Patent Application
20230285244
The present invention relates to a method of tableting under reduced pressure and a device for carrying out the method. The invention is used in industries where it is necessary to make tablets from substances that are difficult to compress.
A process of making tablets is a key technology in making a drug form. Tablets are the most commonly used form of an oral drug. Tablets are mainly produced in a tableting process, i.e. by pressing a mixture of powders or granules. Tableting, regardless of the type of tablet press (rotary, single-punch), takes place in similar stages: moving the punches, filling a cavity with tablet mass, lowering the punches and compressing, pushing a tablet out of a cavity, pushing the tablet out of a die. Before the upper punch enters the die opening of a tablet press, the grains of the tablet mass move relative to each other in such a way that the smaller ones fill the free spaces between the larger ones, making them more accurately arranged. The distribution of grains is described by the number of contact points, which is primarily due to their size, shape, density, surface properties, and the tableting method used. For example, the theoretical free space between closely packed powder grains, characterized by the same size, is approximately 40%. Whereas, the arrangement of the spherical granule grains, such as pellets or cube-shaped grains, will be different. Then, the free space between grains can be reduced to approximately 15%. However, in practice, the arrangement of the spherical grains may be limited by the size and shape of the punches and die used. During penetration of the upper punch into a filled in die, initially only individual contact points between the grains are observed. With a further increase in the pressure force, local deformation occurs—distortion of the grains. The energy loss occurring during this process may result from friction between the powder or granules grains or from friction between the tablet side surface and the die wall. Grain deformation may be flexible, plastic or occur in the form of granularity—fragmentation. The type of deformation depends on the size of pressing force applied, its duration and also on the physical properties of the tablet mass components. If the applied compression force is lower than the yield point, the grains undergo elastic deformation, i.e. they return to their original form. As a result of increasing the pressing force, tablet mass volume reduction occurs, i.e. compression. The occurrence of plastic deformation is then observed. If the grains are brittle and breakable, fragmentation is the dominant deformation mechanism. If final distortion is reached, the potential bonding sites between the grains increase together with their deformation degree. A further compaction takes place as a result of the penetration of small grains into the spaces between the larger grains.
The second stage of compaction—consolidation—consists in combining—creating bonds between the tablet mass individual grains. The observed mutual attraction of the grains is inversely proportional to the distance between them and occurs when they are in a sufficiently close distance. This allows the grains to be continuously connected to each other.
Japanese patent application JP3141544U shows a tableting device construction, where the lower punch is lowered and raised many times during the compression stage. During each cycle of the punch movement, the compressed powder particles are agitated, which releases the air collected between the powder particles.
On the other hand, the Chinese utility model application CN207590976U discloses the construction of a tableting device in which the tableting process is carried out under vacuum conditions. The device includes a tableting chamber with a fixed die and a single movable punch. In the device, a vacuum is generated in the entire volume of the chamber in which the tableting process takes place.
The construction of a tableting device is known from the international patent application WO08087223A1. The device comprises a body to which a transparent housing is attached. In the front part of the machine body there is an eccentric mechanism driving the upper punch, a tableting die and a fixed lower punch. The front part of the body, with punches, is sealingly encased with a transparent housing which includes a flexible sleeve for handling compressed material, inert gas connection inlets, a valveless connection to a vacuum pump to generate reduced pressure during the tableting process.
US patent application US2005147710A describes a method and construction of a device for tableting a substance in a hydroxypropyl methylcellulose (HPMC) coating. The tableting device includes two movable punches, an upper and a lower punch. The lower punch is constructed in such a way that channels are hollowed therein through which a reduced pressure is generated. The tableting process is carried out in such a way that a layer of HPMC is applied to the lower punch, and then a reduced pressure is created in the lower punch. This reduces the volume of the HMPC layer. In the next step, the powder is applied to the thus obtained HPMC layer and it is pressed. The lower punch is raised up, where the second layer of HPMC has been previously applied to the die. The effect is to complete the tablet coating layer with HPMC.
The prior art, despite describing tableting devices under reduced pressure, or under vacuum conditions, and tableting method with these devices, does not show how the tableting process can be performed for substances constituting granulate or tablet mass that crystallize in crystallographic systems such as e.g. regular or tetrahedral or have been subjected to a micronization or nanonization process before tableting without additional binding substances for the tablet granulate particles. Compression of this type crystallites is difficult due to the adsorbed air on their surface, which leads to an increased friction force between the crystallites and an increased surface tension, which effectively reduces the number of contact points between the components of the tableting mass.
The technical problem faced by the invention would therefore be to provide a tableting method that would allow for the reduction of friction between the components of the tableting mass without additional glidants, containing crystallizing substances in a tetrahedral or regular arrangement, micronized or nanonized, reducing the surface tension between them, and where an initial granulation of the tablet mass would not be necessary, and it would be possible to reduce the excipient content, the method should also enable the tablet thickness to be changed without the need for additional operations. Another technical problem would be to provide a tableting device implementing this method.
The first subject of the invention is a method of tableting a tablet mass containing components crystallizing in a tetrahedral and/or regular arrangement and/or subjected to micronization and/or nanonization, carried out in the following steps:
In a preferred embodiment of the invention, in steps b) and c) the pressure in the vacuum chamber of the external tablet press is reduced.
In a further preferred embodiment of the invention the tablet press is selected from the group including: a single-punch tablet press or a rotary tablet press.
In another preferred embodiment of the invention, the tableting mass is selected from the group comprising: polysaccharide, preferably microcrystalline microcellulose, natural silica, preferably diatomaceous earth, crystalline active substance, preferably diosmin or micronized diosmin, vitamin preparation, preferably vitamin D3 coated with hydroxyapatite.
In a further preferred embodiment of the invention, the tablets have a thickness from 2.2 mm to 8.1 mm.
In yet another preferred embodiment of the invention, the pressure is reduced from −0.01 MPa to −0.15 MPa.
The second object of the invention is a tablet mass tableting device comprising a housing and a tableting mechanism, wherein the housing has a bottom wall, a top wall and four side walls that are connected to each other to form a sealed vacuum chamber, and the tableting mechanism is housed in the chamber housing, characterized in that a valve for connecting a vacuum pump is provided on the vacuum chamber side wall.
In a preferred embodiment, the tableting mechanism is a single-punch tablet press or a rotary tablet press.
In a further preferred embodiment of the invention, the chamber with the tableting mechanism is placed in the outer chamber to which a vacuum pump is connected via a vacuum valve in order to reduce the pressure.
In another advantageous embodiment of the invention, the vacuum chamber comprises a lower punch table on which a lower punch is placed, and the chamber contains a tablet press die, wherein the die is located above the lower punch and includes a die cavity for introducing the upper punch in order to introduce a tablet mass therein and to receive the upper punch.
In another preferred embodiment of the invention, the vacuum chamber top wall comprises a die of a single-punch tablet press.
In a further preferred embodiment of the invention, the chamber with the tableting mechanism, which is a single-punch tablet press, is placed in an external vacuum chamber which includes a vacuum valve for connecting a vacuum pump.
In yet another preferred embodiment of the invention, the external vacuum chamber comprises a rotary tablet press having a rotary tablet press base placed on the lower wall of the external vacuum chamber connected to a drive motor and connected to the table by the rotary tablet press rotary die, above which the rotary tablet press upper punch is placed.
Another object of the invention is a kit comprising a device for tableting a tablet mass, as defined in the second aspect of the invention and a vacuum pump which is connected to the device via a vacuum valve.
In a preferred embodiment of the invention, the device is placed in the external vacuum chamber and a vacuum pump is connected to the external chamber via vacuum valve.
According to the method described in the invention, it is possible to directly make tablets from substances crystallizing in a tetrahedral and/or regular arrangement, e.g. argentum nitricum (AgNO3) and/or subjected to micronization or nanonization. Moreover, the solution according to the invention enables tableting of all types of substances with a reduced proportion of excipients and with the omission of granulation process.
Embodiments of the invention have been illustrated in the drawing, which shows
in
in
in
The vacuum chamber 7 or 13 comprises a tableting mechanism which may be a single-punch tablet press or a rotary tablet press. In the case of single-punch tablet press, it can first be placed in the vacuum chamber 7, and then placed together with the vacuum chamber 7 in the external vacuum chamber 13. Thereafter, the tableting mass is introduced into the tablet press cavity from the hopper 8 and the pressure is lowered, in chamber 7 or chambers 7 and 13, so as to achieve the desired tablet thickness in the range from −0.005 MPa to −0.15 MPa and the tablet mass is compressed. Examples of obtaining different tablet thickness are shown in the following embodiments. The compressed tablet is then ejected from the tablet press die cavity. The process can be carried out in a single-punch tablet press (
In the vacuum chamber 7 formed by a housing comprising a top wall A1, a bottom wall A2 and side walls A3, there is a tableting mechanism including the tablet press table 2. The tableting mechanism may be selected from a single-punch tablet press or a rotary tablet press. The chamber 7 may be of any construction. It is important, however, that there is enough space for the tableting mechanism and that it is possible to maintain constant pressure in it during the tableting process of the tablet mass. The schematic drawing (
Another possibility is to place the single-punch tablet press as described above in an additional outer chamber 13, which is also connected to a vacuum pump, not shown in
The tableting mechanism, which is a rotary tablet press, is housed in the vacuum chamber 13, in which a reduced pressure/vacuum is produced by means of a vacuum pump, not shown in
The compression of the tablets was performed under reduced pressure conditions in the tablet press chamber of a single-punch type. For this purpose, a vacuum pump was connected to the sealed lower chamber covering the elements regulating the lower punch and the elements fixing the table and the fixed die. The output pressure on the pump was set in various ranges (0-0.15 MPa). Tableting under standard conditions (atmospheric pressure) was considered a control test.
a) Microcrystalline cellulose was used as a model substance for the first test. The die 5 and punches 1 and 11, matched to it, were used to carry out the tests. The weight of the tablet substance in the die was 1 g.
As a result of the tests, the following results were obtained:
The result of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
b) For the second test, diatomaceous earth (silica of natural origin—SiO2) was used as a model substance. Weight of the tableting substance in the die was 1 g. The die 5 and punches 1 and 11, matched to it, were used to carry out the tests. The obtained results are presented in Table 2.
As a result of the experiment, tablets were obtained from a substance that cannot be compressed under atmospheric pressure.
Another positive effect of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet, the effects of which confirm the observations from the first test with the first model substance (microcrystalline cellulose). The higher the starting pressure, the smaller the measured average thickness of the end product observed.
c) For the third test, diosmin was used as a test substance. The weight of the tablet substance in die 5 was 1 g. The obtained results are shown in Table 3.
As a result of the experiment, tablets were obtained from a substance that cannot be subjected to a tableting process under atmospheric pressure.
An additional positive effect of the experiment, as in the first two cases, was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
d) For the fourth test, microcrystalline cellulose was used as a model substance. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. As a result of the tests, the following results were obtained:
The result of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
f) For the fifth test, diatomaceous earth (silica of natural origin—SiO2) was used as a model substance. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. The obtained results are shown in Table 5.
As a result of the experiment, tablets were obtained from a substance that cannot be compressed under atmospheric pressure.
Another positive effect of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet, the effect of which confirm the observations from the first test with the first model substance (microcrystalline cellulose). The higher the starting pressure, the smaller the measured average thickness of the end product observed.
g) For the sixth test, micronized diosmin was used as a test substance. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. The obtained results are shown in Table 6.
As a result of the experiment, tablets were obtained from a substance that cannot be subjected to a tableting process under atmospheric pressure.
An additional positive effect of the experiment, as in the first two cases, was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
h) For the seventh test, vitamin D3 precoated with hydroxyapatite in a weight ratio of 1:87 plus excipients was used as a test substance. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. The obtained results are shown in Table 7.
As a result of the experiment, tablets were obtained from a mixture that cannot be subjected to a tableting process under atmospheric pressure.
An additional positive effect of the experiment, as in the first two cases, was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
For this purpose, the entire device was placed in a sealed chamber to which a vacuum pump was connected. The output pressure on the pump was set in various ranges (0-0.15 MPa). Tableting under standard conditions (atmospheric pressure) was considered a control test.
a) For the first test, microcrystalline cellulose was used as a model substance. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. The weight of the tableting substance in the die was 1 g. As a result of the tests, the following results were obtained:
The result of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
b) For the second test, diatomaceous earth (silica of natural origin—SiO2) was used as a model substance. The weight of the tableting substance in the die was 1 g. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. The obtained results are shown in Table 9.
As a result of the experiment, tablets were obtained from a substance that cannot be compressed under atmospheric pressure.
Another positive effect of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet, the effect of which confirm the observations from the first test with the first model substance (microcrystalline cellulose). The higher the starting pressure, the smaller the measured average thickness of the end product observed.
c) For the third test, diosmin was used as a test substance. The weight of the tableting substance in the die was 1 g. The obtained results are shown in Table 10.
As a result of the experiment, tablets were obtained from a substance that cannot be subjected to the tableting process under atmospheric pressure.
An additional positive effect of the experiment, as in the first two cases, was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
d) For the fourth test, microcrystalline cellulose was used as a model substance. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. As a result of the tests, the following results were obtained:
The result of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
e) For the fifth test, diatomaceous earth (silica of natural origin—SiO2) was used as a model substance. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. The obtained results are shown in Table 12.
As a result of the experiment, tablets were obtained from a substance that cannot be compressed under atmospheric pressure.
Another positive effect of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet, the effects of which confirm the observations from the first test with the first model substance (microcrystalline cellulose). The higher the starting pressure, the smaller the measured average thickness of the end product observed.
g) For the sixth test, micronized diosmin was used as a model substance. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. The obtained results are shown in Table 13.
As a result of the experiment, tablets were obtained from a substance that cannot be subjected to the tableting process under atmospheric pressure.
An additional positive effect of the experiment, as in the first two cases, was the observation of the relationship between the value of the output pressure observed on the pressure pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
h) For the seventh test, vitamin D3 precoated with hydroxyapatite in a weight ratio of 1:87 plus excipients was used as a test substance. The die 5 and the punches 1 and 11, matched to it, were used to carry out the tests. The obtained results are shown in Table 14.
As a result of the experiment, tablets were obtained from a mixture that cannot be subjected to the tableting process under atmospheric pressure.
An additional positive effect of the experiment, as in the first two cases, was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
For this purpose, a vacuum pump was connected to a sealed chamber built around movable parts—die, punches. The output pressure on the pump was set in various ranges (0-015 MPa). Tableting under standard conditions (atmospheric pressure) was considered a control test.
a) For the first test, microcrystalline cellulose was used as a model substance. The die 15 and the punch 14, matched to it, were used to carry out the tests. The weight of the tableting substance in the die was 1 g. As a result of the tests, the following results were obtained:
The result of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
b) For the second test, diatomaceous earth (silica of natural origin—SiO2) was used as a model substance. Weight of the tableting substance in the die was 1 g. The die 15 and the punch 14, matched to it, were used to carry out the tests. The obtained results are shown in Table 16.
As a result of the experiment, tablets were obtained from a substance that cannot be compressed under atmospheric pressure.
Another positive effect of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet, the effects of which confirm the observations from the first test with the first model (microcrystalline cellulose). The higher the starting pressure, the smaller the measured average thickness of the end product observed.
c) For the third test, diosmin was used as a test substance. The weight of the tablet substance id the die was 1 g. The obtained results are shown in Table 17.
As a result of the experiment, tablets were obtained from a substance that cannot be subjected to the tableting process under atmospheric pressure.
An additional positive effect of the experiment, as in the first two cases, was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
d) For the fourth test, microcrystalline cellulose was used as a model substance. The die 15 and the punch 14, matched to it, were used to carry out the tests. As a result of the tests, the following results were obtained:
The result of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
e) For the fifth test, diatomaceous earth (silica of natural origin—SiO2) was used as a model substance. The die 15 and the punch 14, matched to it, were used to carry out the tests. The obtained results are shown in Table 19.
As a result of the experiment, tablets were obtained from a substance that cannot be compressed under atmospheric pressure.
Another positive effect of the experiment was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet, the effects of which confirm the observations from the first test with the first model substance (microcrystalline cellulose). The higher the starting pressure, the smaller the measured average thickness of the end product observed.
f) For the sixth test, micronized diosmin was used as a test substance. The die 15 and the punch 14, matched to it, were used to carry out the tests. The obtained results are shown in Table 20.
As a result of the experiment, tablets were obtained from a substance that cannot be subjected to the tableting process under atmospheric pressure.
An additional positive effect of the experiment, as in the first two cases, was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
g) For the seventh test, vitamin D3 precoated with hydroxyapatite in a weight ration of 1:87 plus excipients was used as a test substance. The obtained results are shown in Table 21.
As a result of the experiment, tablets were obtained from a mixture that cannot be subjected to the tableting process under atmospheric pressure.
An additional positive effect of the experiment, as in the first two cases, was the observation of the relationship between the value of the output pressure observed on the vacuum pump manometer and the thickness of the obtained tablet. The higher the starting pressure, the smaller the measured average thickness of the end product observed.
| Number | Date | Country | Kind |
|---|---|---|---|
| P.434794 | Jul 2020 | PL | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/PL2021/000050 | 7/27/2021 | WO |
