Léo Picart

Vincent Mazel
email: vincent.mazel@u-bordeaux.fr

Aline Moulin

Vanessa Bourgeaux

Pierre Tchoreloff

product, geometry and process parameters

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Press-coated tablets are pharmaceutical solid dosage forms used for the controlled release of active substances. Usually composed of a core tablet containing the active substance coated in a passive shell, this form allows for a delayed release after the administration of the tablet and specific drug release kinetics [START_REF] Conte | Press-coated tablets for time-programmed release of drugs[END_REF][START_REF] Fukui | Studies on applicability of press-coated tablets using hydroxypropylcellulose (HPC) in the outer shell for timed-release preparations[END_REF]. The reachable lagtime has a great interest for the chronotherapeutics as it makes it possible to treat night symptoms or to release the active substance in a precise place like the colon [START_REF] Lin | Current status and approaches to developing press-coated chronodelivery drug systems[END_REF][START_REF] Maity | Compression-Coated Tablet for Colon Targeting: Impact of Coating and Core Materials on Drug Release[END_REF]. Among other coating techniques, the press-coating is carried out without solvent and offers the possibility to produce at high speeds, which are major advantages in the pharmaceutical industry.

As well as any other type of produced tablets, the mechanical strength of press-coated tablets is a property that need to be measured and followed to guaranty the integrity of the tablet during its life-cycle. This property is measured generally using the diametral compression test, as stated in the European Pharmacopeia <2.9.8>. The diametral compression test has been used for a long time for testing the mechanical resistance of pharmaceutical tablets. It is still today the reference test used at different stages in the industry (development, process monitoring and powder characterization). The experiment consists in applying an increasing compression force to the tablet, along its diameter between two platens, until the tablet breaks.

In the case of flat monolayer tablets, the output of the test is the tensile strength of the tablet, given by the equation [START_REF] Fell | Determination of Tablet Strength by the Diametral-Compression Test[END_REF]

: = 2. . . ( 1
)
where F is the maximal force reached before the tablet breaks, D the diameter of the tablet and t its thickness. It has the advantage of allowing for the comparison of the mechanical strength between different tablets, by varying the powder (particle size, etc.), the formulation (lubricant amount, etc.) or the process parameters [START_REF] Adolfsson | Tablet strength, porosity, elasticity and solid state structure of tablets compressed at high loads[END_REF][START_REF] He | Mechanistic Study of the Effect of Roller Compaction and Lubricant on Tablet Mechanical Strength[END_REF]. Moreover, the tensile strength is an intensive property, i.e. it does not depend on the size of the tablet.

The use of the diametral compression and the calculation of the tensile strength using equation 1 is based on several assumptions, two of them being of major interest in the present case.

First, the tablet should present a tensile failure into two halves along the loading diameter.

Second, the tablet must be homogeneous and must behave as a linear elastic body until failure [START_REF] Fell | Determination of Tablet Strength by the Diametral-Compression Test[END_REF]. If these assumptions may be fulfilled in a case of a single layer tablet, it is obviously not the case for more complex forms. Studies of the use of the diametral compression for bilayer tablets have for example shown that the strength of only one of the layers was in fact tested during the test [START_REF] Castrati | Comparison of breaking tests for the characterization of the interfacial strength of bilayer tablets[END_REF].

The case of press-coated tablets is even more complicated. The press-coated tablets consist of an already compacted core, coated in a shell by powder compression. Due to this particular structure, the densities and mechanical properties are of course not homogenous in the whole compact. The shell itself turns out to have an heterogeneous density after the coatingcompression [START_REF] Ascani | The influence of core tablets rheology on the mechanical properties of press-coated tablets[END_REF][START_REF] Picart | Effect of the compaction parameters on the final structure and properties of a press-coated tablet (Tab-in-Tab): Experimental and numerical study of the influence of core and shell dimensions[END_REF]. Due to this heterogeneity, equation 1 cannot be used to calculate a tensile strength. But even if it is intended to directly use the breaking force detected during the test, the meaning of this force might not be straightforward.

It could indeed correspond to a measure of the strength of the core, of the coating shell or even of the interfacial strength between the two parts of the shell as some non-diametral failures can occur [START_REF] Ascani | The influence of core tablets rheology on the mechanical properties of press-coated tablets[END_REF]. In order to use the test correctly, it is mandatory to correctly identify and interpret the breaking pattern obtained during the test. This was, to our knowledge, never been done in the literature despite a large use of the diametral compression test on press-coated tablets in the industry. Moreover, and particularly with the press-coated tablets, it is a challenge to dispose of a test that can indicate the release attributes of the presscoated tablets. The use of the diametral compression test as an indicator of the release performance of the press-coated tablets might be questioned.

Thus, this study aims to describe and to understand the different failure patterns that can be found during the diametral compression of press-coated tablets. Occurrence of the failure patterns was studied in relation with material properties and coating parameters such as layer thickness and compaction pressure. An experimental and numerical study was carried out to understand the initiation and propagation of the failure, and to explore the role of the process parameters.

Materials and methods

Powders and blend

Two powder mixtures (chosen for the sake of the demonstration) were used in this study. The first one is composed of 99.5% (w/w) microcrystalline cellulose MCC (Vivapur 200, JRS Pharma gmbh, Rosenberg, Germany) and 0.5% magnesium stearate (Partek Mg Lub, Merck, Darmstadt, Germany), and the second one is composed of 99.0% (w/w) granulated lactose monohydrate (Excipress GR150, Armor Pharma, Loudéac, France) and 1.0% magnesium stearate. To homogenize the mixture, the powders were blended during 5 minutes using a Turbula mixer (Wab, Muttenz, Switzerland) set on 49rpm, and were then let 48h at 45% relative humidity (RH) before being used for compaction.

Both powder mixtures were used either to produce the core-tablets or to coat them.

Tablet manufacturing

Compaction simulator

The tablets were manufactured with a compaction simulator Styl'One Evolution (Medelpharm, Beynost, France). This device is a single station instrumented tableting machine. It is fitted with force sensors (accuracy 10 N) on both punches, and the displacements of the punches are monitored using incremental sensors (accuracy 1 µm). The die was filled automatically with a gravity flow feeder containing the powder.

Core compression

The cores were manufactured using euro B flat punches of 8mm diameter. MCC cores were produced at a 150MPa pressure (namely a force of 7.5kN for the chosen punches). Lactose cores were compacted at two different pressures: 150MPa and 300MPa. The three types of cores will be referred in the following text as: MCC150, LAC150 and LAC300 respectively. For all cases, the filling height was adjusted to reach a core thickness of 3.0mm. The core tablets have approximate weights of 198mg, 198mg and 214mg, for MCC150, LAC150 and LAC300

respectively. The three types of core tablets have a solid fraction of 0.831, 0.858 and 0.923 for MCC150, LAC150 and LAC300 respectively.

The core-tablets were let 48h at 45% RH for relaxation before the coating compression.

Coating-compression

All press-coated tablets were manufactured using Euro B round flat punches of 16mm diameter. After the first filling, the core was manually placed on the center of the powder bed.

A minimal tamping force of about 1kN (corresponding to 5MPa) was applied to put the top of the core at the level of the powder bed, prior to the second filling and main compression. Four pressure levels were used for the main compression: 25MPa, 50MPa, 100MPa and 150MPa.

Every coating compression was undergone at a constant punch speed of 12,4mm/s, and no dwell time was applied.

The filling heights were adjusted to have the target thickness of 0.6mm, 1.0mm or 1.8mm for both upper and lower layers after the compression, i.e. the powder over and beneath the core, as drawn on the Figure 1. The corresponding approximate mass of coating powder are given in Table 1.

In the following text, both upper and lower layers will be referred as "layer", as they have the same thickness. Every combination of "core type / shell material / compression pressure / layer thickness" was studied, which resulted in 72 sets of press-coated tablets. For the rest of the study, the press-coated tablets will be designated in the format of the following example: LAC150-MCC -th.1.8mm -100MPa; where "LAC" is the core material, "150" the core compression pressure in MPa, "MCC" the shell material, "1,8mm" the thickness of the layers and "100MPa" the coating-compression pressure.

To ensure the reproducibility of the results, three replicates were produced for each set. The press-coated tablets were let to relax 48h at 45% RH before the characterization.

Diametral compression test and imaging

The diametral compression test was performed using a TA.HDplus texture analyzer (Stable microsystems, Surrey, United Kingdom). Compacts were diametrically compressed between two flat surfaces at a constant speed of 0.5 mm. s -1 until the failure.

A Fastcam Mini high-speed camera (Photron, Tokyo, Japan) was placed in front of the device, and was set to a rate of 1000 images per second to capture the front face of the tablet along the test. Due to the short exposure time of 1ms, the flow of incident light in the camera lens must be high. Therefore, the tablet was strongly lit up by two 70W lamps (Multiled ST, GSVitec, Bad Soden-Salmünster, Germany) during the test. The lamps were switched on a few seconds before the beginning of the test to prevent heating of the tablet.

Digital image correlation

The digital image correlation technique has been widely used in the field of mechanics for assessing the experimental strain fields [START_REF] Lecompte | Quality assessment of speckle patterns for digital image correlation[END_REF]Xu, 2014). This method has also been used in the field of compacted powders and particularly in the pharmaceutical field (Mazel et al., 2016a;[START_REF] Stirling | The application of digital image correlation to Brazilian testing of sandstone[END_REF] and was used in this study to assess the deformation of the tablet surface during the diametral compression test.

Before the diametral compression test, the front surface of the tablets was colored with black ink to create a speckle. This speckle allows for the use of image correlation technique (Mazel et al., 2016b). The images from the high-speed camera were processed using the software Vic-2D (v.6, Correlated Solutions). The chosen output was the normal strain in the direction perpendicular to the loading diameter and parallel to the tablet surface. This strain will be called ε11 in the following text, and corresponds to the normal strain in the direction of the tensile stress that leads to the failure of the tablet.

Numerical modeling

Finite Elements Modeling Abaqus® software (Dassault Systèmes, Vélizy-Villacoublay, France) was used to undergo numerical simulations of the die compression and the diametral compression test of press-coated tablets.

In the same way as different previous studies [START_REF] Picart | Effect of the compaction parameters on the final structure and properties of a press-coated tablet (Tab-in-Tab): Experimental and numerical study of the influence of core and shell dimensions[END_REF][START_REF] Diarra | FEM simulation of the die compaction of pharmaceutical products: Influence of visco-elastic phenomena and comparison with experiments[END_REF], die compression was simulated using the Drucker-Prager-Cap model, with the parameters of microcrystalline cellulose.

For the diametral compression test simulation, a linear elastic model was used to analyze the stress and strain distributions in the tested tablet before failure. The elastic properties of the model were defined according to the die compaction simulations, as presented in Table 2.

The geometry of the tested tablet was simplified in three sections: the core, the layers, and the band (as presented in Figure 1), as the properties are almost homogeneous upon these regions (Figure 2). A mean relative density was chosen for each section, converted into elastic properties and applied to the whole region.

As the geometry, properties and loads are symmetrical, only a quarter of the tablet was modelled and symmetries were applied. Each section was meshed with 3D elements with the properties reported in Table 2, according to a calibration on MCC of a previous work (Diarra et al., 2013). The jaws of the testing device were modelled as an analytical rigid part, on which the force was applied. For the need of the study, two model tablets were submitted to the diametral compression test simulation:

Tablet n°1 : MCC150-MCC -th.0.6mm -50MPa

Tablet n°2 : MCC150-MCC -th.1.8mm -150MPa

Results

Description of the different breaking patterns

When performing the diametral compression test on the different press-coated tablets, four different breaking patterns were found depending on the tablet manufacturing parameters.

These patterns are presented in Figure 3:

A) Total diametral failure (Tot. diam.): the whole tablet, core and shell, breaks along a diametral plan, parallel to the loading diameter. This pattern is the most similar to the classic breaking pattern of a monolayer tablet.

B) Layer lamination (Lam.): the upper layer of the shell is separated from the tablet, along a plan parallel to the tablet face. This breaking profile was already reported for press-coated tablets. [START_REF] Ascani | The influence of core tablets rheology on the mechanical properties of press-coated tablets[END_REF] C) Shell diametral failure (Sh.diam): one layer of the shell or both are broken diametrically. In this case, the core is intact after the failure.

D) Around the core failure (Ar. Core): the crack propagates in the shell, from a loading point to the other and following a path which corresponds to the border of the core. The core is let intact after the failure. diam., Lam., Sh. diam, Ar. core) and "Eject." refers to cases where a crack was already visible just after the ejection from the press, before the diametral compression test. This case, which only occurred for the system MCC150-LAC will be discussed at the start of the next part. In some cells, two patterns are mentioned. It corresponds to cases where the three tablets manufactured using the same parameters did not break the same way. A dash in a cell means that the tablet was not cohesive after ejection and could thus not be studied.

Occurrence of the breaking patterns

As it can be seen in Table 3, both the composition of the tablet and the process parameters have an influence on the breaking pattern observed. Before any interpretation of the pattern, Table 3 shows that the use of the diametral compression test on press-coated tablet is to be taken with caution. Different failure patterns correspond to different failure mechanisms. This means that, the force measured during the test does not have always the same meaning.

Comparisons and interpretations in terms of cohesion should thus be made with caution.

The next part of the study will be focused on understanding the origin of each pattern and the relation between the breaking pattern, the tablet composition and the process parameters.

Discussions

Lamination

At the ejection

Before discussing the failure occurring during the diametral compression test, we would like to focus on the case of the tablets that showed signs of lamination when ejected from the die.

Most of the MCC-LAC tablets showed a crack directly after the ejection, and before the diametral compression test was performed. In these cases, the tablets were considered as already failed and were not studied by diametral compression. This spontaneous fissure is visible on the band, at the upper layer interface (Figure 4.A). A slight cohesion is however kept after the ejection, but the upper face easily tends to separate from the tablet, revealing the fissure path (Figure 4.B). When a lamination at the ejection is observed, it is always located near to the interface between the upper layer and the top part of the band, i.e., the interface between the two powder beds of first filling and second filling. However, the fissure path does not exactly follow the interface plan, but is slightly angled to the core band.

This spontaneous crack might be most probably caused by a difference of elastic recovery between the two powders. The elastic mismatch was already reported to be a cause of the delamination of bi-layer tablets [START_REF] Anuar | Interfacial elastic relaxation during the ejection of bi-layered tablets[END_REF][START_REF] Podczeck | Theoretical and experimental investigations into the delamination tendencies of bilayer tablets[END_REF][START_REF] Busignies | Role of the elasticity of pharmaceutical materials on the interfacial mechanical strength of bilayer tablets[END_REF]. In the case of the bi-layer tablets, the difference of radial recovery creates a residual shear stress at the interface. In the case of press-coated tablets, the difference of axial elastic recovery is more likely to play a role in the failure after decompression [START_REF] Nguyen | Investigation of critical factors affecting mechanical characteristics of press-coated tablets using a compaction simulator[END_REF][START_REF] Picker | Time Dependence of Elastic Recovery for Characterization of Tableting Materials 12[END_REF]. Indeed, if the core material tends to elastically recover more than the shell material, an axial traction stress will appear in the band. If the core tends to recover as much as the shell (or less), this phenomenon shall not be observed. To quantify this thickness recovery, the axial elastic recovery is calculated for monolayer tablets:

% = - ( 2
)
where tout is the tablet thickness measured out of die after the compression; tmin is the minimal in-die thickness that is reached during the compression.

The axial elastic recovery curves, measured on single layer tablets for MCC and Lac can be seen in Figure 5.A. The curves of Figure 5.A show that the axial elastic recovery of MCC is higher than the one of lactose, especially at the studied pressures between 25MPa to 150MPa which is coherent with existing literature [START_REF] Busignies | Role of the elasticity of pharmaceutical materials on the interfacial mechanical strength of bilayer tablets[END_REF]. It is therefore logical to observe the spontaneous failure only in the case of a MCC core and lactose shell tablet.

Lamination during diametral compression test

Beyond this first result, some press-coated tablets have undergone a lamination (case b in

Figure 3) during the diametral compression test. This fracture profile is quite an exception among the others. Indeed this failure mode is the only one where the failure does not occur in a plane normal to the tablet face but in a plane parallel to it. It must be noted that the obtained failure pattern is the same as the one seen previsouly for the lamination at the ejection. It corresponds to a separation of the upper layer of the tablet i.e. the failure occurs in the zone of the interface between the two powders beds used to make the shell as described previsouly.

This lamination only appears for the tablets manufactured at an extremely low compression pressure and with a high layer thickness. These parameters have been identified to cause the lamination breaking profile, but the responsible effects have not been confirmed. However, we can suggest an hypothesis.

Only press-coated tablets with a MCC shell (Table 3.a,b,c) showed lamination in the diametral compression test. Considering the failure pattern, the strength of the layer interface is likely to have a primary role in the lamination. It has been shown in the litterature (Niranjan Kottala et al., 2012) that a MCC-MCC interface is less resistant than a Lactose-Lactose interface for a bilayer tablet. In the same way as the first compression of a bilayer tablet, the tamping of the core of press-coated tablets smoothes powder surface. This smooth surface may not be favorable to the interlocking of the plastic MCC particles, as suggested by Kottala et al.(N. Kottala et al., 2012), especially at low compaction pressure. This effect might be less important for LAC-LAC interface.

The results indicate that even at low pressure, lamination may not occur if the layers are thin enough (e.g. LAC150-MCC 25MPa or MCC150-MCC 50MPa and Th 0,6mm). In these cases, the failure around the core seems to be favored. In fact, the simulations of press-coating show that the band is less dense with thin layers than with a thick layer (Figure 6.A-B). This is very favorable to the failure around the core, as it will be discussed below, and this breaking pattern occurs before the lamination despite a weak interface.

Although interesting regarding the structure and mechanical resistance of press-coated tablets, this breaking pattern has a low probability to be encounterd on industrial tablets.

Indeed, the concerned tablets are obtained under a very low compaction pressure and are characterized by a low cohesion. The next part of the study will now focus on the three other patterns with a failure pattern in the radial direction.

Failures in the radial direction

Digital Image Correlation profiles and crack initiation

Apart from the lamination, the three other breaking profiles show a failure surface normal to the tablet surface. It can be foreseen that the tensile stresses in the direction perpendicular to the loading diameter and parallel to the tablet surface might play an important role in these patterns. Therefore, it was interesting to assess the deformation of the tablet surface in this direction. With the use of Digital Image Correlation, indications about the origin of the crack could be obtained, as well as the development path of the fissure. The processed deformation fields of the tablet surface have been established on Figure 7 for a tablet of each breaking profile: total diametral, shell diametral and around the core. The presented images correspond to a time before the tablet breaks but close enough to the failure to see the surface crack initiation.

The causes of these three profiles, regarding the compaction parameters and mechanical properties in the press-coated tablet, will be discussed in the next parts.

Total diametral failure: a failure of the core

The deformation field from the image correlation (Figure 7.A) seems to indicate a peak of deformation on the center of the face, which was only observed for the tablets that broke with a total diametral failure. It means that the crack opens in the central zone. Given this, for a total diametral failure the initiation of the crack might be situated in the core. If so, the occurrence of the total diametral failure should be influenced by the core mechanical strength, compared to the one of the shell.

Before comparing the core types, it should be noted that for every core-shell pair where the total diametral failure occurs, this pattern only appears at the highest main compaction pressures and layer thicknesses. The increase of compaction pressure obviously increases the density of the shell and its resistance. The influence of the layer thickness is more complex.

As it can be seen in Figure 6, a decrease in the layer thickness promotes a relative increase of the density of the layer and a relative decrease of the density of the band. Thus, it explains why the total diametral failure is less likely to occur with a thin layer: the band is weaker in these cases and could promote a failure in the band before the failure of the core.

The three types of cores were characterized in terms of tensile strength and the results show a highest tensile strength of the MCC150 core (2.7MPa), followed by the LAC300 (2.3MPa), and finally LAC150 (0.9MPa) is the least resistant (Figure 5.B). Moreover, a high loss of resistance of the lactose cores after the coating-compression has been previously demonstrated [START_REF] Picart | Effect of the compaction parameters on the final structure and properties of a press-coated tablet (Tab-in-Tab): Experimental and numerical study of the influence of core and shell dimensions[END_REF], which was much less severe than for the MCC cores. MCC cores should thus be much more resistant than LAC cores.

The influence of the core on the occurrence of total diametral failure can be seen by comparing the tablets with the same MCC shell but different cores: LAC150, LAC300 and MCC150 (Table 3. a, b and c). This comparison clearly shows that total diametral failure appears at lower apparent compression pressure and layer thickness with a less resistant core (e.g. LAC150

vs. LAC300). The total diametral failure does not appear at all with the most resistant core (MCC150). This observation confirms that this breaking profile is most certainly due to a crack initiation located in the core, if a point of the core reaches its breaking stress before any point in the shell does.

Another way of emphasizing the influence of the shell resistance compared to the core resistance, is to compare press-coated tablets that have the same core but a shell with different resistance. In this case, the total diametral failure should appear more frequently when the shell is more resistant. The comparison of the LAC150-MCC and LAC150-LAC tablets (Table 3.a and d) is well suited for this statement. Indeed, as shown on the tabletability curves in Figure 5.B, MCC is much more cohesive than Lactose at every pressure level. Results show that tablets with MCC shell present more total diametral failure patterns than the tablets with a LAC shell. Namely, with layer thicknesses of 1.0mm with a 150MPa pressure and 1.8mm with a 100MPa pressure, the LAC150-MCC showed a total diametral failure while the LAC150-LAC broke around the core.

The observation is the same comparing LAC300-MCC and LAC300-LAC (Table 3.b and e). In these cases of layer thickness/compression pressure, the MCC shell does not break until the lactose core reaches its tensile strength, whereas the lactose shell breaks before the core leading to a failure around the core. This confirms again the hypothesis of a crack initiation located in the core for the total diametral failure.

Fracture in the shell

We will now focus on the two other cases, where the core does not break during diametral compression test (see Figure 3. B and C). In these cases, the experimental deformation fields indicate a fissure initiation close to the loading point, as already demonstrated for cylindrical tablets (Mazel et al., 2016a). However, the crack propagation happens either along the diameter (Figure 7.b), resulting in a shell diametral failure, or surrounding the layer above the core (Figure 7.c), resulting in an around the core profile.

There were three core-shell systems where both profiles were observed according to the manufacturing parameters: LAC150-MCC, LAC300-MCC and MCC150-MCC (Table 3.a, b, c).

The main parameter inducing the one or the other is clearly the layer thickness. With a thin layer (high layer density), the failure tends to follow the path around the core and with a thick layer (low layer density), the diametral path is most likely followed. The numerical simulations of diametral compression test can be used to understand the mechanial causes of these two possible paths.

The first modeled tablet is the MCC150-MCC -thickness 0.6mm -compacted at 50MPa, which is a typical tablet giving rise to the failure around the core. The second considered tablet for numerical modeling is typical of the shell diametral failure and is the MCC150-MCC -Thickness 1.8mm -compacted at 150MPa.

These two modeled tablets have very different dimensions and mechanical properties.

Therefore, to get comparable values of strain, the applied force in the simulation was chosen equal to 20N for the first and to 100N for the second. The results for these two simulations are presented in Figure 8 (a) and (b) respectively, where the chosen output was the σ11 stress fields, i.e., the tensile stress perpendicular to the loading and parallel to the tablet face.

With these two examples, we recognize a high stress concentration near the loading points, that is classically observed during a diametral compression test. However, the stress seems to more develop across the diameter in the case B, where the elastic properties are more homogeneous in the tablet. Also, this stress profile is quite similar to the one of a simple tablet under diametral compression test (Mazel et al., 2016a).

With different mechanical properties and different stress distributions, the strain profiles of these two tablets are of course very different, and are presented in the Figure 9, which output is ε11, the elastic strain in the same direction as the previously presented σ11.

As a reminder, the force applied in the simulation is very inferior to the Breaking force of the tablet to assess the deformation field that develops before the failure. In the case A of Figure 9, the strain clearly develops around the rigid layer, whereas in the case B of Figure 9 where the properties of the different regions are closer, the strain develops diametrically. These two simulation cases represent respectively a tablet that breaks around the core and a tablet with a shell diametral failure, and are in accordance with the strain fields observed experimentally.

Thus, the occurrence of around the core failure can be attributed to the high density difference between the band and the layer regions when the layer is thin [START_REF] Picart | Effect of the compaction parameters on the final structure and properties of a press-coated tablet (Tab-in-Tab): Experimental and numerical study of the influence of core and shell dimensions[END_REF]. In these cases, the highly densified layer constitutes a medium where the propagation of the fissure is more difficult than in the band. Contrary, if the layer is thicker the properties in these regions are closer, and the advantaged propagation path is the shortest: along the diameter.

Further discussion and consequences

The test of a tablet using the diametral compression aims to characterize its mechanical strength. During development, this kind of test is performed to determine if the tablet will be strong enough to avoid defect generation during the post-compaction events (e.g. handling, packaging, etc.). During production, this test is performed to assess if the product obtained is within the specifications. These two approaches are fundamentally different and the results presented above have different consequences on each approach.

The specifications used during production are defined during development. Once defined, the breaking force value is used during production to check if the product performs as expected.

As such, the way the tablet breaks is not really important regarding the quality control during production. Nevertheless, in order to ensure that the product is performing correctly, it would be of interest to verify, in addition to the value of the force, that no modification in the failure pattern occurred.

The results presented in this work have more important consequences for the development stage. First because, depending on the kind of failure obtained, different properties are tested.

For the total diametral failure, the properties of the core are tested whereas for the shell diametral and around the core failures, the results are characteristic of the strength of the shell.

In order to predict the behavior of the tablet during the post-compaction process, the shell properties are the one that matters because the shell will interact with the exterior. But if the total diametral pattern is obtained, i.e. a pattern that mainly tests the resistance of the core, little information will be obtained regarding the objective.

But the problem is even more complicated. When the diametral compression test is applied to a monolayer tablet, the force value can be transformed into a tensile strength value using equation ( 1). This makes it possible to take into account the influence of tablet dimensions on the breaking force obtained. The elastic properties of the tablet have no influence on the relation between the stresses inside the tablet and the force applied during the test. If two tablets have the same dimensions but different composition (i.e. different elastic properties), the ratio between their breaking forces will be the same than the ratio between their tensile strengths. This is no longer true for press-coated tablets. Let's consider the example presented in Figure 10. Figure 10 (A) presents the simulation of MCC150-MCC-th.0.6mm-50MPa, and

Figure 10 (B) shows the case where the tablet has the exact same geometry but with a more rigid core, namely with an elastic modulus of E=2800MPa for the core vs. E=1400MPa in the previous case. In both cases, the same force was applied and the same color scale was kept.

It is clear that, even if the force applied and the dimensions are kept constant, the stress distribution is different in both cases. When the stiffness of the core increases, the stresses increase in the core and decrease in the layer. As a consequence, in order to use this breaking force to characterize the strength inside the tablet, it is mandatory to know the elastic properties inside the tablet, which is very complicated from a practical point of view. Breaking forces obtained during the diametral compression of press-coated tablets are thus very difficult to interpret in terms of actual strength of the tablet.

Finally, and as an opening, the present study opens up the challenge of finding a mechanical test that would be more specific to the press-coated tablets and if possible, partly indicating their release profile. This test should also have an output that is less dependent on the many parameters that can vary in the design of press-coated tablets.

Conclusion

Through this study, it was highlighted that press-coated tablets can break in, at least, four different profiles when submitted to the diametral compression test. The failure pattern depends on the core / shell material and on process parameters: compression pressure and layer thickness. These parameters cause different properties distributions in the press-coated tablet, which result in different crack initiation locations, and different crack propagation paths.

Thanks to digital image correlation, the crack initiations have experimentally been observed at different locations according to the failure profile. These correlate well with the properties fields and stress distribution predicted by the numerical simulations.

Due to these multiple failure patterns, diametral compression test should be used with caution in the case of press-coated tablets. Breaking forces obtained can be characteristic of the core or shell strength depending on the failure pattern. Moreover, it was also shown that even for the same pattern, it might be complicated to compare tablets of different compositions as the relation between the applied force during the test and the stress distribution inside the tablets depends on the elastic properties of the shell and the core. As a consequence, the force output value of the diametral compression test can be used in process monitoring and is likely to indicate an intra-batch or inter-batch deviation, if the manufacturing conditions are close.

Nevertheless, its use during development for characterizing different formulations must be made with caution.

Legend to figures

Figure 1 -Figure 2 -Figure 4 -Figure 5 -Figure 9 -

 12459 Figure 1 -Schematic cross section view of a press-coated tablet and names of the different regions

Table 3

 3

reports the breaking patterns obtained during the diametral compression tests performed on the whole set of press-coated tablets produced in this study. This corresponds to press-coated tablets made of different core and shell, at different pressures and with different layer thicknesses. The four mentioned patterns are referred as explained above (Tot.

Table 1 -

 1 Approximate mass of coating material for the different press-coated tablets

Table 2 -

 2 Elastic properties for the diametral compression test simulations

Table 3 -

 3 Breaking patterns of the press-coated tablets depending on the apparent compression pressure, layer thickness and materials

	Material	Layer thickness	25 MPa	Compression pressure 50 MPa 100 MPa	150 MPa
		0,6mm	N/M	520mg	580mg	620mg
	MCC	1,0mm	660mg	750mg	860mg	890mg
		1,8mm	990mg	1170mg	1350mg	1410mg
		0,6mm	640mg	670mg	700mg	700mg
	LAC	1,0mm	830mg	880mg	900mg	920mg
		1,8mm	1200mg	1310mg	1360mg	1420mg

Table 1 -

 1 Approximate mass of coating material for the different press-coated tablets

		Relative density -from compaction simulation	E (MPa) ν
	MCC150-MCC -th.0.6mm -50MPa	Core section 0.862 Layer section 0.847 Band section 0.595	1517 1407 438	0.3428 0.3357 0.2560
	MCC150-MCC -th.1.8mm -150MPa	Core section 0.920 Layer section 0.920 Band section 0.846	2218 2218 1400	0.3882 0.3882 0.3353

Table 2 -

 2 Elastic properties for the diametral compression test simulations


Aygün Oytun

& Pia

Rämä

Brain signatures of native and non-native words in French-learning 24-month-olds: the effect of vocabulary skills

Keywords: lexical processing, vocabulary skills, phonotactics, event-related potentials, developing brain, toddlers

The event-related potential (ERP) technique provides a temporally accurate measure to distinguish among different linguistic processes. Here, we measured ERPs in response to known words, pseudowords and nonwords in 24-month-old French-learning children to investigate how individual vocabulary skills contribute to the processing of native-like and non-native-like words during a listening task. The N200 was more pronounced for pseudowords than for nonwords while no difference was found between known words and pseudowords. The amplitude difference between known words and pseudowords was, however, correlated with the productive vocabulary. Toddlers with a higher vocabulary score exhibited a bigger difference than toddlers with a lower vocabulary score. Similarly for the frontally distributed late negativity, only those toddlers with higher vocabulary knowledge exhibited a gradient pattern of activity in response to three word types while children with lower vocabulary skills exhibited a similar responsiveness to each word type. Our results suggest that vocabulary skills contribute to the magnitudes of brain signals in response to native and non-native words in a non-referential listening task.

Introduction

Between 6 and 12 months of age, infants improve their ability to discriminate between native phonemes while discrimination of non-native phonemes declines (e.g., [START_REF] Werker | Cross-language speech perception: Evidence for perceptual reorganization during the first year of life[END_REF][START_REF] Kuhl | Infants show a facilitation effect for native language phonetic perception between 6 and 12 months[END_REF]; for a review, see [START_REF] Werker | Perceptual beginnings to language acquisition[END_REF]. Native and non-native phonetic discrimination ability at the age of 7.5 months has been shown to predict later vocabulary development: better native language perception predicted higher productive vocabulary score at 18-and 24-months while better non-native phonetic perception predicted lower vocabulary score [START_REF] Kuhl | Early speech perception and later language development: Implications for the" critical period[END_REF][START_REF] Kuhl | Phonetic learning as a pathway to language: new data and native language magnet theory expanded (NLM-e)[END_REF]. Infants become also sensitive to language-specific phonotactic features of their native language before their first birthday (e.g., Friederici & Wessels, 1993;[START_REF] Jusczyk | Infants′ sensitivity to the sound patterns of native language words[END_REF]. Phonotactic knowledge helps infants to segment words from continuous speech which then allows infants to recognize and understand frequently heard nouns (e.g., [START_REF] Tincoff | Some beginnings of word comprehension in 6-month-olds[END_REF], 2012;[START_REF] Bergelson | At 6-9 months, human infants know the meanings of many common nouns[END_REF][START_REF] Parise | Electrophysiological evidence for the understanding of maternal speech by 9-month-old infants[END_REF]. Vocabulary growth has a slow pace in the beginning but children start to produce new words at a remarkable rate around the end of the second year of life (e.g., [START_REF] Reznick | Rapid change in lexical development in comprehension and production[END_REF][START_REF] Ganger | Reexamining the vocabulary spurt[END_REF].

Consequently, by 24 months children produce (with an extensive individual variation) in average two to three hundred words (e.g., [START_REF] Fenson | MacArthur Communicative Inventories: User's guide and technical manual[END_REF]. At the same time, they also increase the speed and accuracy of native word recognition from speech and lexical representations become more stable [START_REF] Fernald | Rapid gains in speed of verbal processing by infants in the 2nd year[END_REF][START_REF] Fernald | Approaches to Bootstrapping: Phonological, lexical, syntactic and neurophysiological aspects of early language acquisition[END_REF]. On the other hand, the ability to learn non-native words diminishes with age and increasing vocabulary knowledge during the second year of life: 14-month-old infants were capable of associating novel visual items with non-native sounds, while older infants (18-to 20months), especially with higher vocabulary skills, associated only native sounds with novel pictures [START_REF] Graf Estes | Phonotactic constraints on infant word learning[END_REF][START_REF] May | Can a click be a word?: Infants' learning of non native words[END_REF][START_REF] Hay | From flexibility to constraint: The contrastive use of lexical tone in early word learning[END_REF]. Less is, however, known about brain signals associated with processing of phonotactically native and non-native words in the developing brain.

Neuroimaging and electrophysiological techniques, such as near-infrared spectroscopy (NIRS) and event-related potentials (ERPs), have been recently used to study language development in infant populations. These techniques capture linguistic processes even in the absence of an overt (motor or verbal) reaction or attention that are often required in behavioral tasks. While the NIRS detects neural activity with relatively high spatial accuracy, the ERPs measure electrical brain activity in a millisecond range, thus providing a temporally accurate measure of language processes. The ERP components correspond, at least partly, to distinct linguistic sub-processes (e.g., acoustic, phonological, or lexical-semantic) providing a possibility to investigate the timing and the sequence of these processes. Besides, the ERP technique is easily applicable to young children (for reviews see, e.g., [START_REF] Johnson | Recording and analyzing high-density event-related potentials with infants using the Geodesic Sensor Net[END_REF][START_REF] Thierry | The use of event related potentials in the study of early cognitive development[END_REF].

Moreover, several studies have shown that even though the effects were not found behaviorally, the ERPs showed sensitivity to experimental or participant group manipulations (e.g., [START_REF] De Haan | Recognition of the mother's face by six month old infants: A neurobehavioral study[END_REF]Rivera-Gaxiola, Csibra, Johnson, & Karmiolff-Smith, 2000a, b;[START_REF] Kozou | The effect of different noise types on the speech and non-speech elicited mismatch negativity[END_REF][START_REF] Sokka | Job burnout is associated with dysfunctions in brain mechanisms of voluntary and involuntary attention[END_REF] providing further benefits to use the ERPs to map language development.

Increasing word knowledge during the second year of life has been associated with specialized electrophysiological activity. When infants were presented with known and unknown words, the amplitudes of two ERP components, the N200 and N375, were larger for known than for unknown words [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF], 1997;[START_REF] Conboy | Two languages, one developing brain: Event related potentials to words in bilingual toddlers[END_REF]. In younger infants (13-to 17 months), the components were broadly distributed over the scalp [START_REF] Mills | Language comprehension and cerebral specialization from 13 to 20 months[END_REF] while in 20-month-olds they were observed mainly over the left temporal and parietal recording sites [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF]. Also vocabulary skills contributed to the findings: the N200 was more pronounced for known than for unknown words both in low-and high-producers while the difference in the amplitude of the N375 between word types was found only in the high-producers. In bilingual infants, the occurrence and the distribution of ERPs were different for dominant and non-dominant languages [START_REF] Conboy | Two languages, one developing brain: Event related potentials to words in bilingual toddlers[END_REF]. Another ERP study, conducted in 11-month-old English-learning infants, suggested that a more pronounced N2 component in response to familiar words compared to unfamiliar words is associated with an automatic capture of attention towards familiar words [START_REF] Thierry | Familiar words capture the attention of 11month-olds in less than 250 ms[END_REF]. These findings suggest that age, vocabulary skills, and language experience are associated with an increased neural specialization in processing of word meaning.

In a picture-word congruency task, a more pronounced frontally distributed negativity between 100 and 500 ms post word-onset was observed for congruous words, that is, for those words that correctly labeled the pictures when compared to the same words in incongruous picture contexts [START_REF] Friedrich | N400-like semantic incongruity effect in 19-montholds: Processing known words in picture contexts[END_REF][START_REF] Thierry | The use of event related potentials in the study of early cognitive development[END_REF]. Also, a short-term familiarization to previously unknown word-forms augments the magnitude of the N200-500 component in 10-to 12-month-old infants during the test phase (e.g., [START_REF] Kooijman | Electrophysiological evidence for prelinguistic infants' word recognition in continuous speech[END_REF][START_REF] Kooijman | Prosodic structure in early word segmentation: ERP evidence from Dutch ten month olds[END_REF][START_REF] Goyet | Words and syllables in fluent speech segmentation by French-learning infants: An ERP study[END_REF][START_REF] Männel | Prosody is the key: ERP studies on word segmentation in 6-and 12-month-old children[END_REF]. These familiarity effects between 200 and 500 ms after word onset were observed mainly over the frontal recording sites [START_REF] Kooijman | Prosodic structure in early word segmentation: ERP evidence from Dutch ten month olds[END_REF][START_REF] Goyet | Words and syllables in fluent speech segmentation by French-learning infants: An ERP study[END_REF]. While the N200-500 component (or temporally similar early negativity) has been associated with word familiarization and lexical congruence, the N400 component has been linked to more mature lexical-semantic processing, semantic integration, and lexical expectancy both in adults (for review, see [START_REF] Kutas | Thirty years and counting: finding meaning in the N400 component of the event-related brain potential (ERP)[END_REF] and in children (e.g., [START_REF] Friedrich | N400-like semantic incongruity effect in 19-montholds: Processing known words in picture contexts[END_REF][START_REF] Torkildsen | Semantic organization of basic-level words in 20-month-olds: An ERP study[END_REF][START_REF] Rämä | Development of lexical-semantic language system: N400 priming effect for spoken words in 18-and 24-month old children[END_REF][START_REF] Sirri | Cognitive and neural mechanisms underlying semantic priming during language acquisition[END_REF]. The N400 effect (more negative response to incongruent versus congruent stimulus pairs) in adult participants typically appears over the central-posterior recording sites. In young children, the N400 effect has been observed over distributed scalp positions and also in variable time windows from 400 ms to 1200 ms. Some studies have also reported a late frontally distributed negativity, appearing 600 ms to 1200 ms after word-onset (e.g., [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF][START_REF] Mills | Language comprehension and cerebral specialization from 13 to 20 months[END_REF][START_REF] Friedrich | N400-like semantic incongruity effect in 19-montholds: Processing known words in picture contexts[END_REF]Torkildsen, Syversen, Simonsen, Moen, & Lindgren, 2007a). This late component has been suggested to reflect further lexical search [START_REF] Junge | Rapid recognition at 10 months as a predictor of language development[END_REF], lexical-semantic processing (e.g., [START_REF] Friedrich | N400-like semantic incongruity effect in 19-montholds: Processing known words in picture contexts[END_REF] or increased attentional processes during language tasks in young children (e.g., [START_REF] Friedrich | N400-like semantic incongruity effect in 19-montholds: Processing known words in picture contexts[END_REF][START_REF] Torkildsen | Semantic organization of basic-level words in 20-month-olds: An ERP study[END_REF]Torkildsen et al., , 2007a)). Some evidence shows that the infant brain is also differentially responsive to meaningless pseudowords (i.e., nonsense words that obey the phonetic, prosodic, and phonotactic rules of a given language) and to nonwords (i.e., nonsense words that violate phonotactic regularities of a language). The N200 and N375 components were found for pseudowords but not for backwardly presented words in 20-month-old, English-learning infants [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF] while in younger infants (13-to 17-months) no significant difference between pseudowords and backwardly presented words was found [START_REF] Mills | Language comprehension and cerebral specialization from 13 to 20 months[END_REF]. Differences between the two word types were found over the right hemisphere with a broad distribution from anterior to posterior sites. It should be noted that while backwardly presented words serve as a control for the auditory stimuli by having similar physical characteristics of speech stimuli, they violate not only phonotactic, but also phonetic and prosodic features of speech signal. In another study, conducted in 18month-olds, German-speaking infants were presented with monosyllabic pseudowords either with a phonotactically legal or illegal consonant onset structure [START_REF] Steber | So young, yet so mature? Electrophysiological and vascular correlates of phonotactic processing in 18-month-olds[END_REF]. The results demonstrated a larger negativity for legal than for illegal words over the anterior and posterior scalp positions in a time window of 500 ms to 1000 ms. In a lexical-semantic pictureword context, a (short-lived) larger negativity for pseudo-than for nonwords was obtained over the frontal scalp positions in 12-month-olds while only in the 19-month-olds, a larger broadly distributed negativity was found [START_REF] Friedrich | Phonotactic knowledge and lexical-semantic processing in one-year-olds: Brain responses to words and nonsense words in picture contexts[END_REF]. The broadly distributed negativity might reflect a more mature mechanism of semantic integration, in response to phonotactically legal, but not to illegal words [START_REF] Friedrich | Phonotactic knowledge and lexical-semantic processing in one-year-olds: Brain responses to words and nonsense words in picture contexts[END_REF]. Interestingly, only those 19-months-olds whose later language outcome (tested at 30-months) was age-adequate presented a significant difference between the processing of pseudo-and nonwords while children with lower vocabulary knowledge eleven months later did not show differential responses between the word types [START_REF] Friedrich | Early N400 development and later language acquisition[END_REF]. These effects regarding the retrospective language outcome were found over two temporally separate time-windows: between 250 ms and 500 ms, and between 600 ms and 800 ms. To sum up, previous behavioral evidence shows that increasing vocabulary knowledge diminishes the ability to associate novel visual items with phonotactically non-native labels or non-linguistic sounds [START_REF] Graf Estes | Phonotactic constraints on infant word learning[END_REF][START_REF] May | Can a click be a word?: Infants' learning of non native words[END_REF]. There are only a few previous ERP studies that investigated brain signals in response to phonotactically legal versus illegal words in 12 to 20 month old infants [START_REF] Mills | Language comprehension and cerebral specialization from 13 to 20 months[END_REF][START_REF] Friedrich | Phonotactic knowledge and lexical-semantic processing in one-year-olds: Brain responses to words and nonsense words in picture contexts[END_REF][START_REF] Steber | So young, yet so mature? Electrophysiological and vascular correlates of phonotactic processing in 18-month-olds[END_REF]. However, in these ERP studies either stimulus properties or concurrent comprehensive and expressive language skills were not fully controlled or systematically analyzed. The current study aims to clarify whether the magnitudes and the timings of the ERPs in response to pseudowords and nonwords are dependent on vocabulary knowledge to further understand the role of vocabulary in nonnative word processing.

In the present study, 24-month-old, French-learning toddlers were presented with known words, pseudowords and nonwords during the experiment in a non-referential context and their comprehensive and expressive vocabulary skills were evaluated by a parental questionnaire. The participants were presented with four different pseudowords (e.g., "meautai"), four phonotactically illegal nonwords (e.g., "zbaiton"), and four familiar words in French (e.g., "bateau", boat). Our aim was to investigate how comprehensive and productive vocabulary skills contribute to the magnitudes and the timings of the ERPs in response to phonotactically legal and illegal words in French-learning toddlers. Based on earlier behavioral findings [START_REF] Graf Estes | Phonotactic constraints on infant word learning[END_REF][START_REF] May | Can a click be a word?: Infants' learning of non native words[END_REF], we expected that 24 month old Frenchlearning children with higher vocabulary skills would exhibit a larger difference in the amplitudes between the word types indicating a greater sensitivity to word nativeness and meaning also in a non-referential task. Second, we aimed to investigate whether the ERPs are differentially modulated in response to pseudowords and nonwords during the course of the experiment. A short exposure to previously unknown words has been shown to augment the magnitude of the N200-500 component in 10-to 12-month-olds (e.g., [START_REF] Kooijman | Electrophysiological evidence for prelinguistic infants' word recognition in continuous speech[END_REF][START_REF] Goyet | Words and syllables in fluent speech segmentation by French-learning infants: An ERP study[END_REF] while in older infants an increase in the amplitudes of the N200-500 component for novel words was observed only after a referential training task [START_REF] Mills | Watching the infant brain learn words: Effects of vocabulary size and experience[END_REF]. We expected modulations to occur in response to phonotactically legal pseudowords but not in response to phonotactically illegal nonwords.

Material and methods

Participants

The final participant sample included twenty-three (17 girls) 24-month-old children (min: 23 months 7 days, max: 25 months 5 days, mean: 24 months 9 days). All children came from monolingual French-speaking families in the Parisian region. They were recruited through a database of parents who previously volunteered to participate in child development studies. All children were born full-term and none of them suffered from any known hearing or language impairment. Also, there was no atypical development of language in the families. The mean number of years for maternal education was 16 (range from 11 to 19 years). Parents gave written informed consent before participation. Twenty-four other participants were tested but their data were rejected due to noisy (less than ten accepted trials in one experimental condition) electroencephalogram (EEG) recording (n = 14, ), due to technical problems while recording (n = 1), or refusal to put on the EEG cap (n = 9).

The French translation of the MacArthur-Bates Communicative Development Inventory for Words and Sentences (CDI; [START_REF] Fenson | MacArthur Communicative Inventories: User's guide and technical manual[END_REF] was used to measure the productive vocabulary size. The parents were asked to fill the inventory at home during the two weeks following the study. The mean number of produced words was 274 (SD = 190, range from 16 to 686 words) and the mean number of comprehended words was 496 (SD = 143, range from 262 to 751 words). The mean numbers and the ranges were similar to those reported in earlier studies testing French-learning children of the same age (e.g., [START_REF] Rämä | Development of lexical-semantic language system: N400 priming effect for spoken words in 18-and 24-month old children[END_REF][START_REF] Helo | Word Processing in Scene Context: An Event-Related Potential Study in Young Children[END_REF][START_REF] Helo | Influence of semantic consistency and perceptual features on visual attention during scene viewing in toddlers[END_REF]. Based on the median split (467 words for comprehension) of the comprehensive vocabulary inventory scores, the participants were divided into comprehensive language groups: normal-to-high comprehenders (9 girls) and normal-to-low comprehenders (8 girls). Independently, based on the median split (243 words for production) of the productive vocabulary inventory scores, the participants were divided into productive language groups: normal-to-high producers (11 girls) and normal-to-low producers (6 girls). Children in the low comprehender group comprehended on average 378 words (SD = 66, range 262 -449 words) and in the low producer group produced on average 120 words (SD = 77, range 16 -231 words) words while children in the high comprehender group comprehended on average 605 words (SD = 99, range 467 -751 words) and in the high producer group produced on average 415 words (SD = 145, range 243 -686 words). The study was conducted in conformity with the declaration of Helsinki and approved by the Ethics Committee of the University of Paris Descartes.

Stimuli

The audiostimuli consisted of three types of CVCV or CCVCV words: (a) familiar French words (ballon / balɔ ̃ / (ball), cheveux / ʃəvø / (hair), maison / mɛzɔ ̃ / (house), bateau / bato / (boat)), (b) pseudowords (lechon / ləʃɔ , vabeux / vabø, meautai / motɛ, bonsa / bɔ za, and (c) nonwords (vchonbe / vʃɔ bə, chbeula / ʃbøla, bmeausai / bmozɛ, zbaiton / zbɛtɔ ̃ (Table I). Words were selected from three databases: Cross Linguistic Lexical Norms (cdi-clex.org), Stanford Word bank (wordbank.standford.edu) and from our own BabyLab database. Before the experiment, the parents were sent a questionnaire and asked to evaluate if their child understood and/or produced the (familiar) words used in our experiment (among nine other words). They were also asked to express their confidence about the judgement for each word with a 5-point scale (I am sure my child knows the word, I am somewhat confident that my child knows the word, I don't know, I am somewhat confident that my child does not know the word, I am sure my child does not know word). Three parents were not sure whether their child knew one of the words. These children were presented with a visual display of four images, and were asked to point to the correct image after naming. Two of them were able to point to the correct image and were included, one could not, and he was excluded.

Pseudowords and nonwords were constructed by swapping phoneme positions between two word pairs: ballon/balɔ ̃ and cheveux/ʃəvø, and maison/ mɛzɔ ̃ and bateau/bato). As an example, pseudoword /lechon/ was constructed from the words /ballon/ and /cheveux/ by combining the third phoneme of ballon/balɔ , the second phoneme of cheveux/ʃəvø, the first phoneme of cheveux/ʃəvø and the fourth phoneme of ballon/balɔ . Three other pseudowords and also CCVCV nonwords were constructed in a similar manner but an additional consonant was added to CCVCC words to create an illegal onset consonant cluster in French [START_REF] Dell | Consonant clusters and phonological syllables in French[END_REF]. There was no meaning in any of the pseudo-or nonwords. Bi-phoneme (token) frequencies were retrieved from the database Lexique [START_REF] New | Lexique 2: A New French Lexical Database[END_REF]. Average phoneme frequencies and word durations (ms) are shown in Table I. The duration of words varied between 487 ms and 690 ms (mean duration 578 ms, SD = 69 ms). Mean durations of familiar, pseudowords, and nonwords were 561 ms, 526 ms, and 646 ms, respectively.

The words were recorded with TASCAM Linear PCM Recorder (DR-07MKII). The speaker was a female native French phonetician, and she pronounced the words written in the phonetic alphabet. She was asked to pronounce the words slowly, clearly and as neutral as possible. The stimuli were normalised with Praat software (version 6.0.28).

Procedure

Before the testing, parents received a picture book that explained in a child-directed manner what happens during their laboratory visit (e.g., EEG capping, testing session). This book was meant to help both parents and children to be prepared for the testing session. After arriving at the laboratory, the children were allowed to play in the laboratory environment, and they were also familiarized with the EEG cap. During the experiment the child sat on the lap of a parent in a dimly lit room at 70 cm from a computer screen and two loudspeakers from which the sound was delivered. Parents were instructed not to communicate with the child during the experiment. Children were allowed to watch a silent cartoon on the screen throughout the experiment or to play with small toys positioned on the table in front of them during the experiment. Each word (12 words) was presented 60 times during the experiment. Each word type (familiar words, pseudowords and nonwords) included four examples, thus, each child heard each word type 240 times and the total number of stimuli was 720. The presentation order was pseudo-randomised (with consecutive sets of 12 trials) to ensure an even distribution of each word type during the experiment. The same word was never repeated more than twice. The mean stimulus onset asynchrony (SOA) was 1000 ms with a jitter ranging from 950 to 1050 ms. The experiment lasted about 12 minutes.

EEG recording and pre-processing

Continuous electroencephalogram (EEG) was recorded (band-pass was 0.1 -100 Hz, sampling rate was 250 Hz) from 128 electrodes using a Geodesic Sensor Net (GSN, NetStation EGIS V2.0). Impedances were kept below 50 kΩ. EEG was filtered (0.3-30 Hz), segmented (900 ms, beginning 100 ms before target word onset), and ocular artefacts were removed with an ocular artefact removal (OAR) algorithm [START_REF] Gratton | A new method for off-line removal of ocular artifact[END_REF]. The 100-ms prestimulus period determined the baseline for amplitude measures. The epochs including eyemovement artefacts, using the electrodes above and below the eyes, as well as motion artefacts, exceeding ± 180 lV in any channel were excluded. The epochs with more than 30% contaminated channels were also rejected. Individual bad channels were replaced using spherical spline interpolation.

The data was divided into three equal bins according to the number of repetitions of each word type. Each bin consisted of twenty repetitions of each word, thus 80 repetitions of each word type, and lasted about four minutes. The ERPs were analysed for early, middle and late bins. To obtain ERPs, the epochs were averaged separately for each subject, word type (known word, pseudoword, nonword), and phase (early, middle, late). The averaged waveforms were rereferenced to the average of mastoids and baseline corrected. The average waveforms were grand-averaged across all participants. The mean number of accepted EEG epochs was 46

Data and statistics analyses

Similarly to previous literature (e.g., [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF][START_REF] Mills | Language comprehension and cerebral specialization from 13 to 20 months[END_REF][START_REF] Friedrich | Phonotactic knowledge and lexical-semantic processing in one-year-olds: Brain responses to words and nonsense words in picture contexts[END_REF][START_REF] Kooijman | Electrophysiological evidence for prelinguistic infants' word recognition in continuous speech[END_REF][START_REF] Bosseler | Using magnetoencephalography to examine word recognition, lateralization, and future language skills in 14-month-old infants[END_REF], the following three measurement windows were identified from our data: early positivity (time window of 100-250 ms), N200 (time window of 250-500 ms) and late negativity (time window of 500-800 ms). Mean amplitudes were measured over the time-windows post stimulus, relative to a -100 to 0 ms prestimulus baseline period.

Repeated measures analysis of variance (ANOVA) included Word Type (known word, pseudoword, nonword), Phase (early, middle, late), Recording Area (frontal, parietal) and Hemisphere (left, right) as within-subject factors and Productive or Comprehensive Vocabulary Group (separately) as between-subject factors. The mean amplitudes extracted from 16 electrodes over the frontal and the parietal recording areas were included in the statistical analyses. The frontal and the parietal recording sites included the following electrode positions: 12, 13 (FC1), 18, 19 (F1), 20, 24 (F3), 28 (FC5), and 29 (FC3) (frontal left), 5, 112 (FC2), 10, 4 (F2), 118, 124 (F4), 117 (FC6), and 111 (FC4), (frontal right), 52 (P5), 53, 59 (P7), 60 (P3), 61 (P1), 65 (PO7), 66, and 67 (PO3) (left parietal), and 92 (P6), 86, 91 (P8), 85 (P4), 78 (P2), 90 (PO8), 84, and 77 (PO4) (right parietal). The statistical analyses were conducted with SPSS (IBM SPP statistics, version 24) and the Greenhouse-Geisser correction was applied for nonsphericity when appropriate.

Results

Early positivity (P100)

The amplitudes of the P100 were slightly more pronounced for nonwords (mean = 2.52 μV, SD = 3.87 μV) than for known words (mean = 2.10 μV, SD = 3.65 μV) and pseudowords (mean = 2.12 μV, SD = 3.61 μV). There was, however, no main effect of Word Type (F(2, 44) = 0.52, p = 0.588, η 2 = 0.023) or Hemisphere (F(1, 22) = 1.48, p = 0.236, η 2 = 0.063) on the amplitudes of positivity, but the interaction between Word Type and Hemisphere reached the significance (F(2, 44) = 3.48, p = 0.041, η 2 = 0.137). In further analyses, however, significant main effect of Word Type were not observed either over the left (F(2, 44) = 0.92, p = 0.402, η 2 = 0.040) or the right (F(2, 44) = 0.52, p = 0.590, η 2 = 0.023) hemisphere, suggesting that the P100 is not modulated by word type (Fig. 1).

When we re-examined the positivity with Productive and Comprehensive Vocabulary Groups as between subject variables, we observed, besides the interaction between Word Type and Hemisphere (Comprehension: F(2, 42) = 3.40, p = 0.045, η 2 = 0.139; Production: F(2, 42) = 3.37, p = 0.046, η 2 = 0.138), an interaction between Word Type and Comprehensive Vocabulary Group (F(2, 42) = 3.85, p = 0.037, η2 = 0.155). The amplitudes were more positive for nonwords than for pseudowords in the normal-to-low comprehenders (t(10) = -2.31, p = 0.044, d' = 0.773) while in the normal-to-high comprehenders, there was a tendency for more positive amplitudes for pseudowords than for nonwords (t(11) = -2.09, p = 0.061, d' = 0.624). Also, an interaction between Hemisphere and Productive Vocabulary Group (F(1, 21) = 5.96, p = 0.024, η2 = 0.221) was found. However, even though the amplitudes were larger over the right hemisphere in the high-vocabulary group and larger over the left hemisphere in the lowvocabulary group, significant differences between the left and right hemispheres in either vocabulary group were not found (all p > 0.05).

Figure 1 here

N200

The amplitudes of the N200 were more negative for known words (mean = -0.98 μV, SD = 4.61 μV) and pseudowords (mean = -1.22 μV, SD = 4.80 μV) than for nonwords (mean = 1.02 μV, SD = 4.58 μV). The main effect of Word Type (F(2, 44) = 9.95, p = 0.000, η 2 = 0.311) and the interaction between Word Type and Recording Area was significant (F(2, 44) = 12.35, p < 0.001, η 2 = 0.359) on the amplitudes of the N200. The main effect of Word Type was observed over the frontal (F(2, 44) = 17.98, p < 0.001, η 2 = 0.450) but not over the parietal (F(2, 44) = 2.85, p = 0.072, η 2 = 0.115) recording sites (Figs. 1 &2). The amplitudes were significantly more negative for known words than for nonwords (t(22) = -5.03, p < 0.001, d' = 0.973) over the frontal recording sites (Fig. 3 A). The difference between pseudowords and nonwords was also significant (t(22) = -4.63, p < 0.001, d' = 0.907) while no difference was found between known words and pseudowords (t(22) = -0.97, p = 0.341, d' = 0.199). No other main effects (Phase or Hemisphere) or interactions were observed.

When we re-examined the N200 component with Productive and Comprehensive Vocabulary Groups as between subject variables over the frontal recording sites, we observed, besides the main effect of Word Type (Comprehension: F(2, 42) = 19.18, p < 0.001, η 2 = 0.477; Production: F(2, 42) = 18.14, p < 0.001, η 2 = 0.463), the main effect of Comprehensive Vocabulary Group (F(1, 21) = 9.18, p = 0.006, η2 = 0.304). The amplitudes were significantly more negative in the normal-to-low than in the normal-to-high comprehenders (t(21) = 3.03, p = 0.006, d' = 0.814, Fig. 3 C). Even though the interaction between Word Type and Vocabulary Group was not significant ((F(2, 42) = 2.20, p = 0.132, η2 = 0.095), we calculated correlations between vocabulary scores and differences in amplitudes between two word types (known words minus pseudowords, known words minus nonwords, and pseudowords minus nonwords). The results showed that the number of produced words correlated with the difference in amplitudes between known words and pseudowords. The bigger the difference was in the amplitudes (more negativity for known words than for pseudowords), the bigger the productive vocabulary size was (r = -0.597, p = 0.003) indicating that children with higher vocabulary skills were more sensitive to word meaning. No other correlations were found.

Late negativity

The amplitudes of the late negativity were more pronounced for known words (mean = -3.45 μV, SD = 5.50 μV) and for pseudowords (mean = -3.25 μV, SD = 5.03 μV) than for nonwords (mean = -2.36 μV, SD = 4.84 μV). The main effect of Word Type (F(2, 44) = 2.51, p = 0.104, η 2 = 0.102) was not significant on the amplitudes of the late negativity, but the interaction between Word Type and Recording Area reached significance (F(2, 44) = 8.95, p = 0.001, η 2 = 0.289). Similarly to the N200, the main effect of Word Type was observed over the frontal (F(2, 44) = 5.58, p = 0.014, η 2 = 0.202) but not over the parietal (F(2, 44) = 2.01, p = 0.147, η 2 = 0.084) recording sites (Fig. 1 &2). The amplitudes were more negative for known words than for nonwords (t(22) = -2.67, p = 0.014, d' = 0.480) over the frontal recording sites (Fig. 3 B).

The difference between pseudowords and nonwords was almost significant (t(22) = -2.07, p = 0.050, d' = 0.397) while no difference was found between known words and pseudowords (t(22) = -1.88, p = 0.074, d' = 0.374). No other main effects (Phase or Hemisphere) or interactions were observed.

When we re-examined the late negativity with Productive and Comprehensive Vocabulary Groups as between subject variables over the frontal recording sites, we observed, besides the main effect of Word Type (Comprehension: F(2, 42) = 5.28, p = 0.017, η 2 = 0.201; Production: F(2, 42) = 6.11, p = 0.008, η 2 = 0.225), a significant interaction between Word Type and Productive Vocabulary Group (F(2, 42) = 5.10, p = 0.016, η2 = 0.196). There was a significant difference between amplitudes for known words and nonwords (t(11) = -3.51, p = 0.005, d' = 0.949), and pseudowords and nonwords (t(11) = -2.73, p = 0.020, d' = 0.782) in normal-to-high word producers (Fig. 3 D). Also, the difference between known words and pseudowords almost reached the significance (t(11) = -2.11, p = 0.059, d' = 0.652). No significant differences were found in the normal-to-low word producers (all p > 0.05). The results indicate that the late negativity was modulated as a function of word type only in the group of normal-to-high producers. Moreover, there was a tendency for correlation between productive vocabulary skills and the difference in amplitudes between words and pseudowords.

The bigger the difference was in the amplitudes, the bigger the productive vocabulary size was.

However, the correlation did not quite reach statistical significance (r = -0.402, p = 0.057). No other correlations were found.

Discussion

In the present study, we investigated the effects of comprehensive and productive vocabulary skills on brain activity in response to known words, pseudowords and nonwords during the course of an ERP experiment in French-learning toddlers. The N200 was more pronounced for pseudowords than for nonwords while no difference was found between known words and pseudowords. The amplitude difference between known words and pseudowords was, however, correlated with the productive vocabulary. Toddlers with a higher vocabulary score exhibited a bigger difference than toddlers with a lower vocabulary score. Also, the amplitude of the frontally distributed late negativity, measured in the time window of 500 ms to 800 ms, was modulated by an interaction between word type and vocabulary group: children with higher (productive) vocabulary knowledge exhibited a gradient pattern of activity in response to different word types while children with lower vocabulary skills responded similarly to each word type. There are only a few earlier ERP studies investigating brain signals in response to phonotactically illegal nonwords in an explicit [START_REF] Friedrich | Phonotactic knowledge and lexical-semantic processing in one-year-olds: Brain responses to words and nonsense words in picture contexts[END_REF] or an implicit [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF][START_REF] Steber | So young, yet so mature? Electrophysiological and vascular correlates of phonotactic processing in 18-month-olds[END_REF] experimental context in a similar age group. The effects of concurrent vocabulary skills were not systematically evaluated in these studies. In accordance with earlier findings, our results showed that the N200 and late negativity were larger for pseudowords than for nonwords, suggesting that phonotactically legal pseudowords activate lexical search more efficiently than illegal nonwords also in 24-month-old toddlers. In addition, our results provided further evidence about the influence of concurrent vocabulary skills on processing of pseudowords and nonwords.

A negative component around 200 to 500 ms after word onset has been earlier associated with word recognition, word meaning, familiarity, and learning [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF][START_REF] Mills | Language comprehension and cerebral specialization from 13 to 20 months[END_REF][START_REF] Friedrich | Phonotactic knowledge and lexical-semantic processing in one-year-olds: Brain responses to words and nonsense words in picture contexts[END_REF][START_REF] Kooijman | Electrophysiological evidence for prelinguistic infants' word recognition in continuous speech[END_REF][START_REF] Kooijman | Prosodic structure in early word segmentation: ERP evidence from Dutch ten month olds[END_REF][START_REF] Goyet | Words and syllables in fluent speech segmentation by French-learning infants: An ERP study[END_REF][START_REF] Männel | Prosody is the key: ERP studies on word segmentation in 6-and 12-month-old children[END_REF]. Our results showed that the vocabulary group had the main effect on the N200 amplitudes: the amplitudes were more negative for normal-to-low than for normal-tohigh comprehenders, regardless of the word type. This finding is interesting in the light of previous evidence showing that the N200 in response to lexical priming (higher negativity for congruent versus incongruent lexical items) was shown to be more pronounced in infants at a familial risk of dyslexia [START_REF] Torkildsen | Brain responses to lexical-semantic priming in children at-risk for dyslexia[END_REF]) and in infants with lower language skills [START_REF] Friedrich | Early N400 development and later language acquisition[END_REF]. The enhanced lexical priming effect in children with lower vocabulary skills was suggested to be due to a slower or more effortful lexical-phonological processing [START_REF] Friedrich | Early N400 development and later language acquisition[END_REF]. Our results further suggest that more effortful processing in children with lower vocabulary skills might explain the increased N200 also in a non-referential experimental condition. The N200-500 is typically observed over the frontal sites, and it is larger for familiar or known words compared to unknown words. In the current experiment, the negative response between 250 and 500 ms was larger for phonotactically familiar compared to phonotactically unfamiliar words but equally strong for known words and for pseudowords. A similar finding regarding known words and unfamiliar words has been earlier reported in 17-to 21-month-old English learning infants [START_REF] Mills | Watching the infant brain learn words: Effects of vocabulary size and experience[END_REF]. The authors suggested that the use of infant directed speech in their study may have boosted attention towards the unfamiliar words thereby masking effects of semantic processing of familiar words. In our study, the words were not pronounced in infant directed speech so participants' word knowledge is a more likely explanation than a boosted attention towards pseudowords.. The amplitude difference between known words and pseudowords was shown to be correlated with productive vocabulary skills, demonstrating that the higher the vocabulary score was, the bigger the difference was in amplitudes between known and pseudowords. In toddlers with higher vocabulary scores, the amplitude was more negative for words than for pseudowords while in toddlers with lower vocabulary scores, the amplitudes for known and pseudowords were similar than for pseudowords in high producers. Even though all the participants, independent of their vocabulary score, knew the experimental words, the strength of word representations as well as the age of their acquisition might have differed in the two groups, that could explain the correlation effect.

The amplitude of the late negativity, measured in the time window of 500 to 800 ms, was modulated by an interaction between lexical status and vocabulary group: children with higher (productive) vocabulary knowledge exhibited a gradient pattern of activity in response to different word types while children with lower vocabulary skills exhibited a similar responsiveness to each word type. Earlier research has shown that vocabulary skills modulate the occurrence (e.g., [START_REF] Torkildsen | Brain dynamics of word familiarization in 20-month-olds: Effects of productive vocabulary size[END_REF][START_REF] Rämä | Development of lexical-semantic language system: N400 priming effect for spoken words in 18-and 24-month old children[END_REF]), distribution (e.g., Mills et al., 1993[START_REF] Thierry | The use of event related potentials in the study of early cognitive development[END_REF], and timing (e.g., [START_REF] Junge | Rapid recognition at 10 months as a predictor of language development[END_REF] of the language-related ERPs. For instance, 20-month-old toddlers with high productive vocabularies presented an N400 incongruity effect to violations of newly trained associations between novel words and pictures, whereas 20-month-olds with low productive vocabularies did not [START_REF] Torkildsen | Brain dynamics of word familiarization in 20-month-olds: Effects of productive vocabulary size[END_REF]. Also, the N400 priming effect for spoken words was obtained in 24-month-olds and a subgroup of 18-month children with normal-to-high productive skills, which suggests that more advanced productive vocabulary skills contribute to the taxonomic organization of the developing lexical-semantic system [START_REF] Rämä | Development of lexical-semantic language system: N400 priming effect for spoken words in 18-and 24-month old children[END_REF].

Children with lower vocabularies have been shown to present a bilateral or a more scattered distribution of ERPs in response to known and unknown words than children with higher vocabularies, suggesting that neural networks become more specialized with increasing vocabulary skills [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF][START_REF] Mills | Watching the infant brain learn words: Effects of vocabulary size and experience[END_REF]. Moreover, it has been shown that, even though both high and low vocabulary groups displayed a familiarity effect at the time window of 200 ms to 500 ms, only infants with greater vocabularies continued to exhibit the effect at a later time window from 500 ms to 650 ms which led the authors to suggest that the extended response might reflect an additional processing stage related to lexical search for the word [START_REF] Junge | Rapid recognition at 10 months as a predictor of language development[END_REF]. Our results demonstrated the amplitude difference between pseudowords and nonwords both at the earlier and the later time windows, suggesting that both word (phonotactic) familiarity and lexical search processes were affected by vocabulary knowledge. However, even though the ERP technique provides a temporally accurate measure to distinguish among different (linguistic) processes and track their time courses (Kutas & Federmeier, 20110), several cortical processes and components contribute to the scalp distribution of the ERP responses (for review, see Näätänen & Picton, 1987). Accordingly, our results do not suggest that there are two distinct neural processes and further investigations are needed to distinguish between different cognitive and neural events underlying the waveforms.

In accordance with earlier findings in 11- [START_REF] Thierry | Familiar words capture the attention of 11month-olds in less than 250 ms[END_REF] and 20- [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF] month-olds, the P100 was insensitive to word type also in our study. Previously, the P100 was shown to be more pronounced over the left hemisphere in 20-month-olds [START_REF] Mills | Language acquisition and cerebral specialization in 20-month-old infants[END_REF] and in 13-to 17-month-olds with higher comprehension skills [START_REF] Mills | Language comprehension and cerebral specialization from 13 to 20 months[END_REF] while in 13-to 17-month-olds with lower comprehension skills, the P100 was bilaterally distributed [START_REF] Mills | Language comprehension and cerebral specialization from 13 to 20 months[END_REF], suggesting that age and vocabulary skills contribute to a more focalized, left-hemispheric, distribution of activity. In our study, the distribution of the P100 was not asymmetrically distributed. Also, none of the components were modulated during the course of the experiment.

Earlier studies have demonstrated that only a few repetitions of novel words cause an increase in negativity both in explicit (Friedrich & Friederici, 2011;Junge, Cutler & Hagoort, 2012) and implicit (e.g., [START_REF] Kooijman | Electrophysiological evidence for prelinguistic infants' word recognition in continuous speech[END_REF][START_REF] Kooijman | Prosodic structure in early word segmentation: ERP evidence from Dutch ten month olds[END_REF]) tasks, at least in younger infants. In older infants, an increase in N200-500 amplitude was observed only when the novel words were paired with new objects, not when repeated in isolation [START_REF] Mills | Watching the infant brain learn words: Effects of vocabulary size and experience[END_REF]. Similar to our finding, a greater negativity in response to pseudowords than to nonwords (when repeated in isolation) was not modulated during the course of the experiment in 18-month-olds [START_REF] Steber | So young, yet so mature? Electrophysiological and vascular correlates of phonotactic processing in 18-month-olds[END_REF]. There are at least two possibilities to explain the lack of modulation in our study: it is possible that the modulation in toddlers occurs only in the presence of a referential learning, or modulation occurs already after presentation of a few items and thus not detectable in our study.

To conclude, our results demonstrated that frontally distributed N200 and late negativity were modulated by word type and vocabulary skills. The responses were more pronounced for pseudowords than for nonwords while no difference was found between known words and pseudowords. However, vocabulary knowledge affected toddlers' reactivity to different word types: only toddlers with larger vocabularies exhibited a gradient pattern of signal magnitude in response to different word types. It has been earlier suggested that children with less vocabulary knowledge might have less detailed phoneme perception [START_REF] Graf Estes | Phonotactic constraints on infant word learning[END_REF] or weaker memory representations for native phoneme clusters [START_REF] Friedrich | Early N400 development and later language acquisition[END_REF]. Also, accumulation of vocabulary and phonotactic knowledge may limit the pertinent lexical candidates to be learnt and children with larger vocabulary are more likely to reject phonotactically illegal labels in a word learning task [START_REF] Graf Estes | Phonotactic constraints on infant word learning[END_REF]. Based on our findings, we further propose that vocabulary knowledge contributes to the processing of nativelike and non-native-like words in a non-referential task both at the level of word recognition and lexical search. Our results also support the use of ERP technique to investigate temporal sequences of linguistic processes in developmental populations.

(

  range: 23-73; SD = 15), 46 (range: 20-73; SD = 15), and 45 (range: 20-72; SD = 16) for the known words, native pseudowords, and non-native pseudowords, respectively. The mean number of accepted EEG epochs was 48 (range: 25-72; SD = 16), 46 (range: 15-72; SD = 17), and 43 (range: 16-73; SD = 18) for the early, middle, and late bin, respectively. The mean number of accepted trials was not significantly different among the word types (one-way ANOVA: F(2, 68) = 0.004, p = 0.996) or bins (one-way ANOVA: F(2, 206) = 0.485, p = 0.618).

  Figure 2 here

  Figure 3 here

Fig. 1 .

 1 Fig. 1. The grand-average ERPs to known words (dashed lines), pseudowords (thick lines), and

Fig. 2 .

 2 Fig. 2. Isopotential maps showing the across-participants calculated scalp distributions of the

Fig. 3 .

 3 Fig. 3. A. Mean amplitudes for the N200 over the frontal recording sites for known words,

Table 1 :

 1 Average Biphoneme Frequency, Word Frequency and Duration of the Stimuli

	ballon /balɔ /	6469	27	506
	maison /mɛzɔ /	6371	570	496
	bateau /bato/	4209	107	585
	cheveux /ʃəvø/	2907	116	657
	means	4989	205	561
	lechon /ləʃɔ /	786	0	487
	vabeux /vabø/	3600	0	533
	meautai /motɛ/	5449	0	523
	bonsa /bɔ za/	1285	0	561
	means	2780	0	526
	vchonbe /vʃɔ bə/	397	0	628
	chbeula /ʃbøla/	5208	0	627
	bmeausai /bmozɛ/	1703	0	690
	zbaiton /zbɛtɔ /	4059	0	637
	means	2842	0	646
	Total means			578
	SD			69

Non-native Pseudowords Native Pseudowords Known WordsTable 1 :

 1 Biphoneme Frequencies of Stimuli… last one from : freqfilms: la fréquence du mot selon le corpus de sous-titres (par million d'occurrences); biphoneme frequencies from:

Acknowledgements:

We thank all families for their participation and contribution to this research. This work is supported by PME DIM Cerveau et Pensée 2013 and a public grant overseen by the French National Research Agency (ANR) as part of the program "Investissements d'Avenir" (reference: ANR-10-LABX-0083 -LabEx EFL). It contributes to the IdEx Université de Paris -ANR-18-IDEX-0001.