosity and specific surface area changes during tabletting. Powder Technol. 101(3), 240-248. https://doi.org/10.1016/S0032-5910(98)00173-9 McKenna, S. McCafferty, D.F., 1982. Effect of particle size on the compaction mechanism and tensile strength of tablets. J Pharm Pharmacol. 34(6), 347-351. https://doi.org/10.1111/j.2042-7158.1982.tb04727.x Morisseau, K.M., Rhodes, C.T., 1997. Near-infrared spectroscopy as a nondestructive alternative to conventional tablet hardness testing. Pharm Res. 14(1), 108-111. https://doi.org/10.1023/A:1012071904673 Narayan, P., Hancock, B.C., 2005. The influence of particle size on the surface roughness of pharmaceutical excipient compacts. Mater Sci Eng. 407(1), 226-233. https://doi.org/10.1016/j.mseS2005.06.060 Nordström, J., Alderborn, G., Frenning, G., 2018. Compressibility and tablet forming ability of bimodal granule mixtures: Experiments and DEM simulations. Int J Pharm. 540(1-2), 120-131. https://doi.org/10.1016/j.ijpharm.2018.02.006 Nyström, C., Alderborn, G., Duberg, M., Karehill, P.G., 1993. Bonding surface area and bonding mechanism-two important factors for the understanding of powder comparability. J Drug Dev Ind Pharm. 19(17-18), 2143-2196. https://doi.org/10.3109/03639049309047189 Pasikatan, M.C., Steele, J.L., Spillman, C.K., Haque, E., 2001. Near infrared reflectance spectroscopy for online particle size analysis of powders and ground materials. J Near Infrared Spec. 9(3), 153-164. https://doi.org/10.1255/jnirS303 Pasquini, C., 2018. Near infrared spectroscopy: A mature analytical technique with new perspectives–A review. Anal Chim ActS. 1026, 8-36. https://doi.org/10.1016/j.acS2018.04.004 Patel, S., Kaushal, S.M., 2006. Bansal AK. Compression physics in the formulation development of tablets. J Crit Rev Ther Drug Carrier Syst. 23(1), 1-66. https://10.1615/CritRevTherDrugCarrierSyst.v23.i1.10 Patel, S., Kaushal, S.M., Bansal, S.K., 2007. Effect of Particle Size and Compression Force on Compaction Behavior and Derived Mathematical Parameters of Compressibility. Pharm Res. 24(1), 111-124. https://doi.org/10.1007/s11095-006-9129-8

20 of 29

Rantanen, J., Wikström, H., Turner, R., Taylor, L.S., 2005. Use of in-line near-infrared spectroscopy in combination with chemometrics for improved understanding of pharmaceutical processes. Anal Chem. 77(2), 556-563. https://doi.org/10.1021/ac048842u Roberts, R.J., 2011. Particulate Analysis–Mechanical Properties. In: Storey RA, Ymén I, eds. Solid State Characterization of Pharmaceuticals, 1st ed., New Jersey: Blackwell Publishing. 357-386. https://doi.org/10.1002/9780470656792.ch10 Roberts, R.J., Rowe, R.C., 2000. Brittle-Ductile Transitions in Sucrose and the Influence of Lateral Stresses During Compaction. J Pharm Pharmacol. 52(2), 147-150. https://doi.org/10.1211/0022357001773788 Roberts, R.J., Rowe, R.C., 1987. Brittle/ductile behaviour in pharmaceutical materials used in tabletting. Int J Pharm. 36(2-3), 205-209. https://doi.org/10.1016/03785173(87)90157-8 Roberts, R.J., Rowe, R.C., Kendall, K., 1989. Brittle—ductile trasitions in die compaction of sodium chloride. Chem Eng Sci. 44(8), 1647-1651. https://doi.org/10.1016/0009-2509(89)80007-7 Shadangi, M., Seth, S., Senapati, D., 2012. Critical roles play of magnesium stearate in formulation development of a highly soluble drug metformin hydrochloride. Int J Pharm Sci Res. 3(4), 1188-1193. https://pdfs.semanticscholar.org/82b8/a97307a22aa595ca77db73262218e999c10b.pdf Skelbæk-Pedersen, S., Vilhelmsen T., Wallaert V., Rantanen J., 2019. Quantification of fragmentation of pharmaceutical materials after tableting. J Pharm Sci. 108(3), 12461253. https://doi.org/10.1016/j.xphS2018.10.040 Sun, C.C., 2011. Decoding powder tabletability: roles of particle adhesion and plasticity. J Adhes Sci Technol. 25(4-5), 483-499. https://doi.org/10.1163/016942410X525678 Sun, C.C., 2017. Microstructure of tablet—pharmaceutical significance, assessment, and engineering. J Pharm Res. 34(5), 918-928. https://doi.org/10.1007/s11095-016-1989-y Sun, C.C., Grant, D.J., 2001. Effects of initial particle size on the tableting properties of llysine monohydrochloride dihydrate powder. Int. J. Pharm. 215(1), 221-228. https://doi.org/10.1016/S0378-5173(00)00701-8 Tanabe, H., Otsuka, K., Otsuka, M., 2007. Theoretical analysis of tablet hardness prediction using chemoinformetric near-infrared spectroscopy. Anal. Sci. 23(7), 857-862. https://doi.org/10.2116/analsci.23.857

21 of 29

Tuladhar, M.D., Carless, J.E., Summers, MP., 1983. The effects of polymorphism, particle size and compression pressure on the dissolution rate of phenylbutazone tablets. J Pharm Pharmacol. 35(5), 269-274. https://doi.org/10.1111/j.2042-7158.1983.tb02932.x Vromans, H., Bolhuis, G.K., Lerk, C.F., van de Biggelaar, H., Bosch, H., 1987. Studies on tableting properties of lactose. VII. The effect of variations in primary particle size and percentage of amorphous lactose in spray dried lactose products. Int J Pharm. 35(1-2), 2937. https://doi.org/10.1016/0378-5173(87)90071-8 Vromans, H., De Boer, S.H., Bolhuis, G.K., Lerk, C.F., Kussendrager, K.D., Bosch, H., 1985. Studies on tableting properties of lactose. Pharm Weekbl. 7(5), 186-193. https://doi.org/10.1007/bf02307575 Westermarck, S., Juppo, A.M., Kervinen, L., Yliruusi, J., 1998. Pore structure and surface area of mannitol powder, granules and tablets determined with mercury porosimetry and nitrogen adsorption. Eur J Pharm Biopharm. 46(1), 61-68. http://dx.doi.org/10.1016/s0939-6411(97)00169-0

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7.1 APPENDICES

Figure S1. PSDs of fractionated MgSt, DCP, MCC200, lactose, and MCC101. Std. error is provided in error bars.

10 % MgSt/MCC200

5 % MgSt/DCP 1.0

Tensile Strength (MPa)

Tensile Strength (MPa)

1.0 0.8 0.6 0.4 0.2

0.8 0.6 0.4

0-90/125 µm

0.2

>90/ 125-180 µm

0.0

0.0 0

50

100

0

Compression pressure (MPa)

100

10 % MgSt/MCC101

5 % MgSt/Lactose

180-250 µm 250-355 µm

2.0

Tensile Strength (MPa)

1.0

Tensile Strength (MPa)

50

Compression pressure (MPa)

0.8 0.6 0.4 0.2

355-500 µm 1.5 1.0 0.5 0.0

0.0 0

50

100

Compression pressure (MPa)

0

50

100

Compression pressure (MPa)

Figure S2. Tabletability profiles of 5 % MgSt/DCP, 10 % MgSt/MCC200, 5 % MgSt/lactose, and 10 % MgSt/MCC101. SD is shown in error bars. Please note different y-axes.

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Table S1. Measured and calculated SSA of raw MgSt, DCP, lactose, MCC200, and MCC101 and blends (mean (SD), n=3).

Measured SSA of raw Calculated SSA of MgSt and average of blends after compression blends after compression at 100 MPa (m2/g) at 100 MPa (m2/g)

Material

Measured SSA of raw material before compression (m2/g)

MgSt

7.591 (0.471)

13.515 (0.290)

-

DCP

0.397 (0.016)

1.511

1.117

Lactose

0.181 (0.008)

1.341

0.922

MCC200

1.344 (0.091)

2.877

1.969

MCC101

1.121 (0.080)

3.012

1.768

Table S2. Fragmentation rate constants, plateaus, and fragmentation degrees of different particle size fractions of DCP, lactose, MCC200, and MCC101 (mean (SD), n=2).

Material, size fraction

Fragmentation rate

k (µm/MPa)

YP (µm)

Fragmentation degree Relative YΔ (%)

DCP, 0-125 µm

0.050 (0.004)

12.3 (0.3)

58.8 (0.8)

DCP, 125-180 µm

0.077 (0.003)

13.9 (0.5)

80.5 (0.4)

DCP, 180-250 µm

0.124 (0.005)

10.8 (0.8)

90.4 (0.1)

DCP, 250-355 µm

0.131 (0.006)

11.4 (1.2)

92.6 (0.2)

DCP, 355-500 µm

0.134 (0.004)

11.2 (1.2)

94.7 (0.3)

Lactose, 0-125 µm

0.039 (0.003)

14.0 (0.6)

62.6 (0.7)

Lactose, 125-180 µm

0.051 (0.003)

15.8 (0.8)

80.7 (0.8)

Lactose, 180-250 µm

0.058 (0.004)

23.6 (1.4)

80.0 (1.6)

MCC200, 0-125 µm

-

25.8 (0.2) *

-

MCC200, 125-180 µm

0.022 (0.006)

74.4 (1.5)

14.6 (2.1)

MCC200, 180-250 µm

0.024 (0.008)

75.6 (3.5)

25.8 (1.7)

MCC200, 250-355 µm

0.035 (0.004)

114.0 (1.5)

27.1 (0.4)

MCC200, 355-500 µm

0.036 (0.004)

163.1 (3.0)

31.9 (0.1)

MCC101, 0-90 µm

-

13.6 (0.2) *

-

MCC101, >90 µm

0.086 (0.009)

29.7 (0.3)

29.2 (0.4)

* Based on the average and SD of the PSIPs at the highest pressure.

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Plateau

Figure S3. NIR spectra (left), score plot (upper right) and loading plot (lower right) of five size fractions of compressed DCP particles. NIR spectra are colored according to particle size and shaded after compression pressure, darker colors indicate lower pressures. The spectra of the different initial particle size fractions have been offset for visual purposes.

Figure S4. NIR spectra (left), score plot (upper right) and loading plot (lower right) of three size fractions of compressed lactose particles. NIR spectra are colored according to particle size and shaded after compression pressure, darker colors indicate lower pressures. The spectra of the different initial particle size fractions have been offset for visual purposes.

Figure S5. NIR spectra (left), score plot (upper right) and loading plot (lower right) of five size fractions of compressed MCC200 particles. NIR spectra are colored according to particle size and shaded after compression pressure, darker colors indicate lower pressures. The spectra of the different initial particle size fractions have been offset for visual purposes.

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Figure S6. NIR spectra (left), score plot (upper right) and loading plot (lower right) of two size fractions of compressed MCC101 particles. NIR spectra are colored according to particle size and shaded after compression pressure, darker colors indicate lower pressures. The spectra of the different initial particle size fractions have been offset for visual purposes.

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ACKNOWLEDGEMENT/CONFLICT OF INTERESTS Novo Nordisk A/S (Bagsværd, Denmark) has financed the PhD project of Anne Linnet SkelbækPedersen (STAR program). Erik Skibsted and Jian Xiong Wu (Novo Nordisk A/S) are acknowledged for valuable insights into NIR experimental setup and NIR data treatment. Thomas Vilhelmsen and Vibeke Wallaert are employed at Novo Nordisk A/S. Jukka Rantanen has not received any consulting fees from Novo Nordisk A/S.

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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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