FR2823307A1 - Mechanical characterization of pills uses automatic micropress applying preloading cycles when carrying out three-point flexure and microindentation tests - Google Patents

Abstract

Pharmaceutical solid (2) in a micropress (1) undergoes a three-point flexure test and a microindentation test. Prior loading and unloading cycles precede actual measurement in each test. An Independent claim is also included for the micropress (1) able to record functional parameters and to control loading piston (16) displacement toward the pharmaceutical solid (2) located below it. A sensor (18) measures the force exerted, through a head at the piston end. A displacement sensor (17) measures piston movement. Further equipment calculates properties of the solid from the measurements. Preferred features:

Description

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Process 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 sciences, metallurgy, polymer materials sciences, ceramics or concrete industries. In the field of pharmacy, very few studies have been conducted to characterize the mechanical properties of pharmaceutical solids. In a 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 generally being largely in the majority relative to the others. Compacted tablets can be manufactured at a rate of 200,000 to 300,000 tablets per hour. These high production rates, imposed on granular systems that do not directly transmit the applied stresses, often result in the formation of stress heterogeneities and therefore of density inside the tablets. These heterogeneities of density, during relaxation of the tablet due to its viscoelasticity, cause the tablet to tend to break (cleavage, capping) just after compaction and in particular when it is sent into the receiving bins. Knowledge of the mechanical properties of pharmaceutical solids may therefore prove to be advantageous when formulating a medicament so as to avoid such 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 pharmaceutical systems of techniques developed outside the pharmacy. This is how the cohesion characteristics of compacted systems could be

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 addressed by evaluating the internal stress of rupture 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 tenacity of a compacted material, that is to say of its ability to withstand corrosion. rupture by propagation of cracks. Indentation techniques have also been applied to the characterization of compacted solids. These techniques have been exploited by transposing the Brinell or Vickers experimental conditions to measure indentation modules on a number of pharmaceutical systems.

 However, these recent advances do not solve all the problems. In fact, these techniques do not make it possible to completely and accurately characterize 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 disadvantages of the prior art by proposing a method of characterizing the mechanical properties using a dedicated tool and taking into account in particular the viscoelasticity of the product so as to obtain results. of great reliability. The invention will therefore provide a better understanding of the behavior of pharmaceutical powders during the compacting operation as well as their properties after compaction.

 This object is achieved by a method for characterizing the mechanical properties of pharmaceutical solids manufactured by powder compaction, characterized in that it consists in carrying out a three-point bending test and a microindentation test using a micropress, each of the tests comprising, before an actual measurement cycle, at least one prior cycle comprising a charge and a discharge.

 According to another particularity, for a micro-indentation test, a certain time, varying according to the nature of the pharmaceutical solid tested, is left between the charge and the discharge, so as to obtain a relaxation

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 optimum of the pharmaceutical solid to be found during the discharge in the field of elastic deformations of the pharmaceutical solid.

 According to another feature, for a three-point bending test, a predetermined number of prior cycles charge / discharge is performed on the tested pharmaceutical solid until the pharmaceutical solid, a purely elastic response, the number of cycles depending on the nature of the pharmaceutical solid tested.

 According to another feature, in a three-point bending test, the actual measuring cycle consists in applying an ultimate charge on the pharmaceutical solid so as to cause its median rupture.

 The transposition of devices used in other sectors to the pharmacy sector, makes these devices are generally unsuitable and often imprecise for the study of the mechanical properties of pharmaceutical solids. Likewise, the devices specific to pharmaceutical solids developed are generally very imprecise. Indentation techniques have been made more efficient by the use of extensometers which have the advantage of performing simultaneous measurements of force and displacement. This displacement measurement can be correlated with the dimensions of the indentation print thanks to the knowledge of geometrical parameters of the indenter, which can be spherical (Brinell hardness), pyramidal (Vickers hardness) or cylindrical and flat. However, in the field of generally applied forces, the displacements of the indenter integrate for a non-negligible part the mechanical deformations of the measuring device itself, such as the frame and the transmission rods. Indeed, 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 commercialized devices are therefore at the origin of systematic errors. It is clear that the application of much weaker forces would minimize these accidental causes, but it is then the sensitivity of the device displacement sensor that becomes prohibitive for uses in these conditions.

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 Elastic bending tests on compacted system webs can also be used for the determination of their Young's modulus using a micro-indentation apparatus used for a three-point bending test. However, the problem related to the sensitivity of the displacement sensors remains because the field of elastic deformation of the pharmaceutical compact is generally associated with very low forces applied to the pharmaceutical solid.

 The present invention therefore aims to overcome the drawbacks of the prior art by providing a micropresse dedicated to microindentation and three-point bending tests on pharmaceutical solids, this micropress allows in particular to determine the Young's modulus accurately and to avoid the problems of uncertainty related to the displacement sensor.

 This object is achieved by a micropress for highlighting the mechanical properties of pharmaceutical solids, characterized in that it comprises means for recording operating parameters of the micropress, means for controlling the displacement of a loading piston. to the pharmaceutical solid placed under this piston according to the operating parameters, a force sensor measuring the force exerted on the pharmaceutical solid by a head assembled at the end of the piston close to the solid in position, a displacement sensor measuring the displacement of the piston, the latter being located closer to the sample and triggered by triggering means when a force is detected at the force sensor, means for recording the signals emitted by the sensors, means for calculating the quantities characterizing the mechanical properties of the solid as a function of the recorded signals and the parameters operation of the micropress.

 According to another feature, the micropress comprises a computer system running a specific operating software for displaying, by display means of the system, input fields of the operating parameters of the micropress on a screen of the system, the command system, according to certain operating parameters entered, a gear motor actuating, via a ball screw, the

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 loading piston along its axis directed to the pharmaceutical solid in position, the loading piston head supporting an indenter for performing a three-point bending test or a microindentation test on the pharmaceutical solid, the results of this test being collected by the system for being processed by the software, the system comprising the calculation means for calculating the quantities characterizing the mechanical properties of the pharmaceutical solid.

 According to another feature, the control means control the speed of movement of the piston via a regulator of force, position or speed of movement of the piston (16), the PID type (Proportional Integral Derivative).

 According to another feature, the system also comprises means for displaying, in real time, curves relating to the force applied by the piston to the solid as a function of the movement 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 particularity, the pharmaceutical solid rests on a table positioned on a pedestal surmounted by the gearmotor 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 measurement point without have to touch the sample.

 In another feature, the force sensor is an extensometer strain gauge bridge sensor placed on the loading piston just above the head.

 According to another particularity, the displacement sensor is an incremental feeler integral with the head of the loading piston via a first plate, this displacement sensor comprising a tip contact in permanent contact with a reference consisting of a second plate parallel to the first plate, the displacement of the piston causing the

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 sliding of the tip in a sleeve integral with the first plate, the displacement sensor comprising means for measuring the displacement of the tip in the sleeve corresponding to the displacement of the loading piston relative to the pharmaceutical solid.

 According to another particularity, the indenter may be spherical, cylindrical or pyramidal.

 The invention, with its features and advantages, will emerge more clearly on reading the description given with reference to the appended drawings in which: FIG. 1 represents the micropress according to the invention, FIG. 2a represents the mounting operation. of the punch holder and the displacement sensor holder on the micropress according to the invention, - Figure 2b shows the mounting of the indenter on the micropress according to the invention, - Figure 3 shows the software configuration screen. 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 test or three-point bending, - Figure 10 represents the control screen having a micro-indentation curve, - Figure 16 represents the microphone curve. -Trac inductions In a spreadsheet spreadsheet, FIGS. 17a, 18a and 19 show four curves corresponding to four indentation cycles on a 45KN compressed AVICEL PH101 bar, a 45 KN compressed LACTOSE bar, respectively. and a bar of DU-TAS compressed to 45 KN,

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- la figure 25 représente plusieurs courbes représentatives de cinq cycles successifs de charge/décharge exercés sur une barrette d'AVICEL PH101, - les figures 26, 29 et 32 représentent une courbe charge/décharge utilisée pour le calcul du module d'Young, respectivement pour la barrette d'AVICEL PH101, pour une barrette de LACTOSE FF, et pour une barrette de DI-TAB - les figures 27,30 et 33 représentent une courbe d'extrapolation à porosité nulle des valeurs du module d'Young, respectivement pour la barrette d'AVICEL PH101, pour la barrette de LACTOSE FF et pour la barrette de Dl- TAB, - la figure 28 représente plusieurs courbes représentatives de trois cycles successifs de charge/décharge exercés sur une barrette de LACTOSE FF, - la figure 31 représente plusieurs courbes représentatives de trois cycles successifs de charge/décharge exercés sur une barrette de DI-TAB, FIGS. 17b and 18b show the zero-porosity extrapolation curve of the hardness P respectively for an AVICEL PH101 strip and for a LACTOSE FF strip, FIG. 20 represents a strip of a pharmaceutical solid placed on a plate. three-point flexural bench, - figure 21 shows the control screen displaying the control parameters in the context of a three-point bending test, - figure 22 represents, in the context of a three-point bending test , the control screen on which is drawn a curve representative of a load and a discharge, - Figure 23 shows, in the context of a three-point bending test, the control screen on which is traced a representative curve of a load to failure, FIG. 24 represents the curve of FIG. 23 inserted into a spreadsheet,

FIG. 25 represents several representative curves of five successive charging / discharging cycles exerted on a bar of AVICEL PH101; FIGS. 26, 29 and 32 represent a charge / discharge curve used for the calculation of the Young's modulus, respectively for the AVICEL PH101 bar, for a LACTOSE FF bar, and for a DI-TAB bar - Figs. 27,30 and 33 represent a zero porosity extrapolation curve of the Young's modulus values, respectively for the AVICEL PH101 bar, for the LACTOSE FF bar and for the Dl-TAB bar, FIG. 28 represents several representative curves of three successive charging / discharging cycles exerted on a LACTOSE FF bar, FIG. represents several representative curves of three successive cycles of charge / discharge exerted on a bar of DI-TAB,

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- la figure 34 représente une portion de graphique, force exercée en fonction du déplacement de l'indenteur.

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

 The invention will now be described with reference to FIGS. 1 to 34.

 The object 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 process 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 will be positioned the pharmaceutical solid (2) subject of the test.

This XY cross-motion positioning table (11) allows the operator to accurately position the measurement point of the test sample under the indenter, then move the sample to the next measurement 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) attached to the ends of the uprights opposite their fastening end 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, via a regulator of force, position or speed of movement of the piston, the PID type (Proportional Integral Derivative), a piston (16) loading 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 pharmaceutical solid of 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 on the upper piston (160) by means of four screws (163) inserted in the direction of the arrows in FIG. 2a. . The second element (162) has the form of a

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 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 diameter less than the diameter of the first element and decreasing diameters in the direction of the pharmaceutical solid (2) disposed on the XY table (11) fixed on the base (10). On the larger section of the second member (162) is engaged a plate (164) comprising a hole (165) of interlocking, this plate (164) being able to constitute, for example, a support of the displacement sensor of the piston of loading. An indenter (166) of various shapes is inserted into a hole (167) whose cross-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 attached to the punch holder by a clamping nut (168) threaded onto a thread (169) formed on the intermediate diameter section of the second punching support member (162).

 The indenter (166) can take different forms according to the test carried out using the micropress according to the invention. Indeed, this indenter may be, for example, spherical (ball-type Brinell) geometry, the sphere may be of variable diameters, for example 1.00 mm, 1.76 mm, or 2.38 mm. It may be, for example, cylindrical geometry (Boussinesq flat type), its section may be of variable diameters, such as, for example, 0.50 mm, 0.70 mm, 1.00 mm, 2.00 mm . Finally it may be, for example, pyramidal geometry (Vickers type), the pyramid having for example an apex angle of 1360.

 Two different punch holders of the same general shape can be fitted to the upper piston (160) depending on the shape of the indenter (166), one of the supports being adapted to receive the pyramid-shaped indenter (166). while the other is adapted to receive an indenter (166) of spherical or cylindrical geometry.

 According to the invention, the displacement sensor (17) is positioned on its support fixed on the punch support. This displacement sensor (17) is, for example, an incremental feeler comprising a touch point (175) in

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 contact with a reference below its support, for example, the XY table in Fig. 1. This button tip (175) is slidable in a sleeve of the sensor (17). The movement of the piston (16) downwards and therefore of the indenter (166) therefore causes a corresponding sliding in the sleeve of the pressure tip (175) pressed against its reference. The displacement of the pressure tip (175) is measured and corresponds to the displacement of the piston (16) and thus to the depression of the indenter (166) in the pharmaceutical solid (2). According to the invention, the displacement sensor (17) is therefore placed close to the indenter (166) and thus closer to the sample to be indented, which makes it possible to avoid 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 geared motor (15). The displacement sensor will, according to the invention, a reference located on the bearing surface of the sample, on a surface at an equivalent height offset or below these surfaces. The displacement sensor, to avoid problems of uncertainty, should be closer to the indenter and especially below the force sensor that does not have a high rigidity.

de 0. 05um. The resolution of the displacement sensor according to the invention will, for example,

of 0. 05um.

 A force sensor (18) of the type, for example, strain gauge bridge sensor, is placed on the loading piston (16), for example above the displacement sensor (17) for measuring the force exerted by the piston (16) on the pharmaceutical solid (2) during a test. The resolution of the force sensor according to the invention will be, for example, 0. 01 N.

 The extent of the measurements made by the displacement sensor or the force sensor 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 a specific software for controlling the movements of the loading piston (16). The force (18) and displacement (17) sensors are controlled by this computer system (3) and the measurements are collected.

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 in the system software (3). The displacement sensor (17) is, for example, coupled to the force sensor (18) through the computer system (3), so that the displacement measurement is not taken into account at the displacement sensor ( 17) only when a first effort is detected at the level of the force sensor (18). The software allows the simultaneous display, on the same graph, of the effort according to the displacement of the indenter.

The recording of the measurements can begin only when a contact is detected between the indenter (166) and the tested pharmaceutical solid. The displacement of the indenter (166) measured by the displacement sensor (17) therefore corresponds directly to the depression of the indenter (166) in the pharmaceutical solid (2) tested. In particular, this makes it possible to dispense with any possible measurement operation of the size of the cavity formed by the indenter on the solid tested and in particular the depth of this cavity.

 The first contact of the indenter (166) with the pharmaceutical solid (2) corresponds to a first effort measured by the displacement sensor (17).

The intensity of this first effort can be set. It is therefore from this minimum intensity of detection of the contact with the sample chosen by the operator that the recording of the measurements can begin. This setting can be done in a configuration window of the control software of the micropress (1).

 This window is visible in FIG. 3. This window firstly comprises 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 keypad or using a progress bar (31). The setting of this parameter makes it possible to eliminate the parasites likely to trigger the recording of the measurements whereas the contact between the indenter (166) and the pharmaceutical solid (2) is not yet established. This setting may vary depending on the testing environment. In Figure 3, the value is set to 0. 11N.

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 The display window includes a setting field (32) for the piston descent rate (16) before the contact between the indenter (166) and the sample is established. This value, expressed in millimeters per minute, must be optimized according to the loading speed during the test and must take into account the accuracy required in the recording of the start of the effort / displacement graph in relation to the time required for the indenter (166) for contacting the sample. This value can be entered using the numeric keypad or adjusted using a progress bar. In FIG. 3, the value is set at 0.141 mm / min.

The screen window shown in FIG. 3 represents an input field (33) with a value defined by the height at which the indenter is positioned above the sample after the end of a test, by ratio to the height at which the indenter is when a first contact of the indenter (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 from the numeric keypad or using a progress bar. In Figure 3, the value is set to +0.018 mm
The window also comprises an input field (34) corresponding to the correction of the reading of the sensors; This field is entitled, for example, "Reading 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 from the numeric keypad or using a progress bar. In Figure 3, it is fixed at 1.00000.

 The window comprises an input field (35) of a value representative of the speed control precision of the geared 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 null control signal leads to the absence of rotation of the geared motor (15). This value can be entered from the numeric keypad or using a progress bar. In Figure 3, it is set to -8.

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 Finally, this screen window comprises two buttons (36, 37) respectively labeled in FIG. 3, "Tare" (36) and "Cancel tare" (37). These two buttons (36, 37) make it possible, when the operator clicks on it, to reset the reading of the force sensor (18) following an offset of the measurement caused, for example, by an increase in Room temperature. The offset can be caused also, for example, during a change of the indenter (166), the force sensor (18) systematically measuring the weight of the indenter (166) and its support.

 Once these values are 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 setting by clicking on a button called, for example, "Cancel" (39).

 The software makes it possible to parameterize the micropress (1) by screen windows comprising several input fields of 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 characteristic quantities of the mechanical properties of the pharmaceutical solids, as a function of the measurements collected at the displacement sensor (17) and the force sensor ( 18) and stored on the memory (M1) of the computer system (3).

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

 A first test consists in performing a micro-indentation on a pharmaceutical solid (2) using the micropresse (1) according to the invention. An indentation is defined by the application of a charge which corresponds to the penetration of the indenter (166) having a certain geometric shape into a pharmaceutical solid (2) and the removal of the indenter (166) solid (2), this withdrawal being said discharge. A relaxation time, allowing the realization of the plastic deformations as well as the relaxations of the flow stresses which are at the origin of these deformations, is imparted between the charge and the discharge, this relaxation time being variable according to

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 of the nature of the pharmaceutical solid (2) and in particular, depending on the main component component of the pharmaceutical solid and its environment.

 The operating software executed by the computer system (3) collects the data measured by the displacement sensor (18) and the force sensor (17). It thus 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 reduced modulus of elasticity (E *) can be determined. This reduced modulus of elasticity, whose calculation formula is written below, defines, as the Young's modulus, the elasticity response of a material subjected to a stress. But unlike the Young's modulus, the reduced modulus of elasticity calculated at the end of a micro-indentation test overcomes 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 represented 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 an ordinate value corresponding to F and a value H taken in abscissa, as shown in Figure 34.

Hardness, for example Brinell (P), may also be determined. Hardness is the ratio of the applied force to the area of the impression.

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où R est le rayon de l'indenteur et h la profondeur de l'empreinte restant après la décharge. Fmax corresponds to the maximum force applied, D to the diameter of the indenter, d to the diameter of the cavity, d being equal to:

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

 For a micro-indentation test, the indenter (166) is positioned, as shown in Figures 2a and 2b, in the punch holder 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 manually set on the XY (11) table, the test can begin.

 A first step consists in choosing, from the control computer system (3), the control parameters of 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), shown in FIG. 4 mainly comprises three zones (40, 41, 42). A first zone (40), called menu, comprising various scrollable tabs referring to control instructions of the micropress (1). A second zone (41) makes it possible to visualize operating parameters of the micropress (2), to start the test, to follow the movement of the piston (16) and the force applied ... A third zone (42) makes it possible to visualize the tracing in real time of the curve, forced displacement or constraint-displacement.

 To start a test, the operator clicks on a named tab, 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 drop-down "Session" (43). The message represented in FIG. 5a then appears. This message asks the operator if he is sure he wants to start a new session. By clicking a button

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 called, for example, "Yes" (50) of this message, it accesses an entry zone (44) of the second zone (41) of the control screen (4) making it possible to enter a name or a number of session. The software then automatically displays in other input areas (45,46), a sample number, set to 1 by default, as shown in FIG. 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 and click in the "Session" tab (43) on a named statement, for example, "Next Sample". A new message represented in FIG. 5b, of the same type as that previously described, appears. This one asks if the operator wishes to pass to the test of the following sample. In the case where he clicks a named button, for example, "Yes" (51), the input area (44) of the name of the session 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 input area (47) of the second area (41) of the screen (4) and set to 1 by default. These values can be modified using the numeric keypad by clicking in the corresponding entry field (45,47). The entry area (46) of the cycle number is simply informative, so it is locked.

 A second operation is to click on a tab called, for example, "Piston" (48) of the menu area. In this pull-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, shown in FIG. 6, makes it possible to parameterize the control of the movement of the piston (16). First, it is possible from this window to control the piston (16) up or down by checking a corresponding box (60,61), respectively called, for example, "Up" or "Down" to using the mouse. In addition, it is possible

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 to control the movement of the piston (16) automatically or manually by checking the corresponding box (62, 63) with 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 pressure on the "Esc" key of the computer system keyboard (3). Releasing the key automatically stops the piston (16).

When the automatic mode is chosen, it becomes possible to click with the mouse on some icons of the screen window. A first icon (64) makes it possible to progressively increase the speed of the piston. A second icon (65) decreases this speed. A third icon (66) moves the piston (16) directly to 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 Figure 6. When the piston (16) is correctly positioned closer to the surface of the sample to indent, just click on a button called, for example, "quit" (69) of the screen window.

 A third operation is to define the control parameters of the micropress (1) for the test. These control parameters are chosen arbitrarily and must be adjusted according to the behavior of the tested product. In the menu area, click on a tab called "Trial" (49). This selection causes the appearance of a screen window comprising several fields for entering the control parameters of the micropress (1).

This screen window is shown in FIG. 7. It notably comprises a first input field (70) for the loading speed of the piston. This speed can be entered directly into an input area (700) using the numeric keypad or with the mouse by clicking on a progress bar (701). The window includes a second input field (71) of the maximum depression of the indenter (166) in the pharmaceutical solid (2), a third input field (72) of the maximum load applied to the pharmaceutical solid (2) and a fourth input field (73) of the number of cycles

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 load / discharge to be performed, all these fields being of the same type as the first.

 The window includes an input field (74) for a delay between each charge and discharge cycle. This timer can be entered, for example, directly using the keyboard in an input area (740) or with 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, a loading only or a loading and unloading. The window proposes an entry field (77) of the relaxation time using the keyboard or the mouse by clicking on control bars, the relaxation time being defined by the time left between a load and a discharge of the piston. (16). Finally, the window comprises input fields (78, 79) of the acquisition frequency of the points for drawing the curve on the third zone (42) of the control screen (4).

 In FIG. 7, the loading speed is set at 0.060 mm / min, the maximum depression at 0.100 mm, the maximum load at 500 N, the number of cycles at 1, the delay at 0, the cycle comprises a loading and an unloading with a relaxation time between this loading and this unloading set at 5 minutes and the acquisition frequencies at 00.5 seconds, which corresponds to two points per second. When all the control parameters are entered, all that remains is to click on a button called "OK" (80) of 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 called "Cancel" (81).

 A fourth operation to be performed before starting the test is to set the indenter (166) fixed on the punch holder. For this, the operator clicks with the mouse on a tab called, for example, "indenter" (52) in the first zone (40) of the control screen (4). After clicking, a window for setting the indenter (166) appears.

This screen window is represented in FIG. 8. It is necessary to select in this window the type (82) of indenter that is used, that is to say to geometry

<Desc / Clms Page number 19>

 spherical, cylindrical, pyramidal (Vickers) or if it is another type of indenter which must then be specified. In the case where an indenter with cylindrical or spherical geometry is used, it is necessary to specify the diameter (83) of this indenter. Several standard values, such as 0.5, 0.7, 1 or 2 can be checked directly. If it is another diameter, check the box (84) called, for example, "other" and enter in an input area (85) using the keyboard the value of this specific diameter or choose it by clicking with the mouse on a progress bar (86). Finally, it remains only to select in this screen window the type of graph (89) that you want to be 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 constraint taking into account the the contact surface between the indenter (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 FIG. 7, the 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 named button, for example, "Cancel" (88).

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

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

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 As soon as the indenter (166) comes into contact with the sample, the graph can be automatically plotted 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. The recording of the data begins only when the indenter (166) comes into contact with the pharmaceutical solid (2). The effort from which the software estimates that there is a contact between the indenter (166) and the pharmaceutical solid (2) is set in the configuration screen shown in FIG.

 A cycle corresponding to an indentation is then plotted in the third zone (42) of the control screen (4), as shown in FIG.

This cycle thus comprises three parts, a charge (100a), a relaxation time (100b) and a discharge (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 the "Start" button (53) which replaces the "Pause" button or to order the unloading directly 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 shown in Figure 10, the test is definitively stopped. A request for confirmation of the definitive cessation of the test appears in the form of a message represented in FIG. 11. By clicking on a button denominated, for example, "Yes" (110), the test is definitively stopped. Otherwise, by clicking on a named button, 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 immediately start the discharge, he can click with the help of the

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 mouse on a named button, 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) rises to a memorized position, corresponding to its position set in the configuration screen shown in FIG. 3. This message also indicates in a zone (130) the displacement measurement of the piston and the applied force It is also possible to enter in a message a note corresponding to this test. A message shown in Figure 14 and including a text input frame (140) appears to enter that note. If the operator clicks on a named button, for example, "OK" (141), a message shown in Figure 15 indicates that the micro-indentation test is complete.

The operator can still cancel the test, that is to say, erase all the data relating to this test, by clicking on a button called, for example, "Cancel the test" (142). On the message represented in FIG. 15, a button denominated, 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 "next indentation" instruction, the data relating to the test that has just been carried out, are definitively recorded and the operator can proceed to the next step.

 The processing of the data acquired during the test is carried out by transposing them into an open file on a processing software that is integrated or not into the test software. In the case where the processing software is not integrated with the test software, it will be, for example a spreadsheet, such as, for example, the Excel software (trademark) of the company Microsoft. The data (364) is, for example, copied to a special file designed in the spreadsheet, as shown in Figure 16, and processed to reproduce the curve (360) of the test in this file. An area (361) of linearity on the discharge curve (100c) of the test curve is then determined to calculate the reduced modulus of elasticity. The calculation is made from a slope comprising, for example, seven points of this linearity. The value of the modulus of elasticity

<Desc / Clms Page number 22>

 reduced E * is then read in a cell (E22) (362) of the file. The value of the hardness P is calculated from the formula defined above in a cell (EF29) (363) of the file.

 The reduced modulus of elasticity E * can be defined after a certain relaxation time. The relaxation time is the time allowed between the charge and the discharge so that all the plastic deformations are made and that all the flow stresses at the origin of these deformations are relaxed.

Thus, during the discharge, one is theoretically in the field of purely elastic deformations.

 An optimal relaxation time was determined for each excipent by performing several tests on the same bar of pharmaceutical solid, with different relaxation times. The reduced elasticity moduli obtained were then compared so as to know after which relaxation time applied the results stabilize.

 In addition, the analysis of different discharge curves made at the same place shows that this area is elastic because the discharge curves obtained are superimposable.

 Finally, the computation of the reduced modulus of elasticity was carried out according to a determined slope on an area of the most linear discharge curve 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 microindentation assays are three excipients conventionally used in galenic formulation. They have the advantages of being nontoxic, easy to supply, directly compressible, while offering highly differentiated mechanical behaviors representative of those encountered in galenic formulation. However, it should be remembered that the micropresse (1) according to the invention is intended for all types of pharmaceutical solids that can take various forms. The choice of these three compounds (1) is in no way limiting to these compounds and

<Desc / Clms Page number 23>

 which pharmaceutical solid of any form can be characterized by the micropresse (1) according to the invention. The three solids chosen are: - the AVICEL PH 101 (registered trademark) which is a microcrystalline cellulose (SEPPIC, batch no. 6512) chosen for its plastic behavior (Py 50 MPa), - the DI-TAB (registered trademark) which is a calcium phosphate dihydrate (Rhône-Poulenc Inc, lot no 057741) chosen for its fragmentary behavior (Py 275 MPa), - LACTOSE FF (registered trademark) which is a fast-flow-grade atomized lactose (SEPPIC, lot no 859122562) and whose behavior is fragile (Py 109 MPa).

 These three products exhibit different behaviors that are representative of the behaviors of a very wide range of pharmaceuticals. Experimentation on these three products with different behaviors can 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) making it possible to obtain parallelepiped 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 construction of the compacts is carried out in forceplacement with the aid of an instrumented "PERRIER LABOTEST" high-pressure hydraulic press equipped with the measuring module 705. It can impose a compressive force of 300 kN, lower piston. The bars, of variable porosity, were produced by the application of forces F ranging from 10 to 50 kN respectively corresponding to pressures of 42 to 210 MPa.

 The strips thus produced were stored, just after demolding, in petri dishes placed in a humidity bell.

<Desc / Clms Page number 24>

 controlled, 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 (1) 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 measurements measured after relaxation (after 3 days) are slightly higher than those measured just after demolding.

 The height (h) is in turn variable depending on the porosity, so depending on the force applied and the amount 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 with zero porosity; about 2 g for AVICEL PH101 and for LACTOSE FF and about 3 g for DI-TAB which has a true density much higher than the other two excipients.

 After the relaxation time, 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 as:
V = L * 1 * h, hence the density E = 1-Papparente / po with Papparente = M / V
The AVICEL PH101 that served as a support for this study has a true density equal to 1.5378 g / cm3 (standard deviation = 0.0002 g / cm3).

The microscopic observation of AVICEL PH101 shows an elongated, more or less fibrous and irregular shape of its particles. This result has also been confirmed in laser diffraction where the particle size distribution is symmetrical, but with an average diameter of 58 +/- 48 lit.

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

<Desc / Clms Page number 25>

The results obtained (Table 1, in this example on a bar compressed to 45 KN) make it possible to choose the most relevant relaxation time to be used in a test on AVICEL PH101:

<Tb>
<tb> Time <SEP> of <SEP> relaxation <SEP> (min) <SEP> E * <SEP> (MPa)
<tb> 3 <SEP> 9097
<tb> 4 <SEP> 9979
<tb> 5 <SEP> 10720
<tb> 7 <SEP> 10783
<tb> 15 <SEP> 10634
<Tb>

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

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

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

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

 On the other hand, Brinell hardness (P) measurements on AVICEL PH101 strips were also performed. This parameter could be analyzed thanks to the possibility of knowing the exact value of the depth of the residual cavity after the indenter has been removed (166).

d'indentation (P) :

Table 2 shows some results obtained in terms of hardness

indentation (P):

<Tb>
<tb> AVICEL <SEP> PH101 <SEP> (porosity) <SEP> P <SEP> (MPa)
<Tb>

<Desc / Clms Page number 26>

<Tb>
<tb> ai-p1-15-003.004 <SEP> (27.68%) <SEP> 17.6
<tb> ai-p1-15-003. <SEP> 005 <SEP> 28.9
<tb> ai-p2-15-002.001 <SEP> (15.79%) <SEP> 55.3
<tb> ai-p2-15-002.001 <SEP> (15.79%) <SEP> 61.7
<tb> av-45-2-001.003 <SEP> (9.01%) <SEP> 91.7
<tb> av-45-2-001.004 <SEP> (9.01%) <SEP> 95.3
<Tb>

Tab. 2 : exemples de résultats obtenus en terme de dureté d'indentation pour l'AVICEL PH101.

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

 FIG. 17b represents the extrapolation with zero porosity according to the empirical exponential model of RYSHKEWITCH (1953), showing a value (174) coherent of 190 MPa with that found in literature. LACTOSE FF has a true density equal to 1.5314 g / cm3 (standard deviation = 0.0004 g / cm3), which remains close to the AVICEL PH 101. On the other hand, the microscopic observation differentiates it by showing a greater sphericity of its particles. Moreover, in laser diffraction, the particle size distribution is asymmetrical, with an average diameter of 113 +/- 50 m.

 As for the AVICEL PH101, a study was carried out to determine the reduced elastic modulus E * and the Brinell P hardness. Several microindentation tests on compact LACTOSE FF, with different porosities with different relaxation times 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 appropriate relaxation time to implement) during a test on this product:

<Tb>
<tb> Time <SEP> of <SEP> relaxation <SEP> (min) <SEP> E * <SEP> (Mpa)
<tb> 1 <SEP> 16419
<tb> 2 <SEP> 17502
<tb> 3 <SEP> 19511
<Tb>

<Desc / Clms Page number 27>

<Tb>
<tb> 5 <SEP> 18668
<tb> 10 <SEP> 18797
<Tb>

Tab. 3 : détermination du temps de relaxation pour le LACTOSE FF.

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

Thus, the recommended relaxation time for LACTOSE FF is 3 minutes.

As before, we made sure that the modulus of elasticity reduced E * was well determined in an elastic domain, we realized several indentations at the same place (with the relaxation time determined previously) and we thus compared the values of E * obtained (Figure 18a).

In FIG. 18a, we find that the discharge curves (180) at the end of the 3 minute relaxation time are superimposable and have very close values of E * (the standard deviation being 857 MPa ie %). The differences obtained are again very small, which shows a great accuracy in the measurement of E *, and this from the analysis of the first discharge curve.

We also performed Brinell hardness (P) measurements on this excipient, using the same approach as that applied to AVICEL PH101.

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

<Tb>
<tb> LACTOSE <SEP> FF <SEP> (porosity) <SEP> P <SEP> (MPa)
<tb> Lactose <SEP> 18.1
<tb> (24.12%)
<tb> Lactose <SEP> 15-p1-001.005 <SEP> 24.0
<tb> (24.12%)
<tb> Lactose <SEP> 45-p1-001.003 <SEP> 51.3
<tb> (12.61%)
<tb> Lactose <SEP> 45-p1-001.004 <SEP> 60.6
<Tb>

<Desc / Clms Page number 28>

<Tb>
<tb> (12.61%)
<tb> Tr5-l-15c1 <SEP> (24.23%) <SEP> 29.8
<tb> Tr0-l-45c1 <SEP> (13.53%) <SEP> 58.3
<Tb>

Tab. 4 : exemples de résultats obtenus en terme de dureté d'indentation pour le LACTOSE.

Tab. 4: Examples of results obtained in terms of hardness of indentation for LACTOSE.

The DI-TAB is characterized by a true density equal to 2. 4430 g / cm3 (standard deviation = 0.0005 g / cm3), by a large sphericity of the particles observed in optical microscopy and by a bimodal volume particle size distribution with a first average diameter around 160 m and a second between 600 and 800, um.

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 conducting microindentation tests. The compacts of DlTAB, with 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 implement during a test on this product:

<Tb>
<tb> Time <SEP> of <SEP> relaxation <SEP> E * <SEP> (Mpa)
<tb> 20 <SEP> sec <SEP> 22077
<tb> 40 <SEP> sec <SEP> 22008
<tb> 1 <SEP> min <SEP> 23586
<tb> 2 <SEP> min <SEP> 23661
<tb> 3 <SEP> min <SEP> 23673
<Tb>

Tab. 5 : détermination du temps de relaxation pour le D !-TAB. Ainsi, le temps de relaxation préconisé pour le DI-T AB est de 1 minute.

Tab. 5: Determination of the relaxation time for D! -TAB. Thus, the relaxation time recommended for the DI-T AB is 1 minute.

<Desc / Clms Page number 29>

 Here again we made sure that the reduced modulus of elasticity E * was well determined in an elastic domain by carrying out several indentations at the same place (with the previously determined relaxation time) in order to compare the values of module E * obtained (FIG. 19a).

 In FIG. 19, we find that the discharge curves (190), at the end of the relaxation time, are still superimposable and have modulus values E * very close (the standard deviation being 447 MPa, ie 1.9%).

The differences obtained are again very small, which shows a great accuracy in the measurement of E *, and this from the analysis of the first discharge curve. We also performed Brinell (P) hardness measurements on this excipient, using the same approach as that applied to other products.

d'indentation (P) :

Table 6 shows results obtained in terms of hardness

indentation (P):

<Tb>
<tb> DI-TAB <SEP> (porosity) <SEP> P <SEP> (MPa)
<tb> tr0-d-15-c1 <SEP> (33.45%) <SEP> 20.7
<tb> tr1-d-15-c1 <SEP> (33.45%) <SEP> 18.0
<tb> tr5-d-15-c1 <SEP> (33.45%) <SEP> 34.0
<tb> tr0-d-30-c1 <SEP> (28.48%) <SEP> 66.7
<tb> tr1-d-30-c1 <SEP> (28.48%) <SEP> 38.7
<tb> tr2-d-30-c1 <SEP> (28.48%) <SEP> 32.4
<Tb>

Tab. 6 : exemples de résultats obtenus en terme de dureté d'indentation pour le D !-TAB.

Tab. 6: Examples of results obtained in terms of hardness of indentation for D! -TAB.

 Unlike the two previous examples, the classical exponential model used for extrapolation to zero porosity (RYSHKEWITCH model) is difficult to apply to DI-TAB, which makes it difficult to quantitatively interpret the results on large porosities as it is the case in this example.

<Desc / Clms Page number 30>

 The examples presented here in application of the procedure of using the micropress in the context of microindentation tests show the possibility of determining a reduced modulus of elasticity E * and a hardness of indentation Brinell P. In the context of the first parameter, three cases (validated in the range of porosity studied) are distinguished according to the excipient that is analyzed: it is necessary to program a relaxation time equal to 5 minutes when it comes to the AVICEL PH101, while 3 minutes are sufficient for the LACTOSE FF, and 1 minute for the DI-TAB. In addition, the precision obtained on the values of E *, thanks to the proposed mode of graphic determination, is also demonstrated. The determination of the hardness of indentation is also very precise, as has been noted above.

 It should be remembered that all these results are only illustrations and are in no way limiting on the use of the micropress (1). Indeed, the micropress (1) according to the invention can be used to characterize pharmaceutical solids of any shape and 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.

 A second test is to perform a three-point bending on a pharmaceutical solid (2) using the micropresse (1) according to the invention.

 In this context, a number of charge / discharge cycles is applied to a pharmaceutical compact of parallelepipedic geometry positioned on a three-point bending bench. An ultimate load is then applied to cause the median failure of the compact.

 Different quantities can then be determined by graphical study after this test. In particular, these quantities are the breaking stress and the Young's modulus.

 The breaking stress (shear) is determined on the basis of the ratio between the maximum force (Fmax) recorded at the time of rupture and the

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où 1 est la largeur de la barrette, h la hauteur de la barrette, et p la portée du dispositif, c'est-à-dire la distance entre les deux cylindres d'appui. total area created after break, depending on the geometry of the bar and the test conditions.

where 1 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 Young's modulus (E) defines the elastic response of a material during a solicitation. It is a matrix operator that gives a direct proportionality relation between the stress and the axial deformation during a stressing along the axis of compression.

 The material used is similar to that used for the first microindentation test. In a three-point bending test, the sample is manually placed on a three point bending bench (19) attached to the XY table (11) by means of two side screws. The sample is placed on the bending bench (19) so as to have 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 cylindrical geometry of diameter equal to 2.00 mm. The mounting of the indenter (166) is performed as described above with reference to Figures 2 and 3.

 The control screen (4) is identical to that of the microindentation test. The procedure is identical, only the control parameters vary with respect 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 tested product.

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The loading speed (70) is set at 0. 050 mm / minute, the maximum depression (71) at 0. 500 mm, the maximum load (72) at a value less than the breaking strength of the bar, the breaking force being predetermined during a prior test on a similar bar. For a bar of AVICEL PH101 compressed at 50 KN, the maximum load is here set at 40 N. The number of cycles (73) charge / discharge varies depending on the material constituting the tested material. There 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 procedure. The delay (74) between two cycles is set at 20 seconds. The acquisition frequency (78) of the data is fixed at 00 min 00. 1 second. Loading and unloading are selected by checking the corresponding box (76) in the parameter input screen window. The relaxation time (77) is set to zero and the acquisition frequency (79) indicated in this area of the screen window is set to 00 min 00. 1 second.

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

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

The test starts after a click on the "Start" button (53) of this control screen (4).

After the test is completed and the curve is 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) of the control screen menu area (4) and modifies the value of the maximum load (72) to set it to a higher value. to that causing the breaking of the bar. The number of cycles (73) is also set to one. The operator then clicks again on the "Start" button (53) of the control screen (4) to start the break test. The course of this final charge on the pharmaceutical solid is identical to that previously and results in a graphical representation (230) in the third zone (42) of the control screen (4), visible in FIG. 23.

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 The data is then processed in the same way as in the micro-indentation test. The dimensions of the bar are entered into cells of the Excel file. The breaking stress is calculated based on these data in a cell of the file (B17) (240).

 For the calculation of the Young's modulus (E), a line segment (241) is placed on the load curve (242), this segment (241) delimiting on this curve a linear domain in which the calculation of E as shown in Fig. 24. The Young's modulus is calculated in cell B19 (243) in Fig. 24.

 The Young's modulus is calculated after the application of several charge / discharge cycles before the failure test. The application of several cycles makes it possible to achieve a certain stability in the result and can be explained by the irreversible deformations that take place within the tested sample.

 Indeed, the Young's modulus E characterizes a reversible deformation, it must therefore be measured when a solicitation of the material causes a purely elastic response. To verify that one reaches this field it is enough to apply several times an identical charge, while remaining lower than the load which causes 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.

 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 galenic formulation. These are the same as those used in the micro-indentation test, that is, AVICEL PH 101, D! -TAB and LACTOSE FF.

 The strips used for the test are manufactured in the same mode as that used to manufacture the strips used for the microindentation test.

 In order to determine the number of cycles required to stabilize the test conditions, a first test on a bar of AVICEL PH101, compressed at 52 KN, was performed. This first test consists in successively applying five loads of 5 daN then a sixth of 6 daN for

<Desc / Clms Page number 34>

 cause rupture, as shown in Figure 25. It should be noted that these forces were applied at a speed of 0. 050 mm / min. The curves obtained were gathered on the graph (FIG. 25) by deleting the values where F = 0 at the beginning, so as to compare them. These control parameters are of course chosen arbitrarily and must be adjusted according to the behavior of the tested product.

 It is clear from FIG. 25 that it is not exclusively in the elastic range during the first cycle. Plastic deformation phenomena and stable positioning of the bar by crushing of 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 in relation to the elasticity that we are trying to measure.

 A complete study of this principle of application of the cycles was thus carried out on four bars of AVICEL PH101, according to a range of sufficiently large porosity (23% to 9%) to determine a value of E with porosity zero, extrapolated according to the Ryshkewitch model.

For each porosity, there are two steps:
1) Repetition of 5 preliminary cycles (figure 25, first cycle (250)), with loads lower than those causing the rupture (determined for each porosity), then rupture with the sixth charge (figure 25,251), the desired stability being reached from the 4th cycle.

Etch et de la pente à la décharge soit Edech (figure26), en se basant sur le quatrième cycle. 2) Calculation of E by graphical determination of the slope at the load

Etch and discharge slope either Edech (Figure 26), based on the fourth cycle.

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

 The graph in FIG. 27 illustrates the extrapolations with zero porosity that make it possible to compare the raw E values obtained by breaking

<Desc / Clms Page number 35>

sans faire de cycle (Emp) (270) avec les valeurs de E obtenues sur le 4ème cycle (Ech et E) (271).

without making a cycle (Emp) (270) with the values of E obtained on the 4th cycle (Ech and E) (271).

 A difference is thus clearly demonstrated between the values obtained by making several cycles and the raw values obtained by going directly to failure (approximately 25% of gap with zero porosity), which demonstrates the importance of achieving a certain number of cycles before breaking the pharmaceutical solid.

 As for AVICEL PH101, a complete study on 4 LACTOSE strips compressed respectively at 15.25, 30 and 45 KN (ie porosities ranging from 24% to approximately 13%) was carried out.

The same methodology as that used for AVICEL PH101 has been applied, and the conclusions are similar for these two products, with some nuances:
Stability was reached after 2 cycles (280,281) only (Figure 28). A third cycle (282) was therefore performed to cause the bar to break. The values of E, (290) and Edech (291) are relatively close, with an average difference of about 2.5% here (Figure 29).

 Figure 30 illustrates extrapolations with zero porosity, thus allowing Emp values to be compared with the ECh and Edé values. H- A larger difference than the AVICEL PH101 is shown between the values obtained by doing several cycles (300) and those obtained by going directly to failure (301) (about 33% zero porosity difference).

 In application of the principle of applying several charge / discharge cycles before a final charge test leading to rupture, several D! -TAB bars, respectively compressed at 15.30 and 35 KN (ie porosities ranging from 33% to About 27%), were analyzed.

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

 The values of E, (320) and Edech (321) (FIG. 32) are relatively close (the average difference here being less than 0.1%).

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 Figure 33 illustrates the extrapolations with zero porosity allowing us to compare the values of E mp with the values of ECh and Edéh-A difference identical to that which the AVICEL PH101 presented is highlighted between the values (330) obtained. by performing a pre-break cycle and those (331) obtained by going directly to failure, ie about 25% zero porosity deviation.

 The methodology proposed here for the study of the Young modulus in three-point bending, via the micropress (1), is based on the principle of performing cycles prior to fracture.

 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 comes to the AVICEL PH101, while 2 are enough for the LACTOSE FF, and 1 only for the DI-TAS.

 Thus, the realization of a certain number of cycles, depending on the product tested, seems indispensable for the precise and reproducible determination of the Young's Module.

 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 within the scope defined by the scope of the appended claims, and the invention should not be limited to the details given above.

Claims (13)

1. A 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) a three-point bending test and a microindentation test. using a micropress (1), each of the tests comprising before a real measurement cycle, at least one prior cycle comprising a charge and a discharge.  2. Method according to claim 1, characterized in that, for a micro-indentation test, a certain time, variable depending on the nature of the pharmaceutical solid tested, is left between the charge and the discharge, so as to obtain a optimal relaxation of the pharmaceutical solid (2) to be found during the discharge in the field of elastic deformations of the pharmaceutical solid (2).  3. Method according to claim 1, characterized in that, for a three-point bending test, a predetermined number of preliminary cycles is performed on the pharmaceutical solid (2) tested until a purely elastic response is obtained from the pharmaceutical solid, the number of cycles being a function of the nature of the pharmaceutical solid tested.  4. Method according to claim 1 or 3, characterized in that, in a three-point bending test, the actual measuring cycle consists in applying an ultimate charge on the pharmaceutical solid so as to cause its median rupture.  5. Micropresse (1) can implement the method of claims 1 to 4, 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 displacement of a loading piston (16) towards the pharmaceutical solid (2) placed under this piston (16) <Desc / Clms Page number 38>  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 displacement sensor (17) measuring the displacement of the piston (16), the latter being situated closest to the sample and triggered by triggering means when a force is detected at the level of the force sensor (18), means for recording the signals emitted by the sensors (17, 18), means for calculating the quantities characterizing the mechanical properties of the solid as a function of the recorded signals and the operating parameters of the micropress (1).  6. Micropresse (1) according to claim 5, characterized in that it comprises a computer system (3) running a specific operating software for displaying, by display means of the system, fields of data entry. operating parameters of the micropress on a screen of the system (3), the system (3) controlling, depending on certain operating parameters entered, a geared motor (15), operating via a ball screw (14), the loading plunger (16) along its axis directed to the pharmaceutical solid (2) in position, the plunger head (16) supporting an indenter (166) for performing a three point bend test or a microindentation test on the pharmaceutical solid (2), the results of this test being collected by the system (3) for processing by the software, the system (3) comprising the calculation means for calculating the quantities characterizing the mechanical properties of the pharmaceutical solid (2).  7. Micropresse (1) according to claim 5 or 6, characterized in that the control means control the speed of movement of the piston (16) via a force regulator, position or speed of movement of the piston (16), of the PID type (Proportional Integral Derivative). <Desc / Clms Page number 39>  8. Micropresse (1) according to claim 6 or 7, 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 the stress in the pharmaceutical solid (2) as a function of the displacement of the piston (16) towards this solid (2).  9. Micropresse (1) according to one of claims 6 to 8, characterized in that the pharmaceutical solid (2) rests on a table (11) positioned on a base (10) surmounted by the geared motor (15) actuating the piston ( 16) along its axis directed to the pharmaceutical solid (2) via the ball screw (14).  10. Micropresse (1) according to claim 9, characterized in that the table (11) is an XY cross-motion table allowing the operator to accurately position the measuring point of the test sample under the indenter ( 166), then move the sample to the next measurement point without touching the sample.  11. Micropresse (1) according to one of claims 5 to 10, characterized in that the force sensor (18) is a strain gauge bridge sensor extensiometry placed on the piston (16) loading just above the head.  12. Micropresse (1) according to one of claims 5 to 11, characterized in that the displacement sensor (17) is an incremental probe integral with the head of the piston (16) loading via a first plate (164), this displacement sensor (17) comprising a touch tip (175) 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 tip key (170) in a sleeve integral with the first plate (164), the displacement sensor (17) comprising displacement measuring means <Desc / Clms Page number 40>  the touch point in the sleeve corresponding to the displacement of the plunger (16) relative to the pharmaceutical solid (2).  13. Micropresse (1) according to one of claims 6 to 12, characterized in that the indenter (166) can be spherical, cylindrical or pyramidal.