WO2002084254A1

WO2002084254A1 - Method and micro-press for characterising mechanical properties of pharmaceutical solids

Info

Publication number: WO2002084254A1
Application number: PCT/FR2002/001239
Authority: WO
Inventors: Didier Bielawski; Guy Couarraze; Bernard Leclerc; Pierre Tchoreloff
Original assignee: Digipharm
Priority date: 2001-04-10
Filing date: 2002-04-09
Publication date: 2002-10-24
Also published as: FR2823307A1; FR2823307B1

Abstract

The invention concerns a method for characterising mechanical properties of pharmaceutical solids (2) manufactured by powder compaction. The invention is characterised in that it consists in performing on the pharmaceutical solid (2) a three-point flexural test and/or a micro-indentation test and/or a uniaxial compression test, said tests being carried out with a micro-press (1), each of said tests comprising, prior to the real measurement cycle, at least a preparatory cycle comprising loading and unloading, and a certain lapse of time being allowed between loading and unloading. The invention also concerns a micro-press (1) for characterising the mechanical properties of pharmaceutical solids (2), characterised in that it comprises a force sensor (18) measuring the force exerted on the pharmaceutical solid (2), a vertical movement sensor (17) measuring the movement of the piston (16), and two transverse movement sensors (23) measuring the transverse deformation of the pharmaceutical solid (2).

Description

Method and micropress for characterizing the mechanical properties of pharmaceutical solids

The present invention relates to a method for characterizing the mechanical properties of pharmaceutical solids and a micropress making it possible to demonstrate the mechanical properties of pharmaceutical solids.

The determination of the mechanical properties of an object for industrial purposes is known in the prior art in various sectors such as soil science, metallurgy, science of polymeric materials, the ceramic or concrete industries. In the pharmacy field, very few studies have been conducted to characterize the mechanical properties of pharmaceutical solids. In known manner, certain pharmaceutical solids are in the form of a compacted powder comprising the active principle and one or more excipients, one of these excipients being generally in the majority compared to the others. Tablets formed by compaction can be produced at a rate of 200,000 to 300,000 tablets per hour. These high production rates, imposed on granular systems which do not directly transmit the stresses applied, often lead to the formation of stress heterogeneities and therefore of density within the tablets. These density heterogeneities, upon loosening of the tablet due to its viscoelasticity, cause the tablet to tend to break (cleavage, cracking off) just after compaction and in particular when it is sent to the receiving tanks. Knowledge of the mechanical properties of pharmaceutical solids can therefore prove to be advantageous during the formulation of a medicament so as to avoid these untimely breaks.

New approaches have been developed in pharmacy to overcome this relative poverty of characterization of pharmaceutical solids. These approaches are often transpositions to systems pharmaceutical techniques developed outside of pharmacy. This is how the cohesion characteristics of compacted systems could be approached by evaluation of the internal rupture stress on parallelepiped bars in three-point bending test. On the same experimental model applied to notched bars, it is also possible to evaluate the critical stress intensity factor representative of the toughness of a compacted material, that is to say of its ability to resist the rupture by propagation of cracks. Indentation techniques have also been applied to the characterization of compacted solids. These techniques have been exploited by transposing experimental conditions of the Brinell or Vic ers type to measure indentation modules on a certain number of pharmaceutical systems.

However, these recent advances do not solve all the problems. Indeed, these techniques do not allow a complete and precise characterization of pharmaceutical solids. In particular, these techniques do not take into account the viscoelasticity of the product and do not allow a simple and precise characterization of the Young's modulus.

The present invention therefore aims to overcome the drawbacks of the prior art by proposing a method for characterizing the mechanical properties using a dedicated tool and taking into account in particular the viscoelasticity of the product so as to obtain results. very reliable. The invention will therefore make it possible to better understand the behavior of pharmaceutical powders during the compacting operation as well as their properties after compaction.

This object is achieved by a process for characterizing the mechanical properties of pharmaceutical solids produced by powder compaction, characterized in that it consists in performing on the pharmaceutical solid: - either a three-point bending test, - or a micro test -indentation, - either a uniaxial compression test,

- either two tests among the three mentioned above,

- or the three tests, a determined number of preliminary cycles being carried out on the pharmaceutical solid (2) tested until a solid elastic response is obtained from the pharmaceutical solid, the number of cycles being a function of the nature of the pharmaceutical solid tested, and a certain time, variable depending on the nature of the pharmaceutical solid (2) tested, being left between a charge and a discharge, so as to obtain optimal relaxation of the pharmaceutical solid (2) to be, during the discharge, in the area of elastic deformations of the pharmaceutical solid (2), these tests being carried out using a micropress (1) comprising a piston (16), and each of the tests comprising, before an actual measurement cycle, at least one cycle prerequisite including a charge and a discharge. According to another particular feature, during a three-point bending test, the real measurement cycle consists in applying an ultimate load to the pharmaceutical solid so as to cause its median rupture.

According to another particular feature, the method comprises a step of executing software, arranged in a computer system connected to the micropress, allowing at least the entry of operating parameters of the micropress, such as the loading speed of the piston, the maximum displacement of the piston, the maximum load applied to the pharmaceutical solid, the number of charge / discharge cycles to be carried out, the duration between charge and discharge or the frequency of acquisition of the force applied by the piston to the solid in as a function of the displacement of the piston or of the stress in the pharmaceutical solid as a function of the displacement of the piston towards this solid, the step of executing the software being followed by a step of recording the operating parameters of the micropress in means memorization contained in the computer system. According to another particularity, the method comprises a step of displaying in real time, by the software, result curves relating to the force applied by the piston to the solid as a function of the displacement of the piston, to the stress in the pharmaceutical solid as a function of the displacement of the piston towards this solid, or alternatively to the transverse deformation of the pharmaceutical solid as a function of the displacement of the piston, and of recording these curves in the storage means of the computer system.

According to another particular feature, the method comprises a step of calculating from the observed results, by means of calculation included in the computer system, quantities characterizing the mechanical properties of the pharmaceutical solid, such as, for a micro-indentation test, the reduced modulus of elasticity and Brinell hardness, for a three-point bending test, the breaking stress, the modulus of elasticity and toughness, and, for a uniaxial compression test, the Young's modulus and the coefficient of fish. According to another particular feature, the calculation of the Young's modulus determined by a uniaxial compression test requires at least the measurement of the vertical displacement of the piston and of the force applied by the piston, and that the calculation of the Poisson's ratio determined by a test Uniaxial compression requires at least the measurement of the vertical displacement of the piston and the measurement of the transverse deformation of the pharmaceutical solid.

The transposition of devices used in other sectors to the pharmacy sector means that these devices are generally unsuitable and often imprecise for studying the mechanical properties of pharmaceutical solids. Likewise, the devices specific to the pharmaceutical solids developed are generally very imprecise. Indentation techniques have been made more efficient by the use of extensometers which have the advantage of making simultaneous measurements of force and displacement. This displacement measurement can be correlated to the dimensions of the indentation imprint thanks to the knowledge of geometric parameters of the indentor, which can be spherical (hardness Brinell), pyramidal (Vickers hardness) or cylindrical and flat. However in the field of generally applied forces, the displacements of the indentor integrate for a not totally negligible part the mechanical deformations of the measuring device itself, such as the frame and the transmission rods. In fact, in these devices, the measurement of the displacement of the indenter in the solid is generally obtained by counting the number of revolutions of the motor allowing the displacement of the indenter. The usual technologies of devices sold are therefore the source of systematic errors. It is clear that the application of much lower forces would minimize these accidental causes, but it is then the sensitivity of the movement sensor of the devices which becomes unacceptable for uses under these conditions.

Elastic bending tests on bars of compacted systems can also be implemented for the determination of their Young's modulus using a micro-indentation device used for a three-point bending test. However, the problem linked to the sensitivity of the displacement sensors remains because the area of elastic deformations of pharmaceutical compacts is generally associated with very low forces applied to the pharmaceutical solid. The object of the present invention is therefore to overcome the drawbacks of the prior art by proposing a micropress dedicated to micro-indentation and three-point bending tests on pharmaceutical solids, this micropress makes it possible in particular to determine the Young's modulus in a precise way and to avoid the problems of uncertainty linked to the displacement sensor. This object is achieved by a micropress to highlight the mechanical properties of pharmaceutical solids, characterized in that it comprises means for recording operating parameters of the micropress, means for controlling the movement of a loading piston towards the pharmaceutical solid placed under this piston according to the operating parameters, an effort sensor measuring the effort exerted on the pharmaceutical solid by a head assembled at the end of the piston close to the solid in position, a vertical displacement sensor measuring the displacement of the piston, the latter being located as close as possible to the sample and triggered by triggering means when a force is detected at the level of the force sensor, two transverse displacement sensors measuring the transverse deformation of the pharmaceutical solid, the transverse displacement sensors being supported by a movable horizontal ring in rotation situated around the pharmaceutical solid tested, the position of this movable ring which can be adjusted in height, so as to position the transverse displacement sensors substantially at the middle of the pharmaceutical solid, means for recording the signals emitted by the sensors, means for calculating quantities characterizing the mechanical properties of the solid according to the recorded signals and parameters micropress operating res. According to another particular feature, the micropress comprises a computer system executing specific operating software allowing the display, by means of display of the system, of fields for entering the operating parameters of the micropress on a screen of the system, the system controlling, as a function of certain operating parameters entered, a geared motor actuating, by means of a ball screw, the loading piston along its axis directed towards the pharmaceutical solid in position, the head of the loading piston supporting an indenter to perform, on the pharmaceutical solid, a three-point bending test, a micro indentation test or a uniaxial compression test, the latter test requiring the presence of a floating punch between the indenter and the pharmaceutical solid, the results of this test being collected by the system for processing by the software, the system comprising the means of ca lcul to calculate the quantities characterizing the mechanical properties of the pharmaceutical solid. According to another particular feature, the control means control the speed of movement of the piston by means of a force, position or speed of movement regulator of the piston, of the PID (Proportional Integral Derivative) type. According to another particular feature, the system also includes means for displaying in real time curves relating to the force applied by the piston to the solid as a function of the displacement of the piston or to the stress in the pharmaceutical solid as a function of the movement of the piston towards this solid. According to another particular feature, the pharmaceutical solid rests on a table positioned on a base surmounted by the geared motor actuating the piston along its axis directed towards the pharmaceutical solid via the ball screw.

According to another particularity, the table is an XY cross-motion table allowing the operator to precisely position the measuring point of the sample to be tested under the indenter, then to move the sample to the next measuring point without have to touch the sample.

According to another particularity, during a uniaxial compression test, a sample holder is positioned between the table and the pharmaceutical solid. According to another particularity, the movable ring is supported by a horizontal fixed ring, the movable ring being able to rotate with respect to a vertical axis, and with respect to the fixed ring, by means of rollers located between the movable ring and the fixed ring, and the position of the fixed ring being adjustable in height by means of a knurled screw penetrating into a sheath of an internally threaded part and supporting the fixed ring.

According to another particular feature, the force sensor is a sensor with a strain gauge bridge placed on the loading piston just above the head.

According to another particular feature, the displacement sensor is an incremental feeler secured to the head of the loading piston by means of a first plate, this vertical displacement sensor comprising a touch point in permanent contact with a reference consisting of a second plate parallel to the first plate, the displacement of the piston causing the touch point to slide in a sleeve integral with the first plate, the vertical displacement sensor comprising means for measuring the displacement of the test tip in the sleeve corresponding to the displacement of the loading piston relative to the pharmaceutical solid.

According to another particularity, the transverse displacement sensors are incremental probes each comprising a cylindrical test tip, each test tip being horizontal and tangent to the surface of the pharmaceutical solid, and in permanent contact with the pharmaceutical solid, as well as means measuring the displacement of the test probe with respect to the position of the test probe before the test.

According to another feature, the indenter can be spherical, cylindrical or pyramidal.

The invention, with its characteristics and advantages, will emerge more clearly on reading the description made with reference to the appended drawings in which: FIG. 1 represents the micropress according to the invention,

FIG. 2a represents the operation of mounting the punch support and the displacement sensor support on the micropress according to the invention,

FIG. 2b represents the mounting of the indenter on the micropress according to the invention, FIG. 3 represents the configuration screen of the micropress control software,

FIG. 4 represents the control screen on the computer system according to the invention, FIGS. 5a, 5b, 6, 7, 8, 9, 11, 12, 13, 14, 15 represent various messages appearing during the preparation of a micro-indentation or three-point bending test,

FIG. 10 represents the control screen having a micro-indentation curve,

FIG. 16 represents the curve of., micro-indentation plotted in a spreadsheet of a spreadsheet,

- Figures 17a, 18a and 19 represent four curves corresponding to four indentation cycles on respectively an AVICEL PH101 bar compressed to 45KN, a LACTOSE FF bar compressed to 45 KN and a DI-TAB bar compressed to 45 KN ,

- Figures 17b, 18b show the extrapolation curve with zero porosity of hardness P respectively for an AVICEL PH101 strip and for a LACTOSE FF strip, - Figure 20 shows a strip of a pharmaceutical solid placed on a three-point bending bench,

FIG. 21 represents the control screen displaying the control parameters within the framework of a three-point bending test,

FIG. 22 represents, within the framework of a three-point bending test, the control screen on which is drawn a curve representative of a charge and a discharge,

- Figure 23 represents, within the framework of a three-point bending test, the control screen on which is drawn a curve representative of a load until rupture, - Figure 24 represents, within the framework of a three-point bending test, a curve representative of a load and a discharge inserted in a spreadsheet,

FIG. 25 represents several curves representative of five successive charge / discharge cycles exerted on an AVICEL PH101 bar, - Figures 26, 29 and 32 show a charge / discharge curve used for the calculation of the elastic modulus, respectively for the AVICEL PH101 bar, for a LACTOSE FF bar, and for a DI-TAB bar - the FIGS. 27, 30 and 33 represent an extrapolation curve with zero porosity of the elasticity modulus values, respectively for the AVICEL PH101 bar, for the LACTOSE FF bar and for the DI-TAB bar,

- Figure 28 represents several curves representative of three successive cycles of charge / discharge exerted on a strip of LACTOSE

FF

FIG. 31 represents several curves representative of three successive charge / discharge cycles exerted on a bar of DI-TAB,

FIG. 34 represents a portion of the graph, force exerted as a function of the displacement of the indenter,

FIG. 35 represents the micropress according to another embodiment of the invention,

- Figure 36 shows a top view of the micropress according to the embodiment of Figure 35, - Figures 37a and 37b show, respectively, poor and good centering of the pharmaceutical solid with respect to spherical test tips of transverse displacement sensors according to the embodiment of FIG. 35,

FIGS. 37c and 37d represent, respectively, poor and good centering of the pharmaceutical solid relative to the cylindrical test tips of the transverse displacement sensors according to the embodiment of FIG. 35,

FIG. 38a represents a definition of the micro-indentation test matrix on the pharmaceutical solid, FIG. 38b represents a map of the zones of higher density of the pharmaceutical solid,

- Figure 39 shows a cracked bar as part of a three-point bending test performed to determine the toughness. The invention will now be described in conjunction with FIGS. 1 to 39.

The objective of the invention is therefore to characterize intrinsic parameters of the cohesion of pharmaceutical solids, so as to better understand the behavior of pharmaceutical powders during the compression operation to form solids. The device according to the invention, to demonstrate these properties, consists of a micropress (1). This micropress (1) according to the invention consists of a base (10) on which is fixed a so-called XY table (11), on which the pharmaceutical solid (2) which is the subject of the test will be positioned. This XY cross-motion positioning table (11) allows the operator to precisely position the measuring point of the sample to be tested under the indenter, then move the sample to the next measuring point without having to touch the sample. The base (10) comprises, for example, three uprights (12) standing perpendicularly. These uprights (12) are distributed on the base (10) in a triangle, so as to support in a completely stable manner a plate (13) fixed to the ends of the uprights opposite their end for fixing to the base (10) and substantially parallel to the base. (10). On this plate (13) is fixed a ball screw (14) surmounted by a geared motor (15). This geared motor (15) actuates on command, by means of a force, position or displacement speed regulator of the piston, of the PID (Proportional Integral Derivative) type, a loading piston (16) sliding in the ball screw (14) along its axis through the plate (13) to come into contact with the pharmaceutical solid (2) disposed on the XY table (11) fixed on the base (10).

With reference to FIGS. 2a and 2b, the piston (16) consists of an upper piston (160), for example cylindrical, at the end closest to the solid pharmaceutical which is fixed a punch support consisting of two elements. The first cylindrical element (161), for example of the same diameter as the upper piston (160), is fixed to the upper piston (160) using four screws (163) introduced in the direction of the arrows in FIG. 2a . The second element (162) has the shape of a cylinder of revolution with two successive shoulders forming three sections of different diameter and is fixed coaxially on the first element (161). The sections of the second element are of smaller diameter than the diameter of the first element and of decreasing diameters in the direction of the pharmaceutical solid (2) placed on the XY table (1 1) fixed on the base (10). On the largest section of the second element (162) fits a plate (164) comprising a nesting hole (165), this plate (164) possibly constituting, for example, a support for the vertical displacement sensor (17 ) of the loading piston. An indenter (166) which can take various forms is inserted into a hole (167) whose section conforms to the shape of the section of the indenter, along the axis of the smallest section of the second element (162) of the punch holder. This indenter (166) is fixed to the punch support by a tightening nut (168) coming to be screwed on a thread (169) formed on the intermediate diameter section of the second element (162) of the punch support. The indenter (166) can take different forms depending on the test carried out using the micropress according to the invention. Indeed, this indenter could be, for example, of spherical geometry (of Brinell ball type), the sphere being able to be of variable diameters, for example 1, 00 mm, 1, 76 mm, or 2.38 mm. It may be, for example, of cylindrical geometry (of the Boussinesq flat type), its section possibly being of variable diameters, such as, for example, 0.50 mm, 0.70 mm, 1.00 mm, 2.00 mm . Finally, it could be, for example, of pyramidal geometry (of the Vickers type), the pyramid having for example an angle at the top of 136 °.

Two different punch supports of the same general shape can be adapted on the upper piston (160) according to the shape of the indenter (166), one of the supports being adapted to receive the indentor (166) with pyramidal geometry while the other is adapted to receive an indenter (166) of spherical or cylindrical geometry.

A floating punch (1600), shown in Figure 35, can be positioned between the indenter (166), for example spherical, and the pharmaceutical solid (2). The floating punch (1600) is, for example, cylindrical, with a notch on its upper face allowing the insertion of the indenter (166). The floating punch (1600) has a lower face that is larger than the upper face of the pharmaceutical solid (2), which makes it possible to apply a load to an entire face of the pharmaceutical solid (2). The floating punch (1600) is not rigidly attached. It is simply positioned between the indenter (166) and the pharmaceutical solid (2). This avoids measurement errors possibly linked to a lack of parallelism between the lower and upper faces of the pharmaceutical solid (2). A sample holder (29) can be positioned between the XY table (11) and the pharmaceutical solid (2) in order to raise the pharmaceutical solid (2) relative to the piston (16).

According to the invention, the vertical displacement sensor (17) is positioned on its support fixed on the punch support. This vertical displacement sensor (17) is, for example, an incremental feeler comprising a touch point (170) in contact with a reference located below its support, for example, the XY table in FIG. 1. This point key (170) is sliding in a sleeve of the vertical displacement sensor (17). The displacement of the piston (16) downward and therefore of the indenter (166) therefore causes a corresponding sliding in the sleeve of the test tip (170) pressed against its reference. The displacement of the test tip (170) is measured and corresponds to the displacement of the piston (16) and therefore to the insertion of the indenter (166) into the pharmaceutical solid (2). According to the invention, the vertical displacement sensor (17) is therefore placed near the indenter (166) and therefore as close as possible to the sample to be indented, which avoids approximate measurements taking into account all the stiffness defects of the entire micropress (1). This is the case in the prior art where the displacement is measured, for example, by counting the number of revolutions of the gear motor (15). According to the invention, the vertical displacement sensor (17) will have a reference located on the bearing surface of the sample, on a surface at an equivalent offset height or below these surfaces. The vertical displacement sensor (17), to avoid the problems of uncertainty, must therefore be as close as possible to the indenter and especially below the force sensor which does not have great rigidity. The resolution of the vertical displacement sensor (17) according to the invention will, for example, be 0.05 μm.

In the embodiment of Figures 35 and 36, the pharmaceutical solid (2) has a cylindrical shape. A horizontal movable ring (22) is located around the pharmaceutical solid (2) and is supported by a fixed ring (21), also horizontal, whose vertical position is adjustable. The movable ring (22) can rotate around a vertical axis, and relative to the fixed ring (21), thanks to rollers (26), for example four in number, positioned between the fixed ring ( 21) and the movable ring (22). The movable ring (22) supports two transverse displacement sensors (23) arranged symmetrically with respect to the pharmaceutical solid (2). The transverse displacement sensors (23) can therefore rotate around the pharmaceutical solid (2), which makes it possible to carry out several measurements of the transverse deformation of the pharmaceutical solid (2), when the latter is subjected, for example, to compression , and thus to make an average of the different measurements. The fixed ring (21) is supported by a vertical block (28) comprising an internally threaded sleeve, in which a vertical knurled screw (27) is inserted. The assembly formed by the fixed ring (21), the mobile ring (22) and the transverse displacement sensors (23) can therefore be moved in height by sliding the vertical block (28) around the knurled screw (27 ) during rotation of the knurled screw (27). The transverse displacement sensors (23) are of the same type as the vertical displacement sensor (17). The test probes (25) of the transverse displacement sensors (23), shown in particular in FIGS. 36 and 37a to 37d, are horizontal cylinders, this in order to avoid measurement errors which could be linked to a fault in centering of the movable ring (22) relative to the pharmaceutical solid (2). The test probes (25) of the transverse displacement sensors (23) have their longitudinal axis perpendicular to the longitudinal axis of the transverse displacement sensors (23). The contact between the test probes (25) of the transverse displacement sensors (23) and the pharmaceutical solid (2) is punctual.

The measurement of the transverse displacement makes it possible to determine, as explained below, for example, the Poisson's ratio v.

A force sensor (18), for example of the strain gauge bridge sensor type, is placed on the loading piston (16), for example above the vertical displacement sensor (17) to measure the 'force exerted by the piston (16) on the pharmaceutical solid (2) during a test. The resolution of the force sensor (18) according to the invention will, for example, be 0.01 N.

The extent of the measurements made by the displacement sensors (17, 23) or the force sensor (18) makes it possible to test any type of pharmaceutical material and therefore any type of pharmaceutical solid (2).

According to the invention, the micropress (1) comprises a computer system (3) having specific software for controlling the movements of the loading piston (16). The force (18) and displacement (17, 23) sensors are controlled by this computer system (3) and the measurements are collected in the system software (3). The vertical displacement sensor (17) is, for example, coupled to the effort sensor (18) through the computer system (3), so that the displacement measurement is not taken into account at the level of the displacement sensor vertical (17) only when a first force is detected at the level of the force sensor (18). The software allows the simultaneous display, on the same graph, of the effort as a function of the displacement of the indenter. The recording of the measurements can only start when a contact is detected between the indenter (166) and the pharmaceutical solid tested. The displacement of the indenter (166) measured by the vertical displacement sensor (17) therefore corresponds directly to the insertion of the indenter (166) into the pharmaceutical solid (2) tested. This makes it possible in particular to get rid of any operation for measuring the size of the imprint formed by the indentor on the solid tested and in particular the depth of this imprint.

The first contact of the indenter (166) on the pharmaceutical solid (2) corresponds to a first force measured by the vertical displacement sensor (17). The intensity of this first effort can be configured. It is therefore from this minimum intensity of detection of contact with the sample chosen by the operator that the recording of measurements can begin. This setting can be made in a configuration window of the micropress control software (1).

This window is visible in Figure 3. This window firstly includes an input field (30) of this minimum intensity. This field (30) is called for example "Contact with the sample detected at". The operator can then set the value of the intensity expressed in Newton using the numeric keyboard or using a progress bar (31). The setting of this parameter makes it possible to eliminate the parasites liable to trigger the recording of the measurements when the contact between the indentor (166) and the pharmaceutical solid (2) is not yet established. This parameter may vary depending on the test environment. In Figure 3, the value is fixed at 0.11 N.

The screen window includes a parameter setting field (32) for the piston descent speed (16) before contact between the indenter (166) and the sample is established. This value, expressed in millimeters per minute, must be optimized as a function of the loading speed during the test and must take account of the precision required in recording the start of the graph effort / displacement compared to the time necessary for the indenter (166) to come into contact with the sample. This value can be entered using the numeric keypad or adjusted using a progress bar. In figure 3, the value is fixed at 0.141 mm / min. The screen window represented in FIG. 3 represents an input field (33) of a value defined by the height at which the indenter is positioned above the sample after the end of a test, by relative to the height at which the indenter is when a first contact of the indentor (166) on the pharmaceutical solid (2) is detected. This value is accompanied by a "plus" sign and is expressed in mm. The value can be entered using the numeric keypad or using a progress bar. In figure 3, the value is fixed at +0.018 mm.

The window also includes an input field (34) corresponding to the correction of the reading of the sensors. This field is entitled, for example, "Read Load x" and makes it very easy to record the result of a periodic recalibration procedure of the force sensor (18). This value can be entered using the numeric keyboard or using a progress bar. In Figure 3, it is fixed at 1.00000.

The window includes an input field (35) of a value representative of the precision of the speed control of the gear motor (15) which causes the displacement of the loading piston. This value is called, as shown in Figure 3, for example, "offset" (+/- 10). This value is adjusted so that a zero control signal results in the absence of rotation of the gear motor (15). This value can be entered using the numeric keyboard or using a progress bar. In Figure 3, it is set to -8.

Finally, this screen window comprises two buttons (36, 37) entitled respectively in FIG. 3, "Taring" (36) and "Cancel taring" (37). These two buttons (36, 37) allow, when the operator clicks on them, to reset the reading of the effort sensor (18) following a shift in the measurement caused, for example, by an increase in the ambient temperature. The offset can also be caused, for example, during a change of the indenter (166), the force sensor (18) systematically measuring the weight of the indentor (166) and its support. Once these values have been selected, the operator only has to validate by clicking with the mouse on a button called, for example, "OK" (38). The operator can also decide not to validate and keep his old configuration by clicking on a button called, for example, "Cancel" (39). The software makes it possible to configure the micropress (1) by screen windows comprising several fields for entering these operating parameters. These parameters are recorded on a memory (M1) of the system so that they can be used in the calculations of the quantities characteristic of the mechanical properties of pharmaceutical solids, as a function of the measurements collected at the level of the displacement sensors (17, 23) and of the sensor. effort (18) and recorded on the memory (M1) of the computer system (3).

Three types of mechanical tests can in particular be performed by this micropress (1) on a pharmaceutical solid (2).

A first test consists in practicing micro-indentation on a pharmaceutical solid (2) using the micropress (1) according to the invention. An indentation is defined by the application of a load which corresponds to the penetration of the indentor (166) having a certain geometric shape within a pharmaceutical solid (2) and by the withdrawal of the indentor (166) solid (2), this withdrawal being said discharge. A relaxation time, allowing the plastic deformations to occur as well as the relaxations of the flow stresses which are at the origin of these deformations, is allocated between the charge and the discharge, this relaxation time can be variable depending on the nature of the pharmaceutical solid (2) and in particular, depending on the main component of the pharmaceutical solid and its environment.

In addition, depending on the nature of the pharmaceutical solid (2) tested, it may be necessary to apply a determined number of charge / discharge cycles to the pharmaceutical solid (2) before the actual measurement cycle.

The operating software executed by the computer system (3) collects the data measured by the vertical displacement sensor (17) and by the force sensor (18). For the micro-indentation test, the presence of transverse displacement sensors (23) is not necessary since the solid is not substantially deformed transversely. The operating software therefore allows the acquisition of the force applied by the indenter as a function of the displacement of the indenter in the solid. It is therefore possible, by studying the graphical curves plotted using these data, to determine certain mechanical properties of the solid (2) studied. In the case of the micro-indentation test, the modulus of elasticity is reduced

(E *) will be able to be determined. This reduced elasticity modulus, the calculation formula of which is written below, defines, like the Young's modulus, the elasticity response of a material subjected to a stress. But, unlike Young's modulus, the reduced elastic modulus calculated after a micro-indentation test is freed from the fish coefficient. In the case where the indenter is spherical, this reduced modulus of elasticity is expressed as follows:

R corresponds to the radius of the indenter (166), F corresponds to the force applied at the end of the relaxation time as shown in FIG. 34. A linear portion is identified at the end of the relaxation time on the discharge curve (340) obtained on the graph expressing the force exerted as a function of the displacement of the indenter (166), the slope of this linear portion being calculated from a value on the ordinate corresponding to F and a value H taken on the abscissa, as shown in FIG. 34.

The hardness, for example Brinell (P), can also be determined. Hardness corresponds to the ratio between the force applied and the surface of the impression.

Fmax corresponds to the maximum force applied after the relaxation period, D to the diameter of the indentor, d to the diameter of the imprint, d being equal to:

d = 2 ^ {R ² - {R -h) ² )

where R is the radius of the indenter and h the depth of the imprint remaining after the discharge.

For a micro-indentation test, the indenter (166) is positioned, as shown in FIGS. 2a and 2b, in the punch support corresponding to its shape as described above. In the context of the test described below, the indenter (166) has a spherical geometry with a diameter of

2.38 mm. Once the test sample is positioned manually on the table

XY (11), the test can start.

A first step consists in choosing, from the control computer system (3), the control parameters for the test carried out. These parameters are entered into the operating software from a control screen (4) displayed on the computer system screen (3).

This control screen (4), represented in FIG. 4 mainly comprises three zones (40, 41, 42). A first zone (40), called the menu, comprising various drop-down tabs referring to micropress control instructions (1). A second zone (41) makes it possible to display operating parameters of the micropress (2), to launch the test, to follow the displacement of the piston (16) and the applied force ... A third zone (42) allows to visualize the plotting in real time of the curve, force-displacement or stress-displacement.

To start a test, the operator clicks on a tab called, for example, "Session" (43) in the menu area. When it is a first test on a first sample, the operator clicks on an instruction called, for example, "new" in the "Session" drop-down tab (43). The message shown in Figure 5a then appears. This message asks the operator if he is sure he wants to start a new session. By clicking on a button called, for example, "Yes" (50) of this message, he accesses an input area (44) in the second area (41) of the control screen (4) allowing to enter a name or session number. The software then automatically displays in other input areas (45, 46), a sample number, set to 1 by default, as shown in Figure 4, and a number corresponding to the cycle number, set to 0 by default. These values can be changed using the numeric keypad by entering a value in the corresponding fields (45, 46).

Instead of selecting a new session, it is possible to stay in the same session and click in the "Session" tab (43) on an instruction called, for example, "Next sample". A new message shown in FIG. 5b, of the same type as that previously described, appears. The latter asks if the operator wishes to proceed to the test of the next sample. If he clicks on a button called, for example, "Yes" (51), the input area (44) of the session name can be entered. When this is done, the software automatically displays a sample number in the input area (45) of the second area (41) of the control screen, set to 1 by default, and an indentation number also in a new entry area (47) of the second area (41) of the screen (4) and set to 1 by default. These values can be changed using the numeric keypad by clicking in the corresponding input area (45, 47). The input area (46) of the cycle number is merely informative, and is therefore locked.

A second operation consists in clicking on a tab called, for example, "Piston" (48) in the menu area. In this drop-down tab, it is possible to click on an instruction, called, for example, "position". This function makes it possible to position the piston (16) as close as possible to the surface of the sample to be indented. By clicking on "position", a screen window appears. This screen window, represented in FIG. 6, makes it possible to configure the control of the displacement of the piston (16). First of all, it is possible from this window to control the piston (16) up or down by checking a corresponding box (60, 61), called respectively, for example, "Up" or "Down" at using the mouse. In addition, it is possible to control the movement of the piston (16) automatically or manually by checking the corresponding box (62, 63) using the mouse in the screen window. When the manual mode is chosen, the displacement of the piston (16) can be obtained, for example, by continuous pressing of the "Esc" key on the computer system keyboard (3). Releasing the button automatically stops the piston (16). When the automatic mode is chosen, it becomes possible to click with the mouse on certain icons in the screen window. A first icon (64) makes it possible to gradually increase the speed of the piston. A second icon (65) makes it possible to decrease this speed. A third icon (66) makes it possible to move the piston (16) directly at the maximum speed, which will be, for example, 2mm per minute. Finally, a last icon (67) stops the movement of the piston (16). It is also possible to choose the speed of the piston (16) by moving, for example, a central progress bar (68) available on the screen window, as shown in FIG. 6. When the piston (16) is correctly positioned as close as possible to the surface of the sample to be indented, it suffices to click on a button called, for example, "exit" (69) from the screen window. A third operation consists in defining the micropress control parameters (1) for the test. These control parameters are chosen arbitrarily and must be adjusted according to the behavior of the product tested. In the menu area, click on a tab called "Test" (49). This selection causes the appearance of a screen window comprising several fields for entering the micropress control parameters (1). This screen window is represented in FIG. 7. It notably comprises a first input field (70) for the loading speed of the piston. This speed can be directly entered in an input area (700) using the numeric keyboard or with the mouse by clicking on a progress bar (701). The window includes a second input field (71) for the maximum insertion of the indenter (166) into the pharmaceutical solid (2), a third input field (72) for the maximum load applied to the pharmaceutical solid (2) and a fourth input field (73) of the number of charge / discharge cycles to be carried out, all of these fields being of the same type as the first. In general, only one cycle is necessary before the actual measurement for a micro-indentation test. But, if necessary, depending on the excipient, several preliminary cycles can be carried out.

The window includes an input field (74) for a time delay between each charge and discharge cycle. This time delay can be entered, for example, directly using the keyboard in an input area (740) or using the mouse by clicking on several progress bars (741). The screen window also includes the possibility of choosing, for example, by checking a corresponding box (75, 76), if it is desired to take into account in a cycle, loading only or loading and unloading. The window offers an input field (77) for the relaxation time using the keyboard or the mouse by clicking on regulation bars, the relaxation time being defined by the time left between a charge and a discharge of the piston. (16). Finally the window includes fields for entering (78, 79) the frequency of acquisition of the points for drawing the curve on the third zone (42) of the control screen (4).

In FIG. 7, the loading speed is fixed at 0.060 mm / min, the maximum insertion at 0.100 mm, the maximum load at 500 N, the number of cycles at 1, the time delay at 0, the cycle includes a loading and an unloading with a relaxation time between this loading and this unloading fixed at 5 minutes and the acquisition frequencies at 00.5 seconds, which corresponds to two points per second. When all the control parameters have been entered, all that remains is to click on a button called "OK" (80) in the screen window to validate these parameters. Otherwise, if the operator does not wish to validate the parameters entered and keep the old parameters, he must click on a button in the screen window called "Cancel" (81).

A fourth operation to be carried out before starting the test, consists in setting the indenter (166) fixed on the punch support. For this, the operator clicks with the mouse on a tab called, for example, "indentor" (52) in the first area (40) of the control screen (4). After clicking, an indenter setting screen window (166) appears. This screen window is represented in FIG. 8. It is necessary to select in this window the type (82) of indenter which one uses, that is to say with spherical, cylindrical, pyramidal (Vickers) or s geometry. 'This is another type of indenter which must then be specified. In the case where an indenter with cylindrical or spherical geometry is used, the diameter (83) of this indentor must be specified. Several standard values, such as 0.5, 0.7, 1 or 2 can be checked directly. If it is another diameter, you must check the box (84) called, for example, "other" and enter the value of this specific diameter in an input area (85) using the keyboard or choose it by clicking with the mouse on a progress bar (86). Finally, it only remains to select in this screen window the type of graph (89) which one wishes to see drawn during the test on the third zone (42) of the control screen (4). It will be possible to opt for a graph giving the force exerted by the piston (16) as a function of the displacement of the piston (16) or for a graph giving the stress as a function of the displacement of the piston (16), the stress taking account of the contact surface between the indentor (166) and the pharmaceutical solid (2). This contact surface is variable depending on the shape of the indenter (166). As in the screen window shown in Figure 7, validation is done by a mouse click on a button called, for example, "OK" (87) or the cancellation of the operation by a mouse click on a button called, for example, "Cancel" (88).

The parameters for controlling the displacement of the piston corresponding to the values entered in the screen window of FIG. 7 and the parameters for controlling the indenter (166) corresponding to the values entered in the screen window in FIG. 8, appear after validation in the second zone (41) of the control screen (4). The values that appear in Figure 4 do not match the values shown in the screen windows in Figures 7 and 8.

The micro-indentation test can now start by clicking with the mouse on a button called, for example, "Start" (53) on the control screen (4). A message shown in Figure 9 then appears, signaling to the operator that the indentor (166) will come into contact with the sample to be tested. This message also specifies in a zone (90) the charge applied at this time to the test sample.

As soon as the indenter (166) comes into contact with the sample, the graph can be drawn automatically in the third zone (42) of the control screen (4). The values of the load and the corresponding displacement of the piston (16) can also be displayed in real time in fields (54, 55) of the second zone (41) of the control screen and also on the axes of the graph. of the third zone (42), as shown in FIG. 10. Data recording does not start until the indentor (166) comes into contact with the pharmaceutical solid (2). The effort from which the software estimates that there is contact between the indentor (166) and the pharmaceutical solid (2) is configured in the configuration screen shown in Figure 3.

A cycle corresponding to an indentation is then traced in the third zone (42) of the control screen (4), as shown in FIG. 10. This cycle therefore comprises three parts, a charge (100a), a relaxation time ( 100b) and a landfill (100c).

It is possible to stop the test at any time by clicking on a button called, for example, "Pause" (101) which replaces the "Start" button (53) when the test has started. Then, once stopped, It is possible to resume the test by re-clicking on the "Start" button (53) which replaces the "Pause" button or to directly order the unloading by clicking on a button called, for example, "Unloading" (56), as shown in Figure 4.

By clicking on a button called, for example, "End of the test" (102) and represented in FIG. 10, the test is definitively stopped. A request for confirmation of the final cessation of the test appears in the form of a message represented in FIG. 11. By clicking on a button called, for example, "Yes" (110), the test is definitively stopped. Otherwise, by clicking on a button called, for example, "No" (111), the test is not stopped and can resume normally.

At the end of the charge, the remaining relaxation time is indicated by a message shown in FIG. 12. If the operator wishes to reduce this relaxation time and start discharging immediately, he can click using the mouse over a button called, for example, "Continue" (120) available on this message.

At the end of the test, a message shown in Figure 13 appears. This message indicates that the piston (16) goes up to a memorized position, corresponding to its position configured in the configuration screen represented in FIG. 3. This message also indicates in a zone (130) the measurement of displacement of the piston and applied force. It is also possible to enter a note corresponding to this test in a message. A message represented in FIG. 14 and comprising a frame (140) for entering text appears to enter this note. If the operator clicks on a button called, for example, "OK" (141), a message shown in Figure 15 indicates that the micro-indentation test is complete. The operator can also cancel the test, ie erase all the data relating to this test, by clicking on a button called, for example, "Cancel the test" (142). On the message shown in FIG. 15, a button called, for example, "OK" (150) makes it possible to definitively validate the test. When the operator clicks on the "Session" tab (43) of the first zone (40) of the control screen (4), then selects in this tab, the instruction "next indentation", the data relating to the test which has just been carried out, are definitively recorded and the operator can proceed to the next step. The data acquired during the test is processed by transposing it into an open file on a processing software integrated or not in the test software. In the case where the processing software is not integrated with the test software, the latter will be, for example a spreadsheet, such as, for example, Excel software (registered trademark) from the company Microsoft. The data (364) are, for example, copied into a special file designed in the spreadsheet, as shown in FIG. 16, then processed to reproduce the curve (360) of the test in this file. A zone (361) of linearity on the discharge curve (100c) of the test curve is then determined to calculate the reduced elastic modulus. The calculation is carried out from a slope comprising, for example, seven points of this linearity. The value of the reduced elastic modulus E * is then read in a cell (E22) (362) of the file. The hardness P value is calculated from the formula defined above in a cell (EF29) (363) of the file.

The reduced elastic modulus E * can be defined after a certain period of relaxation. The relaxation time is the time allowed between charging and discharge so that all the plastic deformations take place and all the flow constraints at the origin of these deformations are relaxed.

Thus, during the discharge, one theoretically finds oneself in the field of purely elastic deformations. An optimal relaxation time was determined for each excipent by carrying out several tests on the same strip of pharmaceutical solid, with different relaxation times. The reduced moduli of elasticity obtained were then compared so as to know at the end of which relaxation time applied the results stabilize. In addition, the analysis of different discharge curves carried out at the same location shows that this domain is elastic because the discharge curves obtained are superimposable.

Finally, the calculation of the reduced elastic modulus was carried out according to a determined slope over an area of the discharge curve as linear as possible. As described above, a slope has been defined, for example, from seven points taken as close as possible to the end of the relaxation time so as to position itself in an elastic domain.

The materials presented here as an example of the application of the procedure for using the micropress in the context of micro-indentation tests are three excipients conventionally used in galenical formulation. They have the advantages of being non-toxic, easy to supply, directly compressible, while offering very differentiated and representative mechanical behaviors from those encountered in galenical formulation. However, it should be remembered that the micropress (1) according to the invention is intended for all types of pharmaceutical solids which can take various forms. The choice of these three compounds (1) is in no way limiting on these compounds and any pharmaceutical solid of any form can be characterized by the micropress (1) according to the invention. The three solids chosen are: - AVICEL PH 101 (registered trademark) which is a microcrystalline cellulose (SEPPIC, lot n ° 6512) chosen for its plastic behavior (Py ≈ 50 MPa),

- DI-TAB (registered trademark) which is a calcium phosphate dihydrate (Rhône-Poulenc Inc, lot n ° 057741) chosen for its fragmentary behavior (Py ≈ 275 MPa),

- LACTOSE FF (registered trademark) which is an atomized lactose of fast-flow quality (SEPPIC, lot n ° 859122562) and whose behavior is fragile (Py ≈ 109 MPa). These three products exhibit different behaviors which are representative of the behaviors of a very wide range of pharmaceutical products. Experimentation on these three products with different behaviors could therefore be generalized to this very wide range of pharmaceutical products. The compaction of the granular systems studied was carried out without internal lubrication, with a mold geometry (punches + matrix) allowing to obtain parallelepipedic compacts (bars).

All the active surfaces of the mold used were lubricated with magnesium stearate, before the production of each of the bars. The analysis of the production of the compacts is carried out in force-displacement using a high-pressure hydraulic press "PERRIER LABOTEST" instrumented, fitted with the measuring module 705. It can impose a compression force of 300 kN, by raising the lower piston. The bars, of varying porosities, were produced by the application of forces F ranging from 10 to 50 kN corresponding respectively to pressures from 42 to 210 MPa.

The bars thus produced were stored, just after they were removed from the mold, in petri dishes placed in a humidity-controlled bell, maintained at 50% relative humidity (RH%) with a saturated solution of sodium dichromate dihydrate. The bars have a length (L) equal to 40.00 mm and a width (I) equal to 6.20 mm (theoretical values deduced from the dimensions of the mold).

It should be noted that these values are theoretical because the dimensions measured after relaxation (after 3 days) are slightly higher than those measured just after demolding.

The height (h) is itself variable according to the porosity, therefore according to the force applied and according to the quantity of powder introduced into the mold. Thus, for the sake of standardization, the mass of powder weighed for a bar was determined in order to obtain a height of 5 mm at zero porosity; that is to say approximately 2 g for AVICEL PH101 and for LACTOSE FF and approximately 3 g for DI-TAB which has a true density much higher than the two other excipients.

After the time allowed for relaxation, each bar was exactly weighed (M in g) and measured using a digital caliper allowing the exact calculation of the porosity.

Let V be the volume of the bar such that:

V = L * I * h, hence the density ε = 1 - _apparent p / Po with _apparent p = M / V

The AVICEL PH101 which served as support for this study has a true density equal to 1.5378 g / cm ³ (standard deviation = 0.0002 g / cm ³ ). Microscopic observation of the AVICEL PH101 shows an elongated, more or less fibrous and irregular shape of its particles. This result was moreover confirmed by laser diffraction where the particle size distribution by volume is symmetrical, but with an average diameter of 58 +/- 48 μm.

For the determination of E * and P, we applied the method indicated in the procedure for carrying out micro-indentation tests on AVICEL PH101 compacts, of different porosities with different relaxation times ranging from 3 to 15 minutes.

The results obtained (Table 1, in this example on a bar compressed to 45 KN) make it possible to choose the relaxation time most relevant to implement during a test on AVICEL PH101, no prior charge / discharge cycle being necessary for these three products:

Tab. 1: determination of the relaxation time for AVICEL PH101.

Thus, the relaxation time recommended for the AVICEL PH101 is 5 minutes.

In order to make sure that the reduced elastic modulus E * was well determined in an elastic domain, several indentations in the same place (with the relaxation time determined previously) were carried out so as to compare the values of E * obtained (figure 17a).

In FIG. 17a, after relaxation, the discharge curves (175) are superimposable and have very close E * values (the standard deviation being 255 MPa or 2.1%). The differences obtained are therefore very small, which attests to a high accuracy in the measurement of E *, and this from the analysis of the first discharge curve.

In addition, Brinell (P) hardness measurements on AVICEL PH101 strips were also carried out. This parameter could be analyzed thanks to the possibility of knowing the exact value of the depth of the imprint remaining after the removal of the indenter (166).

Table 2 shows some results obtained in terms of indentation hardness (P):

Tab. 2: examples of results obtained in terms of indentation hardness for the AVICEL PH101.

FIG. 17b representing the extrapolation with zero porosity according to the empirical exponential model of RYSHKEWITCH (1953), shows a value (174) consistent with 190 MPa with that encountered in literature. The LACTOSE FF has a true density equal to 1.5314 g / cm ³ (standard deviation = 0.0004 g / cm ³ ), which remains close to the AVICEL PH101. On the other hand, microscopic observation differentiates it by showing a greater sphericity of its particles. In addition, in laser diffraction, the particle size distribution is asymmetrical, with an average diameter of 113 +/- 50 μm.

As for the AVICEL PH101, a study was carried out to determine the reduced elastic modulus E * and the Brinell P hardness. Several micro-indentation tests on compacts of LACTOSE FF, of different porosities with different relaxation times ranging from 1 to 10 minutes were carried out according to the method described above.

The results obtained (Table 3, in this example on a bar compressed to 45 KN) allow us to choose the most relevant relaxation time to be implemented during a test on this product:

Tab. 3: determination of the relaxation time for the LACTOSE FF.

Thus, the relaxation time recommended for LACTOSE FF is 3 minutes. As before, we made sure that the reduced elastic modulus E * was well determined in an elastic domain, we carried out several indentations in the same place (with the relaxation time determined previously) and we thus compared the values of E * obtained (Figure 18a). In Figure 18a, we see that the discharge curves (180) at the end of the relaxation time of 3 minutes are superimposable and have very close E ^* values (the standard deviation being 857 MPa or 4.7%) . The differences obtained are again very small, which attests to a high accuracy in the measurement of E *, and this from the analysis of the first discharge curve. We also carried out Brinell (P) hardness measurements on this excipient, using the same approach as that applied to AVICEL PH101.

Table 4 shows the results obtained in terms of indentation hardness (P):

Tab. 4: examples of results obtained in terms of indentation hardness for the

LACTOSE.

The DI-TAB is characterized by a true density equal to 2.4430 g / cm ³ (standard deviation = 0.0005 g / cm ³ ), by a large sphericity of the particles observed by optical microscopy and by a bimodal particle size distribution with a first mean diameter around 160 μm and a second between 600 and 800 μm.

A similar study was carried out on this third example: E * and P were therefore determined by applying the method indicated in the procedure for carrying out micro-indentation tests. The DI-TAB compacts, having different porosities, were tested with different relaxation times ranging from 20 seconds to 3 minutes.

The results obtained (Table 5, in this example on a bar compressed to 30 KN) allow us to choose the most relevant relaxation time to be implemented during a test on this product: Tab. 5:

Thus, the relaxation time recommended for DI-TAB is 1 minute. Here again we made sure that the modulus of elasticity reduced

E * was well determined in an elastic domain by carrying out several indentations in the same place (with the relaxation time previously determined) in order to compare the values of modulus E * obtained (FIG. 19a). In FIG. 19, we note that the discharge curves (190), at the end of the relaxation time, are still superimposable and have very close modulus E * values (the standard deviation being 447 MPa or 1.9%). The differences obtained are again very small, which attests to a high accuracy in the measurement of E *, and this from the analysis of the first discharge curve. We also carried out Brinell (P) hardness measurements on this excipient, using the same approach as that applied to the other products.

Table 6 shows the results obtained in terms of indentation hardness (P):

Tab. 6: examples of results obtained in terms of indentation hardness for the

DI-TAB.

Unlike the two previous examples, the classic exponential model used for extrapolation with zero porosity (model of

RYSHKEWITCH) is difficult to apply to DI-TAB, which makes it difficult to quantitatively interpret the results on high porosities as is the case in this example.

The examples presented here in application of the procedure for using the micropress in the context of micro-indentation tests show the possibility of determining a reduced elastic modulus E * and a Brinell P indentation hardness. from the first parameter, three cases (validated in the range of porosity studied) are distinguished according to the excipient which is analyzed: it is necessary to program a relaxation time equal to 5 minutes when it is a question of the AVICEL PH101, while that 3 minutes are sufficient for the LACTOSE FF, and 1 minute for the DI-TAB. In all three cases, no prior cycle is necessary. In addition, the precision obtained on the values of E *, thanks to the graphical determination mode proposed, is also demonstrated.

The determination of the indentation hardness is also very precise, as was noted above.

It should be remembered that all these results are only illustrations and are not in any way limiting on the use of the micropress (1). In fact, the micropress (1) according to the invention can be used to characterize pharmaceutical solids of any shape and of any composition. The three excipients were chosen because they exhibit different behaviors representative of the behaviors of a very wide range of pharmaceutical solids. The results obtained can therefore be generalized to this very wide range of pharmaceutical products exhibiting these different behaviors.

The micro-indentation test allows a measurement of the Brinell hardness and the elasticity of a material at a particular point on its surface. It is interesting to generalize this measurement to an entire area of a material, in particular to an entire face, in order to have "statistical" information of this face. In fact, during the powder compression cycle in order to form a tablet, the force is applied to the upper face of the powder bed present in the mold. This effort is more or less well transmitted to the underside of the powder bed depending on the products. The difference between the force transmitted on the lower face of the powder bed and that transmitted on the upper face of the powder bed is "lost" by the effect of friction on the internal walls of the mold. The ratio between the force transmitted on the underside of the powder bed and that transmitted on the upper face of the powder bed is called the "transmission coefficient" of the compression force. We can therefore generalize the calculation of a surface transmission coefficient with regard to Brinell hardness and elasticity.

The average value of Brinell hardness or elasticity provides information on the overall behavior of the face studied. FIG. 38a shows an example of three positions of the indentor (166) relative to a pharmaceutical solid (2). The set of different measurement points forms a matrix (200).

The standard deviation of the Brinell hardness or elasticity measurements reflects the distribution of the areas of high density on this face. Figure 38b shows a example of the density on one side of a pharmaceutical solid (2), the darkest areas being those of highest density and the lightest, those of lowest density. This generalized micro-indentation test makes it possible to account for the heterogeneity of the surface densities of a material. A second test consists in practicing three-point bending on a pharmaceutical solid (2) using the micropress (1) according to the invention.

In this context, a number of charge / discharge cycles is applied to a pharmaceutical compact with parallelepiped geometry positioned on a three-point bending bench. An ultimate load is then applied so as to cause the median rupture of the compact. Depending on the nature of the pharmaceutical solid (2) tested, it may be necessary to allocate a relaxation time between the charge and the discharge.

Different quantities can then be determined by graphic study after this test. In particular, these quantities are the breaking stress, the modulus of elasticity and the toughness.

The breaking stress (σ _r ) is determined on the basis of the ratio between the maximum force (Fmax) recorded at the time of the break and the total surface created after the break, depending on the geometry of the bar and the conditions of trial.

σ _* = -

2l ^λ

where I is the width of the bar, h the height of the bar, and p the range of the device, that is to say the distance between the two support cylinders.

The modulus of elasticity (E) defines the elastic response of a material during a stress. It is about a matrix operator which gives a relation of direct proportionality between the stress and the axial deformation at the time of a request following the compression axis.

p _ F max- pr

4δh ³ l The material used is similar to that used for the first micro-indentation test. For the three-point bending test, as for the micro-indentation test, the presence of transverse displacement sensors (23) is not necessary since the solid is not substantially deformed transversely. In a three-point bending test, the sample is placed manually on a three-point bending bench (19) fixed to the XY table (11) by means of two lateral screws. The sample is placed on the bending bench (19) so as to present three points of contact with three pins (20) provided for this purpose, as shown in FIG. 20. For this test, the indenter (166) used is with a cylindrical geometry with a diameter equal to 2.00 mm. The assembly of the indenter (166) is carried out, as described above with reference to FIGS. 2 and 3.

The control screen (4) is identical to that of the micro-indentation test. The operating mode is identical, only the control parameters vary compared to the micro-indentation test. The control parameters, as we have already written above, are chosen arbitrarily and must be adjusted according to the behavior of the product tested.

The loading speed (70) is fixed at 0.050 mm / minute, the maximum insertion (71) at 0.500 mm, the maximum load (72) at a value lower than the breaking force of the bar, the breaking force being predetermined during a prior test on a similar strip. For an AVICEL PH101 bar compressed to 50 KN, the maximum load is here fixed at 40 N. The number of charge / discharge cycles (73) varies according to the material constituting the material tested. It will be four for the AVICEL PH101, two for the LACTOSE FF and one for the DI-TAB. These values will be explained in the examples according to the operating mode. The time delay (74) between two cycles is fixed at 20 seconds. The data acquisition frequency (78) is fixed at 00 min 00.1 second. Loading and unloading are chosen by checking the corresponding box (76) in the screen for entering parameters. The relaxation time (77) is calculated in the same way so that for the micro-indentation test and the acquisition frequency (79) indicated in this area of the screen window is fixed at 00 min 00.1 second.

As before, when all the parameters are fixed, it remains to click with the mouse on the "OK" button (80).

The control screen (4) indicates these parameters in its second area (41), as shown in FIG. 21.

The test starts after a click on the "Start" button (53) on this control screen (4). Once the test has been completed and the curve drawn in the third zone (42) of the control screen (4) as shown in FIG. 22, the rupture test is applied to the bar. For this, the operator clicks again on the "Test" tab (49) in the menu area of the control screen (4) and modifies the value of the maximum load (72) to fix it at a value greater than that causing the bar to break. The number of cycles (73) is also fixed at one. The operator then clicks again on the "Start" button (53) on the control screen (4) to launch the rupture test. The course of this ultimate charge on the pharmaceutical solid is identical to previously and results in a graphic representation (230) in the third zone (42) of the control screen (4), visible in FIG. 23.

The data is then processed in the same way as during the micro-indentation test. The dimensions of the bar are entered in cells of the Excel file. The breaking stress is calculated according to these data in a cell of the file (B17) (240). The modulus of elasticity is calculated after the application of several charge / discharge cycles before the rupture test. The application of several cycles makes it possible to achieve a certain stability in the result and is explained by the irreversible deformations which take place within the sample tested.

Indeed, the modulus of elasticity characterizes a reversible deformation, it must therefore be measured when a stress on the material leads to a purely elastic response. To verify that this area has been reached, it suffices to apply the same load several times, while remaining lower than the load which generates the rupture. The similarity between the charge and discharge curves and the reproducibility of these cycles must therefore attest to the correct configuration of the test.

For the calculation of the elastic modulus, a line segment (241) is placed on the discharge curve (242), this segment (241) delimiting on this curve a linear domain in which the calculation of the elastic modulus will be done , as shown in Figure 24. The elastic modulus is calculated in cell B19 (243) in Figure 24. The materials presented here as an example of the application of the procedure for using the micropress in the context of three-point bending tests are three excipients conventionally used in galenical formulation. These are the same as those used in the micro-indentation test, i.e. AVICEL PH 101, DI-TAB and LACTOSE FF.

The bars used for the test are manufactured in the same mode as that used to make the bars used for the micro-indentation test.

With a view to determining the minimum relaxation time for each excipient, several tests have been carried out, for each excipient, on the same strip of pharmaceutical solid. The elasticity modules obtained were then compared so as to know at the end of which relaxation time applied the results stabilize.

In order to determine the number of cycles necessary to stabilize the test conditions, a first test on an AVICEL PH101 strip, compressed to 52 KN, was carried out. This first test consists in successively applying five loads of 5 daN then a sixth of 6 daN to cause rupture, as shown in Figure 25. It should be noted that these forces were applied at the speed of 0.050 mm / min. The curves obtained were collated on the graph (Figure 25) by deleting the values where F = 0 at the start, so as to compare them. These control parameters are of course chosen arbitrarily and must be adjusted according to the behavior of the product tested.

It is clear from FIG. 25 that one is not situated exclusively in the elastic range during the first cycle. Phenomena of plastic deformation and stable positioning of the bar by crushing certain grains located on its surface (the parts of the sample in contact with the three-point support not being perfectly flat) are therefore probably at the origin of parasitic phenomena with respect to the elasticity that one seeks to measure.

A complete study of this principle of application of the cycles was therefore carried out on four AVICEL PH101 strips, according to a sufficiently wide range of porosity (23% to 9%) to determine a value of E with zero porosity, extrapolated according to the Ryshkewitch model. For each porosity, there are two stages:

1) Repetition of 5 previous cycles (Figure 25, first cycle (250)), at loads lower than those causing rupture (determined for each porosity), then rupture at the sixth load (Figure 25, 251), the desired stability being reached on 4 ^ènηe cycle. 2) Calculation of E by graphical determination of the slope at load ie

“E _ch ” and the slope at the discharge, ie “E _chill ” (figure 26), based on the fourth cycle.

It can be seen in FIG. 26 that the values of E _ch (260) and E _deGh (261) are relatively close, respectively 3738 MPa and 3790 MPa in this example, which gives an average difference of less than 2% if we takes into account all the tests carried out.

The graph in FIG. 27 illustrates the extrapolations with zero porosity which make it possible to compare the raw E values obtained by going to failure without making a cycle (E _mp ) (270) with the E values obtained over the 4 ^th cycle ( E _ch and E _déc ) (271). A difference is thus clearly highlighted between the values obtained by making several cycles and the raw values obtained by going directly to rupture (approximately 25% of deviation at zero porosity), which demonstrates the importance of achieving a certain number cycles before breaking the pharmaceutical solid.

As for AVICEL PH101, a complete study on 4 strips of LACTOSE compressed respectively to 15, 25, 30 and 45 KN (ie porosities ranging from 24% to 13% approximately) was carried out.

The same methodology as that used for AVICEL PH101 was applied, and the conclusions are similar for these two products, with a few nuances:

Stability was reached after 2 cycles (280, 281) only (Figure 28). A third cycle (282) was therefore carried out to cause the breakage of the bar. The values of E _ch (290) and E _dech (291) are relatively close, with an average difference here of around 2.5% (Figure 29).

FIG. 30 illustrates the extrapolations with zero porosity thus making it possible to compare the values of E _mp with the values of E _ch and of E _dech . A greater difference than that which concerned AVICEL PH101 is demonstrated between the values obtained by making several cycles (300) and those obtained by going directly to rupture (301) (approximately 33% of deviation at zero porosity).

In application of the principle which consists in applying several charge / discharge cycles before a final load test leading to rupture, several bars of DI-TAB, compressed respectively to 15, 30 and 35 KN (i.e. porosities ranging from 33% to 27 about%), have been analyzed.

The conclusions are still close to the previous ones. Stability was reached after only 1 cycle (310) (Figure 31).

The values of E _ch (320) and E _dech (321) (Figure 32) are relatively close (the mean difference here being less than 0.1%). Figure 33 illustrates the extrapolations with zero porosity allowing us to compare the values of E _mp with the values of E _ch and E _dech . A difference identical to that presented by the AVICEL PH101 is highlighted between the values (330) obtained by carrying out a cycle prior to rupture and those (331) obtained by going directly to rupture, that is to say approximately 25% of difference at zero porosity.

The methodology proposed here for the study of the modulus of elasticity in three-point bending, via the micropress (1), is based on the principle of carrying out cycles prior to rupture. Three cases (validated in the range of porosity studied) are distinguished according to the excipient which is analyzed: it is necessary to carry out 4 cycles when it is a question of AVICEL PH101, while 2 are sufficient for LACTOSE FF, and 1 alone for DI-TAB.

Thus, carrying out a certain number of cycles, depending on the product tested, seems essential for the precise and reproducible determination of the modulus of elasticity.

The three-point bending test makes it possible to determine the modulus of elasticity and the breaking stress of a material. It is also interesting to determine the "toughness" of a material. This quantity quantifies the resistance of a material to the propagation of a crack, and corresponds to the critical value of the stress concentration factor K _1C (MPa. M ¹ ' ² ) of a material.

The principle of the toughness measurement is shown in Figure 39. The toughness is measured, in a three-point bending test, on previously cracked bars. A crack (201) is produced on the pharmaceutical solid (2) after the powder compacting operation to obtain the pharmaceutical solid (2). The crack (201) is made substantially in the middle of the bar, over the entire width of one of the faces of the bar. The crack (201) has a depth "a" equal, for example, to 1 mm and as narrow as possible. For the three-point bending test, the bar is positioned with the crack on the underside of the bar.

The test protocol developed using the micropress consists in carrying out only one and only loading until the sample breaks.

The value of the toughness is calculated according to the force existing at the time of the rupture, that is to say the maximum force on the results curve, and the dimensions of the bar:

K _1C = Y. σ _r . (a) 0 '.5

where a is the depth of the crack (201), Y is a polynomial function, and σ _r is the breaking stress determined by a classic three-point bending test on an uncracked bar. The polynomial function Y is worth:

Y = A ₀ + A ₁ (a / h) + A ₂ (a / h) ² + A ₃ (a / h) ³ + A ₄ (a / h) ⁴ where A ₀ = 1.9 + 0.0075 (p / h ) A, = -3.39 + 0.08 (p / h) A ₂ = 15.4 - 0.2175 (p / h) A ₃ = -26.38 + 0.2815 (p / h)

A ₄ = 26.83 - 0.145 (w / h) h being the height of the bar and p the range of the device.

A third test consists in carrying out a uniaxial compression test on a pharmaceutical solid (2) using the micropress (1) according to the invention.

The uniaxial compression test is carried out on a cylindrical pharmaceutical solid (2). It makes it possible to determine the Young's Modulus E and the Poisson's ratio v of a material. This test is conventionally used in rock mechanics on soil samples taken by coring, or in civil engineering on concrete specimens, all of these samples being relatively large. The diameter of these test pieces is conventionally between 40 mm to 150 mm, and their height is substantially equal to twice the diameter. The difficulty with pharmaceutical solids is the small size of the test pieces, the diameter of which cannot, in general, exceed 10 mm and the height, sometimes 4 or 5 mm.

The control screen (4) is identical to that of the three-point micro-indentation and bending tests. The procedure is identical. While having previously verified that it is located in a zone of elastic stresses of the material, a pre-stress cycle is carried out, then a loading + relaxation + unloading cycle.

The sample has an initial length L and an initial diameter D. When it is subjected to an axial load F, it sees its length decrease by ΔL and its diameter increase by ΔD. The measurement of the transverse deformation makes it possible to know ΔD.

We can then calculate the values of the Young's modulus E and of the Poisson's ratio v as follows:

AD / D

E - F / S and v = - MIL AL / L

E being expressed in MegaPascal (MPa) and v being without unit. S is the area of application of the constraint.

For example, the Poisson's ratio of a metal or a geomaterial is close to 0.3. In the same way as with a three-point bending test, it is possible to program preloadings and a relaxation time depending both on the material, and carry out a loading and unloading cycle in order to measure, at the time of unloading, and just after relaxation, the Young's modulus from the slope of the linear segment. In the same way as for the measurement of the modulus of elasticity by means of a three-point bending test, the micropress (1) is capable of applying a force F (in Newton) and of measuring the longitudinal deformation of the sample ΔL (in mm) thanks to the vertical displacement sensor (17). However, for the uniaxial compression test, the presence of transverse displacement sensors (23) is necessary since the solid is deformed transversely.

The initial length of the pharmaceutical solid (2) is measured before the test using a digital caliper. The initial diameter of the pharmaceutical solid (2) is measured before the test using the transverse displacement sensors (23). Before placing the pharmaceutical solid (2) on the micropress (1), the test probes (25) of the transverse displacement sensors (23) are brought into contact in order to determine the value of zero. This value is memorized by the software. After the pharmaceutical solid (2) has been placed on the micropress (1), before the test, the test tips (25) of the transverse displacement sensors (23) are brought into contact with the pharmaceutical solid (2) in order to to determine the value of the diameter of the solid. The transverse displacement measurements made by the transverse displacement sensors (23) will therefore be relative values, corresponding to a measurement of the variation in the diameter of the pharmaceutical solid (2) relative to the diameter of the pharmaceutical solid (2) before the measurement.

It is possible to make additional measurements of the diameter of the pharmaceutical solid (2) by rotating the movable ring (22) around the pharmaceutical solid (2) in order to be able, for example, to make two measurements at 90 °, then to average, in case the sample is not completely symmetrical.

After placing the pharmaceutical solid (2) on the micropress (1), and before measuring the diameter of the solid by the transverse displacement sensors (23), the movable ring (22) is adjusted in height so as to what the transverse displacement sensors (23) are located at the middle of the pharmaceutical solid (2).

Figures 37a and 37c show poor centering (2450) of the rings (21, 22) relative to the center (2410) of the pharmaceutical solid (2). In this case, if spherical test probes (25) are used, the measurement is incorrect because the distance between the two test probes is not equal to the diameter of the sample (13). On the other hand, the use of cylindrical touch points (25) makes it possible to counteract the defect in eccentricity by the length of the cylindrical touch points, which are positioned perpendicularly to the axis of the pharmaceutical solid (2), and which therefore measure the greatest possible distance equal to the diameter of the pharmaceutical solid (2).

Figures 37b and 37d show correct centering (2450) of the rings (21, 22) relative to the center (2410) of the pharmaceutical solid (2). In this case, the measurement made by the transverse displacement sensors (23) effectively corresponds to the diameter of the sample (13).

During the actual measurement cycle, the curve of the transverse displacement as a function of the piston displacement can be displayed in real time by the software. it should be obvious to those skilled in the art that the present invention allows embodiments in many other specific forms without departing from the scope of the invention as claimed. Therefore, the present embodiments should be considered by way of illustration, but may be modified in the field defined by the scope of the appended claims, and the invention should not be limited to the details given above.

Claims

1. Method for characterizing the mechanical properties of pharmaceutical solids (2) produced by powder compaction, characterized in that it consists in carrying out on the pharmaceutical solid (2):

- either a three-point bending test,

- either a micro-indentation test,

- either a uniaxial compression test,

- either two tests among the three mentioned above, - or the three tests, a determined number of preliminary cycles being carried out on the pharmaceutical solid (2) tested until obtaining from the pharmaceutical solid a purely elastic response, the number of cycles being a function of the nature of the pharmaceutical solid tested, and a certain time, variable depending on the nature of the pharmaceutical solid (2) tested, being left between a charge and a discharge, so as to obtain optimal relaxation of the pharmaceutical solid (2 ) to find themselves, during discharge, in the field of elastic deformations of the pharmaceutical solid (2), these tests being carried out using a micropress (1) comprising a piston (16), and each of the tests comprising , before an actual measurement cycle, at least one prior cycle comprising a charge and a discharge.

2. Method according to claim 1, characterized in that, during a three-point bending test, the real measurement cycle consists in applying an ultimate load on the pharmaceutical solid (2) so as to cause its median rupture.

3. Method according to one of claims 1 or 2, characterized in that it comprises a step of executing software, arranged in a computer system (3) connected to the micropress (1), allowing at least the entry of operating parameters of the micropress (1), such as the speed of loading the piston (16), the maximum displacement of the piston (16), the maximum load applied to the pharmaceutical solid (2), the number of charge / discharge cycles to be carried out, the time between charge and discharge or the frequency d acquisition of the force applied by the piston (16) on the solid (2) as a function of the displacement of the piston (16) or of the stress in the pharmaceutical solid (2) as a function of the displacement of the piston (16) towards this solid (2), the step of executing the software being followed by a step of recording the operating parameters of the micropress (1) in storage means (M1) contained in the computer system (3).

4. Method according to claim 3, characterized in that it comprises a step of displaying in real time, by software, result curves relating to the force applied by the piston (16) on the solid (2) in as a function of the displacement of the piston (16), of the stress in the pharmaceutical solid (2) as a function of the displacement of the piston (16) towards this solid (2), or also to the transverse deformation of the pharmaceutical solid (2) as a function of the displacement of the piston (16), and recording of these curves in the storage means (M1) of the computer system (3).

5. Method according to claim 4, characterized in that it comprises a step of calculation from the results observed, by calculation means included in the computer system (3), quantities characterizing the mechanical properties of the pharmaceutical solid, such that, for a micro-indentation test, the reduced elastic modulus and the Brinell hardness, for a three-point bending test, the breaking stress, the elastic modulus and the toughness, and, for a compression test uniaxial, Young's modulus and Poisson's ratio.

6. Method according to claim 5, characterized in that the calculation of the Young's modulus determined by a uniaxial compression test requires at least the measurement of the vertical displacement of the piston and of the force applied by the piston, and that the calculation of the Poisson's ratio determined by a test of Uniaxial compression requires at least the measurement of the vertical displacement of the piston and the measurement of the transverse deformation of the pharmaceutical solid (2).

7. Micropress (1) to highlight the mechanical properties of pharmaceutical solids (2), characterized in that it comprises means for recording operating parameters of the micropress (1), means for controlling the movement of '' a piston (16) for loading towards the pharmaceutical solid (2) placed under this piston (16) according to the operating parameters, a force sensor (18) measuring the force exerted on the pharmaceutical solid (2) by a head assembled at the end of the piston (16) close to the solid (2) in position, a vertical displacement sensor (17) measuring the displacement of the piston (16), the latter being located closest to the sample and triggered by triggering means when an effort is detected at the effort sensor (18), two transverse displacement sensors (23) measuring the transverse deformation of the pharmaceutical solid (2), the transverse displacement sensors (23) and ant supported by a movable horizontal ring (22) in rotation situated around the pharmaceutical solid (2) tested, the position of this movable ring (22) being adjustable in height, so as to position the transverse displacement sensors (23) substantially in the middle of the pharmaceutical solid (2), means for recording the signals emitted by the sensors (17, 18, 23), means for calculating the quantities characterizing the mechanical properties of the solid as a function of the recorded signals and parameters of the micropress (1).

8. Micropress (1) according to claim 7, characterized in that it comprises a computer system (3) executing specific operating software allowing the display, by display means of the system, of input fields of the operating parameters of the micropress on a system screen (3), the system (3) controlling, depending on certain operating parameters entered, a gear motor (15), actuating via a ball screw (14), the loading piston (16) along its axis directed towards the pharmaceutical solid (2) in position, the head of the loading piston (16) supporting an indenter (166) for carrying out, on the pharmaceutical solid (2), a three-point bending test, a micro-indentation test or a uniaxial compression test, the latter test requiring the presence a floating punch (1600) between the indenter (166) and the pharmaceutical solid (2) the results of this test being collected by the system (3) to be processed by the software, the system (3) comprising the means of calculation to calculate the quantities characterizing the mechanical properties of the pharmaceutical solid (2).

9. Micropress (1) according to claim 7 or 8, characterized in that the control means control the speed of movement of the piston (16) by means of a force, position or speed of movement regulator of the piston (16), of the PID (Proportional Integral Derivative) type.

10. Micropress (1) according to claim 8 or 9, characterized in that the system (3) also comprises means for displaying in real time curves relating to the force applied by the piston (16) on the solid (2 ) as a function of the displacement of the piston (16) or under stress in the pharmaceutical solid (2) as a function of the displacement of the piston (16) towards this solid (2).

11. Micropress (1) according to one of claims 8 to 10, characterized in that the pharmaceutical solid (2) rests on a table (11) positioned on a base (10) surmounted by the gearmotor (15) actuating the piston ( 16) along its axis directed towards the pharmaceutical solid (2) via the ball screw (14).

12. Micropress (1) according to claim 11, characterized in that the table (11) is an XY cross-motion table allowing the operator to precisely position the measuring point of the sample to be tested under the indenter (166), then move the sample to the next measuring point without having to touch the sample.

13. Micropress (1) according to one of claims 11 or 12, characterized in that, during a uniaxial compression test, a sample holder (29) is positioned between the table (11) and the pharmaceutical solid ( 2).

14. Micropress (1) according to one of claims 7 to 13, characterized in that the movable ring (22) is supported by a fixed horizontal ring (21), the movable ring (22) being able to rotate around a vertical axis, and relative to the fixed ring (21), by means of rollers (26) located between the movable ring (22) and the fixed ring (21), and the position of the fixed ring ( 21) being adjustable in height by means of a knurled screw penetrating into a sleeve of a part (28) internally threaded and supporting the fixed ring (21).

15. Micropress (1) according to one of claims 7 to 14, characterized in that the force sensor (18) is a sensor with a strain gauge bridge placed on the piston (16) for loading just at- above the head.

16. Micropress (1) according to one of claims 7 to 15, characterized in that the vertical displacement sensor (17) is an incremental feeler secured to the head of the piston (16) for loading via a first plate (164), this displacement sensor (17) comprising a touch point (170) in permanent contact with a reference consisting of a second plate parallel to the first plate, the displacement of the piston (16) causing the sliding of the probe tip (170) in a sleeve integral with the first plate (164), the vertical displacement sensor (17) comprising means for measuring the displacement of the probe tip in the sleeve corresponding to the displacement of the loading piston (16) relative to the pharmaceutical solid (2).

17. Micropress (1) according to one of claims 7 to 16, characterized in that the transverse displacement sensors (23) are incremental feelers each comprising a cylindrical touch tip (25), each touch tip (25) being horizontal and tangent to the surface of the pharmaceutical solid (2), and in permanent contact with the pharmaceutical solid (2), as well as means for measuring the displacement of the test tip (25) relative to the position of the tip button (25) before the test.

18. Micropress (1) according to one of claims 7 to 15, characterized in that the indenter (166) can be spherical, cylindrical or pyramidal.