WO2020079699A1

WO2020079699A1 - Apparatus and method for prediction of tablet defects propensity

Info

Publication number: WO2020079699A1
Application number: PCT/IL2019/051139
Authority: WO
Inventors: Michael Levin; Hans Leuenberger; Ofer Aqua
Original assignee: M.O Advanced Technologies (Moat) Ltd
Priority date: 2018-10-16
Filing date: 2019-10-22
Publication date: 2020-04-23

Abstract

An apparatus for measuring indentation and breaking hardness of medicinal tablets (for instant drug release, controlled drug release, etc.) is disclosed. Instead of, or in addition to, measuring indentation optically, the depth of indent under known loads is measured by counting stepper motor movements. A line of ratio of both measurements over a practical range of compression forces is then inspected for signs of nonlinearity and inflection points, indicating capping or lamination propensity. The method and its proposed embodiment will help optimize pharmaceutical tablet formulation and manufacturing conditions, and thus avoid potential quality problems. It will be appreciated that this apparatus can be used not only in the field of medicinal tablets but also for other types of compacts used in other fields such as in veterinary medicine, formulations used for treatment in agriculture, compacts used as consumer products, ceramic and metallurgical powder compacts and formulations used for various industrial applications, and the like.

Description

APPARATUS AND METHOD FOR PREDICTION OF TABLET

DEFECTS PROPENSITY

BACKGROUND

Pharmaceuticals are frequently packaged as discrete tablets, thereby ensuring that a constant dosage is taken. For ease of swallowing, tablets may be coated, and the edges of tablets are typically rounded. Commonly tablets are disk shaped or cylindrical. The flat surfaces of the disks and the ends of the cylinders may be domed.

Formulation development of solid dosage forms (such as tablets) involves mixing API (Active Pharmaceutical Ingredients) with various inactive ingredients, such as excipients, lubricants, glidants, disintegrants, etc. to ensure desired tablet properties, such as hardness, friability, disintegration and in vivo dissolution. The powder mix is then subject to compression in a tablet press. At early stages of formulation development, tablet presses are slow with minimal number of compression stations to avoid excessive waste of API which is usually expensive.

Once the desired tablet properties are achieved, pre-clinical and clinical studies are undertaken to evaluate its efficacy. Tablets for such studies are made on medium- speed tablet presses. Once the desired drug effect is demonstrably achieved, the product is submitted to a regulatory body (such as FDA) for approval. The next stage in the development is scale-up and the establishment of a pilot plant, where the presses are larger and faster, and are capable of commercial production speeds.

As a tablet product moves along the scale-up path, various tableting problems may occur due to the increased rate of compression. Referring to the position in vertical dies used in tablet presses, common failures that may occur include capping and lamination, which denote spalling of the bottom and top surfaces.

The capping or lamination of tablets is caused by internal stresses, which are formed during compression of the tablet mixture, and which are present during ejection from the tablet press. The capping or lamination usually occur at higher pressures and higher speeds and may depend on the type of tooling and tableting machine.

Capping happens when a fracture occurs at the top of the tablet and the top, or cap, separates itself from the body of the solid tablet.

Previously, it was assumed that capping is caused by compressed air trapped in the die. Today it is clear that trapped air is not the primary cause of capping. It may, however, play a role, with pronounced aerophilic, powder molding compounds at very high speed and very strong compression.

The common reasons for capping are radial pressures acting on the compact during compression, an inhomogeneous density distribution and residual stresses in the compact, as well as the elastic expansion of the particles and of the entire compact during ejection from the tablet mold.

Capping fracture occurs at the top of a tablet as it is ejected from the die by the lower punch. If a fracture occurs in the lower part of the tablet, it is referred to as lamination, and is discussed below.

Lamination is the term used to describe splitting tablet into layers. Lamination is essentially the same as capping and with similar causes. It is, nevertheless, important to diagnose the lamination issue correctly to ensure that proper steps are taken to solve the problem. Lamination often occurs due to the over-compression of the tablet. Too much compression can lead to the granules flattening out and thus preventing them from locking together. This can also happen when light or fine particles do not combine, as these particles do not compress well. To prevent this, the thickness of the tablet needs to be reduced, and/or the dwell time increased to allow the fine particles to combine. To increase dwell time, pre-compression can be employed, or the speed of the tablet machine can be reduced. Another option is to use a tapered die rather than a perfectly cylindrical die bore. Tapered dies generally do not exhibit capping or laminating problems.

In general, searching for causes of tablet defects requires differentiating between the influence of the material properties (such as plasticity, brittleness, deformation behavior, stress reduction, kinetics, etc.), and those of processing factors (such as the tableting machine model, pressing tools, compression force, compaction speed, etc.).

Reducing tablet press speed may alleviate these problems but it is undesirable since it results in decreased production output. Reducing compaction pressure to avoid capping/lamination is not possible at post-approval stages since this affects the properties of the tablet, such as hardness and dissolution. In order to optimize manufacturing, the standard practice is to go back to formulation development and to reformulate the product in an attempt to avoid capping and/or lamination in the production stage. This practice is extremely expensive and inefficient because clinical studies and approval process need to be repeated.

The common mechanical test applied to tablets for quality control purposes is compression to failure (breaking force or pressure) along the longest axis of the tablet. This is variously referred to in the literature as 'radial tensile strength' or 'hardness'. Machines for such testing are called tablet hardness testers. They often include mechanisms like motor drives, and the ability to send measurements to a computer or printer. The patent literature describes various implementations of such hardness testers. One of the earliest U.S. patents describing a device to measure tablet hardness was US 2,041,869 issued to Smith in 1936. US 4,022,056 to Barland describes a hardness tester with a pivotally mounted element moving between anvils to break a test object. US 4,393,717 to Mason and Allister describes an apparatus to measure thickness, diameter and breaking hardness of multiple tablets in sequence. US 4,472,960 to Motoyama et al. describes a device that measures a number of tablet properties, including breaking hardness. US 5,555,768 to Shaffer et al, describes automatically positioning a tablet in a proper orientation for a hardness test, wherein it is compressed between a ram and anvil that are progressively forced together until the tablet is crushed. A modified breaking hardness tester was described by Poska et al. in CA 1,239,295 and by Itschi in EP 1,357,350. Most of the above patents use a similar tablet crushing mechanism but differ in the method of delivery and orientation of the tested tablets. In all such inventions, the minimum force needed to crush the tablet is measured and recorded. Thus, what is actually measured is the ultimate compression strength (i.e. the compaction strength at failure), with units of force, which is referred as‘crushing’, or‘breaking hardness’ and, when divided by unit area, can be expressed in units of pressure.

In an ideal fracture (Fig. 3) the radial tensile strength s_t is calculated as s_G =— where K is breaking force, T is the tablet diameter, and t is the tablet thickness.

Numerous patents exist for Brinell indentation hardness testers, named after August Brinell, a Swedish Metallurgical Engineer. One of the earliest U.S. patents in this area was US 1,320,748 from 1919.

Unlike breaking hardness testers, Brinell testers are not used for quality assurance of pharmaceutical tablets, most likely because they usually require cumbersome optical measurements to quantify indentation and thus providing relatively low precision. However, indentation hardness under controlled conditions can be an extremely useful measurement of local plasticity of material. It is infrequently used to determine the consolidation mechanisms of drugs and excipients.

Bielawski et al. in W02002084254A1 describes an invention that, among others, provides a micro-indentation test for characterizing mechanical properties of pharmaceutical solids.

In the Brinell hardness tester, indentation hardness is calculated as P =

2 F

where F is indentation force made by a ball of diameter D required to

produce a spherical impression of height h and diameter d (Fig. 4). The Brinell hardness thus quantifies in particular the plasticity of a pressed compound. If the residual stress in the axial direction after decompression is reduced by brittle fracture rather than by plastic flow, capping occurs.

Numerous publications in scientific literature are directed to the capping phenomenon, its causes and prevention (see the partial literature list in references herein below). It was suggested by Jetzer and Leuenberger (1984) that the ratio of indentation hardness to breaking hardness over the range of compression forces of compacts with capping/lamination propensity shows a sharp change in slope at some critical force level. For predominantly brittle materials this slope is linear. For plastically deformable materials the slope is linear only at higher pressures, indicating a process of hardening and increased tendency of brittle fracture.

In tablets made of some predominantly plastic or viscoelastic materials, at some critical pressure level, the increase of tensile strength abruptly slows down while indentation hardness continues to increase, demonstrating tendency for capping or lamination.

Relevant publications include:

• US1320748A 11/1919 Fisher

• US2041869A 5/1936 Smith

• US4022056A 5/1977 Barland

• US 4,393,717 1/1981 Mason et al. US 4,472,960 7/1981 Motoyama et al.

US 5,555,768 3/1995 Shaffer et al.

Foreign Patent Documents

CA1239295A 7/1988 Poska et al.

JPH 1078422 A 3/2000 Shieifuaa et al.

W02002084254A1 10/2002 Bielawski et al.

EP1357350B1 6/2005 Ischi

Other Publications

Aulton ME, Tebby HG, White PJ. Proceedings: Indentation hardness

testing of tablets. J Pharm Pharmacol. 1974

Aulton ME, Tebby HG. Time-dependent deformations of tablets

during indentation testing [proceedings] J Pharm Pharmacol. 1976

Simoni L, et al. Hardness test of tablets. Comparative studies of some

automatic and manual apparatuses. Boll Chim Farm. 1976

Galer J, et al. Hardness measure of tablets. Automatically apparatus with

interchangeable head (author's transl. J Pharm Belg. 1976

Jetzer W, Leuenberger H. Zur Bestimmung der Deckeltendenz von

pharmazeutischen Wirk- und Hilfsstoffen. Pharm. Acta Helv. 59. Nr.

1, 1984

· Perales M, et al. Study of the compaction mechanisms of lactose-based

direct compression excipients using indentation hardness and Heckel

plots. J Pharm Pharmacol 1994.

• Akseli I, et al. Development of predictive tools to assess capping

tendency of tablet formulations. Powder Technology, (236: 139-148,

2013.

• Vallabh CKP, et al. Early detection of capping risk in pharmaceutical

compacts. Int J Pharm 2018

SUMMARY OF THE INVENTION

This invention relates to the manufacture of pharmaceutical tablet dosage form. It relates particularly to a prediction of the propensity of undesirable defects such as capping and lamination in such tablet production. Implementation of this invention is expected to result in quality control/quality assurance improvement and significant cost savings of pharmaceutical production.

The method of testing may involve measuring indentation and breaking hardness of compacts made at a range of compression forces and thereafter analyzing the load to failure data and comparing indention hardness with breaking strength.

The results and conclusions thus obtained may indicate the capping/lamination propensity, or lack thereof, which could then be used to for quality control and quality assurance purposes.

A first aspect is directed to a tablet quality testing apparatus for testing a test object comprising an indentation hardness tester and a breaking hardness tester.

The tablet quality testing apparatus may further comprise a means for applying a gradually increasing force to the test object in stepwise fashion and halting such force application and extracting indentation depth when a predefined force level is reached.

Preferably the tablet controlling apparatus further comprises a drive means for applying a force to the test object as well as means for stopping such movement and indicating the applied force when the test object fractures. A method of predicting defects of powder compacts occurring during manufacturing at higher levels of compression forces and rates.

Preferably the tablet quality testing apparatus further comprises data acquisition and analysis system quantifying and reporting mechanical failure propensity in manufacturing conditions.

A second aspect is directed to a method for testing for a propensity of mechanical failure in tablet processing during early stage development; the method involving calculation of a ratio of indentation to breaking hardness over the practical range of compression forces.

Preferably the method further comprises measuring indentation resistance and ultimate compression resistance with means to predict and quantify capping and lamination propensity.

A third aspect is directed to a method of optimizing processing parameters for tablets comprising measuring indentation resistance and ultimate compression resistance whilst optimizing manufacturing parameters selected from the group comprising formulation particulars and granule size, compaction pressure and speed, as well as tooling size and shape.

BRIEF DESCRIPTION OF FIGURES

For a better understanding of the invention and to show how it may be carried into effect, reference will now be made, purely by way of example, to the accompanying drawings.

With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the invention only, and are presented to provide what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention; the description taken with the figures making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

In the accompanying figures:

Fig. 1 is a schematic illustration of capping;

Fig. 2 is a schematic illustration of lamination;

Fig. 3 is a schematic illustration of breaking hardness testing;

Fig. 4 is a schematic illustration of indentation hardness testing;

Fig. 5 is one embodiment of an apparatus that combines both breaking and indentation hardness testing;

Fig. 6 is a schematic representation of one embodiment of the invention which has the addition of a camera for capturing images of the indent and/or crack pattern on failure;

Fig. 7 is an illustration of one possible flowchart of testing;

Fig. 8 is a graphic representation of the testing done on Formulation A (Aspirin) on tablets made at low tableting speed using a single punch press; Fig 9 is a graphic representation of the testing done on Formulation B (Caffeine); at which the capping propensity becomes visible, depends on the speed of compression;

Fig. 10. is a graphic representation of the testing done on Formulation C (Caffeine- Aspirin 50:50 mix);

Fig. 11 is a graph summarizes the results of Fig.8, Fig.9 and Fig.10, wherein the formulation A (Aspirin) shows a significant capping propensity, the formulation B (Caffeine) shows no capping propensity and the formulation C (Caffeine- Aspirin mix) shows a capping propensity that depends on the proportion of the capping inducing component in the mix.

DESCRIPTION OF EMBODIMENTS

When compressing pharmaceutical formulations into tablets, various common failure modes are known.

With reference to Fig. 1, a common failure that may occur is capping. Here the upper face 12 of a pill 10 breaks off.

With reference to Fig. 2, another common failure is lamination, which denotes spalling of the bottom 21 and top 22 surfaces of the tablet 20

Fig. 3 is a schematic illustration of breaking hardness testing.

Fig. 4 is a schematic illustration of indentation hardness testing.

To quantify capping tendency, we propose a method of quantifying capping propensity based on non-linearity of, or an inflection point in, the line of ratio of indentation breaking hardness over the range of compression forces.

With reference to Fig. 5, a preferred embodiment of an apparatus for such quantification includes a carousel 52 for handling compacts, with a weighing station 54, a thickness measuring station 55, an indentation hardness measuring station 56 and a station for measuring breaking hardness 58. Also included is a connection to a PC 60 and a connection to a power line.

In a preferred embodiment of indentation tester, the stepper motor moving of the ball is stopped when a pre-assigned force F as measured by a load cell is reached, and the indentation depth h is measured by counting steps of the motor, since each step is of a known length. For breaking hardness measurement, instead of loading between plates, it is proposed to load using an indention hardness probe, typically a Brinell ball, and to first apply a standard load to obtain indentation hardness data, and then to continue loading stepwise until failure, giving compressive strength data. Alternatively, indentation and breaking hardness measurements can be made at separate testing stations.

Results of measurements from such a system are fed to a computer that calculates and reports the degree of capping tendency of the tested formulation, see Fig. 6. A camera for imaging the indentation may provide additional insight into the resulting impression including the presence of possible existing microcracks. The photographic or video documentation of the breaking hardness test can be used as a valuable tool for additional quality assurance purposes during routine mass production and in appropriate special applications for the detection of counterfeit products.

With reference to Fig. 5, a schematic representation of the proposed embodiment, a tablet 10 is tested with indenter 32 against a plate 14 by a movement caused by motor 16 controlled by a controller 20 that also is operating a camera 22. The resulting image is uploaded via controller 24 to a data acquisition device on line 26. Both controllers transmit information to a central processing unit (not shown) that generates test reports.

With reference to Fig. 7, one possible method of testing is shown. The testing method comprises the steps of:

(a) Placing tablet in tester in desired orientation

(b) Measuring indentation depth at predefined load

(c) Load to compression failure

(d) Measure load at compression failure

(e) Calculate indentation hardness / compressive failure force ratio

(f) Make additional testing documentation (image)

It is recommended to measure the indentation hardness and the breaking hardness on of the same tablets.

Testing materials with different capping / lamination propensity will generate results that will enable a quantifiable prediction and, consequently, avoidance of such failure in production (Fig. 8, 9, 10, 11). Fig. 8 shows the results of testing done on Aspirin. The smooth graph without any visible sharp slope change of R/st, indicates that no capping or lamination is expected at any speed. The dimensionless slope of the regression line is formulation specific.

Fig. 9 shows the results of testing done on caffeine tablets. The clear change in slope of R/st indicates a significant capping / lamination propensity. The inflection point, where the slope of the ratio line is changing sharply, in this case (tablets made at slow compression speed) corresponds to about 16 kN of compression force.

Fig. 10 shows the results of testing formulation C which is a (Caffeine- Aspirin 50:50 mix). Two linear regression lines with distinctly different slopes are obtained. The change in slope occurs at an intersection point when P ~ 150 MPa, / st ~ 1.4 MPa, which corresponds to a specific compression force being a function of the tableting speed, which in this case is low. Note that any increase in the proportion of a mix component exhibiting capping propensity (caffeine) will increase non-linearity of the line slope.

Fig. 11 summarizes the results of Fig.8, Fig.9 and Fig.10. The formulation A (Aspirin)shows a significant capping propensity, formulation B(Caffeine) shows no capping propensity and formulation C (Caffeine- Aspirin mix) shows a capping propensity that depends on the proportion of the capping inducing component in the mix.lt will be appreciated that this apparatus can be used not only in the field of medicinal tablets but also for other types of compacts used in other fields such as in veterinary medicine, formulations used for treatment in agriculture, compacts used as consumer products, ceramic and metallurgical powder compacts and formulations used for various industrial applications, and the like.

In the claims, the word“comprise”, and variations thereof such as“comprises”, “comprising” and the like indicate that the components listed are included, but not generally to the exclusion of other components.

Persons skilled in the art will appreciate that the present invention is not limited to what has been particularly shown and described herein above. Rather the scope of the present invention is defined by the appended claims and includes both combinations and sub combinations of the various features described hereinabove as well as variations and modifications thereof, which would occur to persons skilled in the art upon reading the foregoing description.

Claims

1. A tablet quality testing apparatus for testing a test object comprising an indentation hardness tester and a breaking hardness tester.

2. The tablet quality testing apparatus of claim 1 further comprising a means for applying a gradually increasing force to the test object in stepwise fashion and halting such force application and extracting indentation depth when a predefined force level is reached.

3. The tablet quality testing apparatus of claim 1 further comprising a drive means for applying a force to the test object as well as means for stopping such movement and indicating the applied force when the test object fractures. A method of predicting defects of powder compacts occurring during manufacturing at higher levels of compression forces and rates.

4. The tablet quality testing apparatus of claim 1 further comprising data acquisition and analysis system quantifying and reporting mechanical failure propensity in manufacturing conditions.

5. A method for testing for a propensity of mechanical failure in tableting during early stage development; the method involving calculation of a ratio of indentation to breaking hardness over the practical range of compression forces.

6. The method of claim 5, comprising measuring indentation resistance and ultimate compression resistance with means to predict and quantify capping and lamination propensity.

7. A method of optimizing processing parameters for tablets comprising measuring indentation resistance and ultimate compression resistance whilst optimizing manufacturing parameters selected from the group comprising formulation particulars and granule size, compaction pressure and speed, as well as tooling size and shape.