Method for evaluating tablet moldability

Abstract

To provide a method for evaluating tablet moldability that can readily evaluate and predict moldability of a tablet.SOLUTION: A method for evaluating moldability of tablets including an active pharmaceutical ingredient includes the steps of: measuring hardness of a compression molding that is compression-molded by loading an active pharmaceutical ingredient with a compression load in a range of 0 to 200 MPa; and determining, as an index, when compression loads of optional two points within the range where the compression load is 0 to 200 MPa are compared to each other, evaluating that such a case is preferable when the hardness increases with an increase in the compression load, and evaluating that such a case is a defect when the hardness decreases relative to the increase in the compression load.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a method for evaluating the compactibility of tablets containing a drug substance, based on evaluation of the tableting characteristics of the drug substance used in a pharmaceutical formulation, and more particularly to a method for predicting and evaluating tableting problems during compaction of tablets containing the drug substance, based on evaluation of the tableting characteristics of the drug substance, which is an active ingredient procured from multiple manufacturing companies (sources). [Background technology]

[0002] In Japan, the use and spread of generic drugs is being promoted in order to reduce medical costs, and a high penetration rate is being achieved.

[0003] Furthermore, generic drugs have a strong role to play in social infrastructure, and in order to contribute to the health of the nation, the government and the generic drug industry as a whole are working to ensure a stable supply of them. As part of these efforts, in order to secure a stable supply of active ingredients (active pharmaceutical ingredients), there is a demand to procure active ingredients (active pharmaceutical ingredients) from multiple manufacturers (sources) (dual sourcing or multi-sourcing) rather than relying on a single manufacturer.

[0004] However, even if the drug substance has the same ingredients, the properties of the drug substance may differ due to differences in the manufacturing methods of each manufacturer. Even if drug substances from different manufacturers are used, the drug substances are blended with the same additives, and formulated under the same manufacturing conditions, problems may arise in the manufacturability of tablets when a drug substance from a certain manufacturer is used.

[0005] In particular, when using drug substances from multiple manufacturers, it is known that some tablets may experience tableting problems such as capping or lamination during the formulation (tabletting) process, resulting in poor appearance of the finished tablets, reduced marketability, and changes in the physical properties of the tablets, making it impossible to adopt the drug substance.

[0006] In order to avoid the above-mentioned tableting problems, quantitative evaluation of tableting characteristics is carried out using various devices and measurement methods. For example, Patent Document 1 discloses a method for evaluating the compression molding characteristics of powders in advance when compressing powdered medicines, powdered foods, etc.

[0007] Furthermore, Patent Document 2 discloses an evaluation method in which the residual die inner wall pressure is measured when powder is compressed under a compression load using a tablet press, and problems such as cracking or breakage of the powder compression molded product are predicted from the amount of change in the residual die inner wall pressure relative to changes in the compression load. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Publication No. 3-291548 [Patent Document 2] Japanese Patent Application Laid-Open No. 2012-177577 Summary of the Invention [Problem to be solved by the invention]

[0009] However, in order to evaluate tablet formability, it is necessary to granulate a mixture containing not only the active ingredient, but also other additives, to form a tablet powder, and then to apply a compression load (tabletting pressure) to tablet the mixture and evaluate the tablets formed. This evaluation is problematic in terms of both economic and time burdens.

[0010] Furthermore, when active ingredients (APIs) are procured from multiple manufacturing companies (sources) and used to manufacture tablets, it is difficult to evaluate the tableting characteristics using previously known methods for evaluating tableting characteristics when APIs from second or subsequent sources are used.

[0011] Therefore, an object of the present invention is to provide a method for evaluating tablet formability that can easily predict and evaluate tablet formability, even when drug substances are procured from multiple manufacturing companies (sources) and tablets are manufactured. Specifically, an object of the present invention is to provide a method for evaluating (determining) tablet formability that can evaluate tableting characteristics using a single drug substance used in tablet formation and predict and evaluate in advance problems such as tableting failures and internal cracks that may occur during the production of tablets containing drug substances and other additives that are actually manufactured and sold. [Means for solving the problem]

[0012] Therefore, in order to solve the above problems, the present inventors have conducted extensive research and have discovered a method for evaluating tablet formability that can predict and evaluate the risks of tableting problems and the like during the formulation of tablets containing a drug substance by evaluating the tableting properties of a compressed product obtained from the drug substance, thereby completing the present invention.

[0013] That is, the present invention relates to a method for evaluating the moldability of a tablet containing a drug substance, which comprises measuring the hardness of a compression-molded product obtained by applying a compression load in the range of 0 to 200 MPa to the drug substance and evaluating the tablet moldability as an index of good when the hardness increases with increasing compression load when the compression load is compared with any two points within the range of 0 to 200 MPa, and evaluating the tablet moldability as poor when the hardness decreases with increasing compression load.

[0014] In the method for evaluating tablet formability of the present invention, it is preferable that one of the two compression loads is a compression load exceeding 100 MPa.

[0015] In the method for evaluating tablet formability of the present invention, when comparing any three compression loads obtained by adding one additional compression load to any two compression loads within the range of 0 to 200 MPa, if the hardness increases with increasing compression load, the tablet is evaluated as good, and if the hardness decreases with increasing compression load at at least one of the three compression loads, the tablet is evaluated as poor.

[0016] In the method for evaluating tablet formability of the present invention, it is preferred that, of the compression loads at any three points, at least one point exceeds 100 MPa and the other point is 100 MPa or less. [Effects of the Invention]

[0017] According to the present invention, by evaluating the relationship between the compression load and hardness of a compression molded product of a drug substance, it is possible to predict and evaluate the possibility of tableting problems during formulation of tablets containing drug substances from second or subsequent sources, without having to granulate a mixture of an actual drug substance and other additives to form a tablet powder and then compress the tablet powder to form tablets.In addition, by evaluating the relationship between the compression load and hardness of a compression molded product when a drug substance from a second or subsequent source is used, it is possible to predict and evaluate the possibility of tableting problems during formulation of tablets containing drug substances from second or subsequent sources, which is useful. [Brief explanation of the drawings]

[0018] [Figure 1] Graph showing the relationship between compression load and hardness of compressed tablets containing azilsartan (active ingredient) and additives [Figure 2] Graph showing the relationship between compression load and hardness of compression molded products using azilsartan (active pharmaceutical ingredient) alone [Figure 3] Graph showing the relationship between compression load and hardness of compressed tablets containing levetiracetam (active pharmaceutical ingredient) and excipients [Figure 4] Graph showing the relationship between compression load and hardness of compressed products using levetiracetam (active pharmaceutical ingredient) alone [Figure 5] Graph showing the relationship between compression load and hardness of compressed tablets containing ramelteon (active ingredient) and additives [Figure 6] Graph showing the relationship between compression load and hardness of compression molded products using Ramelteon (active pharmaceutical ingredient) alone DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention relates to a method for evaluating the moldability of a tablet containing a drug substance, which comprises measuring the hardness of a compression-molded product obtained by compressing the drug substance under a compression load in the range of 0 to 200 MPa, and evaluating the tablet moldability as an index of good when the hardness increases with increasing compression load when the compression load is compared at any two points within the range of 0 to 200 MPa, and evaluating the tablet moldability as poor when the hardness decreases with increasing compression load. The above-mentioned drug substance means (i) a powder (powder) of the drug substance alone, and (ii) a drug substance granule obtained by granulating the powder (powder) of the drug substance alone. In addition to the above (i) and (ii), the evaluation method for tablet formability of the present invention can also be used with (iii) a mixture in which additives and the like are added to the powder of the single drug substance within a range that does not affect the evaluation method of the present invention, and (iv) a compressed product obtained by compressing a granule of the mixture obtained by granulating the mixture.

[0020] The method for evaluating tablet formability of the present invention involves applying a compression load (tabletting pressure) to the drug substance to compress it, measuring the hardness of the compressed product of the drug substance as the compression load increases, and comparing the compression loads at any two points within a range of 0 to 200 MPa, preferably any three points including one additional compression load, to evaluate the hardness as good if the hardness increases with increasing compression load, and evaluating the hardness as poor if the hardness decreases at at least one point with increasing compression load. By evaluating the relationship between the compression load and hardness of the compressed product of the drug substance evaluated as poor in this way, it is possible to predict and evaluate the risk of tableting problems and the like for tablets (prepared by granulating a mixture containing the drug substance and additives in an actual production line to form a tableting powder, and then tableting the tableting powder to form a formulation (tablet)).

[0021] Furthermore, in the method for evaluating tablet formability of the present invention, it is preferable that one of the two compression loads exceeds 100 MPa, and it is more preferable that at least one of the three compression loads obtained by adding the one compression load exceeds 100 MPa and the other is 100 MPa or less. In the evaluation, a case in which the hardness decreases with an increase in the compression load is evaluated as poor, but there are cases in which the hardness decreases when the compression load reaches a boundary of around 100 MPa, and this can be used as an index for evaluation.

[0022] The method for evaluating tablet formability of the present invention will be described in detail below. However, the method for evaluating tablet formability of the present invention should not be construed as being limited to the following embodiments and examples.

[0023] (Compression molded product) A compression molded product is formed by compressing a powder (powder) of a single drug substance. The compression molded product includes a "tablet," which is a type of powder compression molded product formed by compressing powder or granules, and the tablet is widely used in the formulation of pharmaceuticals, the formation of powdered foods, etc. Furthermore, the tablet must be strong enough to maintain its shape until it is actually used (taken), and it is important to prevent problems such as tableting failures and internal cracks from occurring during formulation.

[0024] In the formulation, a tableting powder containing other additives in addition to the drug substance is usually used, and therefore the tendency for the drug substance to solidify alone is not evaluated, and when a tableting powder containing the drug substance and additives is actually formulated, problems such as difficulty in solidifying due to the drug substance can occur, making it impossible to evaluate (determine) the tendency for the drug substance itself to solidify. However, by using the method for evaluating tablet formability of the present invention, for example, by applying a compression load to a powder (powder) of the drug substance alone or to a drug substance granule obtained by granulating the powder (powder) of the drug substance alone and measuring the hardness of the resulting compression-molded product, the tendency for the drug substance alone to solidify can also be evaluated, which is useful.

[0025] (Tablet molding) The formulation (tablet manufacturing process) can be carried out by a known method without any particular limitations. For example, a mixture of the active ingredient, the drug substance, and other additives can be granulated, and the resulting tablet powder can be placed in a tablet press. An upper and lower punches placed in the tablet press are used to apply a compressive load and tablet the mixture, thereby forming the formulation (tablets) and obtaining tablets.

[0026] (Molding of compressed products (excluding tablets)) The compression molding can be carried out by known methods without any particular limitations, but can be carried out by any of the following methods: (i) a powder (powder) of the active ingredient alone; (ii) a granulated drug substance obtained by granulating the powder (powder) of the active ingredient alone; (iii) a mixture of the powder of the active ingredient alone to which additives and the like have been added within a range that does not affect the evaluation method of the present invention; and (iv) a granulated mixture obtained by granulating the mixture, which is used as a tablet powder. The tablet powder is then placed in a tablet press, and a compression load is applied using an upper punch and a lower punch placed in the tablet press, and the tablet powder is compression-molded to obtain a compression molded product.

[0027] (active ingredient (drug substance)) The compression-molded product (tablet) contains an active ingredient, which is the active ingredient and the main ingredient in the compression-molded product (tablet). The method for evaluating tablet formability of the present invention is useful in that it can predict and evaluate the tablet formability of tablets made using mixtures that actually contain additives in addition to a drug substance, based on the behavior of hardness when a compression load is applied to the tablet powder (the relationship between compression load and hardness), i.e., a compression load of 0 to 200 MPa is applied to the tablet powder to form a compression molded product, and the hardness of the compression molded product is measured. When the hardness increases with increasing compression load, the product is evaluated as "good", and when the hardness decreases with increasing compression load, the product is evaluated as "poor". The drug substance used in the evaluation method of the present invention is not particularly limited. For example, the above behavior can be achieved because the interparticle bonding strength between drug substances is strong or the drug substance has high plastic deformability, and drug substances having such properties can be evaluated using the evaluation method of tablet formability of the present invention.

[0028] Furthermore, it is preferable to use a drug substance that is not highly adhesive (cohesive). If the drug substance itself is highly adhesive, it may be difficult to measure the hardness of the drug substance in tablet form (tablet state) when a compression load is applied during tableting. However, even if the drug substance has high adhesiveness, the tablet formability evaluation method of the present invention can be used by using an additive such as a lubricant, and using a mixture of these or a granulated product of the mixture, for the purpose of improving the fluidity and compressibility of the drug substance itself, within a range that does not affect the evaluation method of the present invention.

[0029] (Other additives) The compression molded product (tablet) may contain known additives such as binders, disintegrants, excipients, lubricants, and fluidizing agents in addition to the active ingredient. The binder is a substance that affects the mechanical strength of the tablet, and examples thereof include starch paste, gum arabic paste, and hydroxypropyl cellulose. The disintegrants and excipients are used to absorb water, swell, and disintegrate the tablet, facilitating the release of the active ingredient, and examples of such disintegrants and excipients include lactose and starch. The lubricant and fluidizing agent are added to improve the fluidity of the powder and facilitate compression molding, and examples of such agents include wax and talc.

[0030] [Granulation] Granulation refers to the process of converting raw materials into granules from powder form to improve handleability, as raw materials are rarely used to manufacture pharmaceuticals, such as by tableting. Granulation is a process of producing granules of approximately uniform shape and size from raw materials. Granulation methods include known methods such as wet and dry methods. Granulators used for granulation include extrusion granulators, agitator granulators, fluidized bed granulators, tumbling granulators, and tumbling granulators. The products obtained by granulation, as well as powders and mixtures for direct compression that do not require granulation, are also referred to as tablet powders. In addition, in the method for evaluating tablet formability of the present invention, a granulated drug substance obtained by granulating a powder (powder) of the drug substance alone, or a granulated mixture obtained by granulating a mixture of the drug substance powder and an additive or the like, can be obtained using the known method described above. As described above, in the present invention, (i) a powder (powder) of a single drug substance, (ii) a drug substance granule obtained by granulating the powder (powder) of the single drug substance, (iii) a mixture obtained by adding additives, etc. to the powder of the single drug substance to the extent that they do not affect the evaluation method of the present invention, and (iv) a granule of the mixture obtained by granulating the mixture are technically classified as tableting powders used for forming the compression-molded product (tablet). However, when tableting powders used in the actual production of pharmaceuticals are used, it is not possible to appropriately evaluate tablet formability. However, when the tableting powders (i) to (iv) are used, the risk of tablet compression problems and the like can be predicted and evaluated by the evaluation method for tablet formability of the present invention, which is useful.

[0031] [Compression load] The compression load refers to the load (force) applied when the tableting powder is filled into a die hole in a tablet press used to form a compression-molded product (tablet) and compressed into the tableting powder by an upper punch, while the lower punch is inserted into the die and fixed. The load is not particularly problematic as long as it is within a general range that allows formulation, for example, approximately 50 to 300 MPa. In the method for evaluating tablet formability of the present invention, the compression load is continuously applied at 0 to 200 MPa, and by applying a compression load within this range, the behavior based on the drug substance (the relationship between compression load and hardness) can be confirmed. From this behavior, when a mixture of the drug substance and other additives is actually blended to form a compression-molded product (tablet), problems such as tableting failure and internal cracks in the resulting compression-molded product (tablet) can be prevented.

[0032] [Compression Speed] The compression speed when applying the compression load is not particularly problematic as long as it is within a general range that can produce a compression-molded product (tablet), for example, about 10 to 50 mm / min. By keeping the compression speed low (slow), the hardness of the resulting compression-molded product (tablet) can be increased.

[0033] [Compression molding conditions] Conditions for the compression molding include, for example, when a certain tableting powder is compression molded (tableted), the inner diameter of the die hole is 1 to 10 mmφ, the compression speed of the tableting powder is 10 to 50 mm / min, the compression load is 1 to 200 MPa, and the filling amount of the tableting powder (mass of powder filled into the die hole is 10 to 200 mg). The shape of the punch surface is not particularly limited as long as it allows confirmation of the behavior based on the drug substance (the relationship between compression load and hardness), and may be a flat surface that applies uniform pressure to the punch surface, or an R-surface with a curvature radius that applies non-uniform pressure. [Example]

[0034] Specific examples of the above-described evaluation method for tablet moldability will be described in detail below.

[0035] (Method for forming compressed products (tablets)) Powders (tablet powders) obtained by blending each of the drug substances shown in Table 1 below with additives and granulating them, or powders (tablet powders) obtained by granulating each of the drug substances alone (plain drug substances) were placed in a benchtop powder compression property evaluation device (manufacturer: Gamlen Tableting Ltd, device name: GTP-2, model: D500) so that the filling amount was 100 mg, and tablets were formed using a 6 mmφ flat punch at a compression speed of 30 mm / min and with a compression load (tabletting pressure) of 0 to 200 MPa, to form compression molded products (including tablets) and prepare each sample.

[0036] (Hardness measurement method) When the compression molded products were formed, the hardness (TFS: MPa) of each compression molded product (sample) was measured under the compression load (tabletting pressure) conditions of approximately 35 MPa, approximately 105 MPa, and approximately 175 MPa using a hardness tester (manufacturer: Gamlen Tableting Ltd, device name: GALMEN TABLET TENSILE ANALYSER (TTA)). For each condition of the compression load (tabletting pressure), the hardness was measured three times, and the average value was taken as the hardness (TFS) under each condition.

[0037] Regarding the evaluation of tablet formability, the evaluation results (behavior) based on the relationship between hardness (TFS) and compression load (tabletting pressure) are shown in Tables 2 to 7, and Figures 1 to 6 corresponding to Tables 2 to 7, respectively.

[0038] Table 2 shows the relationship between compression load and hardness (TFS) of compressed tablets (tablets) made using tableting powder containing azilsartan (active ingredient) and common additives required for tablet formation (formulation), such as excipients, binders, and disintegrants. Figure 1 shows the graph. Table 3: The relationship between compression load and hardness (TFS) of compressed tablets using tablet powder of azilsartan (active pharmaceutical ingredient) alone is shown in Figure 2.

[0039] Table 4 shows the relationship between compression load and hardness (TFS) of compressed tablets (tablets) using tableting powder containing levetiracetam (active ingredient) and common additives required for tablet molding (formulation), such as excipients, binders, and disintegrants. The graph is shown in Figure 3. Table 5: The relationship between compression load and hardness (TFS) of compressed tablets using tablet powder of levetiracetam (active pharmaceutical ingredient) alone is shown in Figure 4.

[0040] Table 6 shows the relationship between compression load and hardness (TFS) of compressed tablets (tablets) made using tableting powder containing ramelteon (active ingredient) and common additives required for tablet molding (formulation), such as excipients, binders, and disintegrants. Figure 5 shows the graph. Table 7: The relationship between compression load and hardness (TFS) of compressed tablets using tablet powder of ramelteon (active pharmaceutical ingredient) alone is shown in Figure 6.

[0041] [Table 1]

[0042] [Table 2]

[0043] [Table 3]

[0044] [Table 4]

[0045] [Table 5]

[0046] [Table 6]

[0047] [Table 7]

[0048] In order to confirm not only the behavior of the drug substance alone (the relationship between compression load and hardness) but also the actual tablet formability, it was confirmed whether or not tableting problems occurred in the tablets obtained when tableting powder containing a mixture of drug substance and additives on the production line. When azilsartan was used as the active ingredient for the tablets, the compression load was 94.9 MPa for Company A (1st source) and 99.9 MPa for Company B (2nd source); when levetiracetam was used, the compression load was 195.0 MPa for Company A (1st source) and 231.0 MPa for Company B (2nd source); and when ramelteon was used, the compression load was 161.0 MPa for Company A (1st source) and 168.1 MPa for Company B (2nd source).

[0049] Furthermore, as the confirmation method, tableting powders containing the active ingredients and additives shown in Table 1 above were sent to the production line, and the number of tablets that experienced tableting problems out of the total number of tablets produced (using azilsartan: 670,000 tablets, using levetiracetam: 300,000 tablets, using ramelteon: 1.3 million tablets) was confirmed. If no tableting problems occurred, it was judged that there was no tableting problem, and if one or more tableting problems occurred, it was judged that there was a tableting problem.

[0050] From Tables 2 and 3 (Figures 1 and 2) above, it can be seen that for the compression molded products (tablets) made using the tableting powder of "a mixture containing azilsartan (drug substance) and general additives required for formulation" from Company A (1st source) and Company B (2nd source), and for the compression molded products made using the tableting powder of "azilsartan (drug substance) alone," there was an (almost) proportional relationship between compression load and hardness for the former "mixture." On the other hand, for the latter "drug substance alone," there was an (almost) proportional relationship for Company A's tablets, but not for Company B's tablets, and it was confirmed that hardness decreased when the compression pressure exceeded 100 MPa.

[0051] Furthermore, tablets were actually formed using tableting powders from Company A (1st source) and Company B (2nd source) of "a mixture containing azilsartan (active ingredient) and general additives required for formulation" to check for the occurrence of tableting problems. Tableting problems were confirmed in the tablets from Company B, which had a reduced hardness, and it was confirmed that the tableting properties of actual tablets can be predicted and evaluated in advance by using the tableting property evaluation method of the present invention.

[0052] From Tables 4 and 5 (Figures 3 and 4) above, it was confirmed that in the compression molded products (tablets) made using the tableting powder of "a mixture containing levetiracetam (active ingredient) and general additives required for formulation" from Company A (1st source) and Company B (2nd source), and the compression molded products made using the tableting powder of "levetiracetam (active ingredient) alone," in the case of the former "mixture," there is an (approximately) proportional relationship between compression load and hardness, and in the case of the latter "active ingredient alone," there is an (approximately) proportional relationship for Company A's tablets, but there is no (approximately) proportional relationship for Company B's tablets, and that the hardness decreases when the compression pressure exceeds 100 MPa.

[0053] Furthermore, tablets were actually formed using tableting powders of "a mixture containing levetiracetam (active ingredient) and general additives required for formulation" from Company A (1st source) and Company B (2nd source), and the occurrence of tableting problems was confirmed. Tableting problems were confirmed in the tablets from Company B, which had a reduced hardness, and it was confirmed that the tableting properties of actual tablets can be predicted and evaluated in advance by using the tableting property evaluation method of the present invention.

[0054] From Tables 6 and 7 (Figures 5 and 6) above, in the case of compressed products (tablets) made using the tableting powder of "a mixture containing ramelteon (active ingredient) and general additives necessary for formulation" from Company A (1st source) and Company B (2nd source), and compressed products made using the tableting powder of "ramelteon (active ingredient) alone," in the case of the former "mixture" and the latter "active ingredient alone," the tablets from Company A and Company B were in an (almost) proportional relationship, and no decrease in hardness was observed.

[0055] Furthermore, tablets were actually formed using tableting powder from Company A (1st source) and Company B (2nd source) of "a mixture containing ramelteon (active ingredient) and general additives required for formulation" to check for the occurrence of tableting problems. No tableting problems were observed from either company, confirming that the tableting moldability evaluation method of the present invention can be used to predict and evaluate the tableting moldability of actual tablets in advance. [Industrial Applicability]

[0056] The method for evaluating tablet formability of the present invention is useful because it allows prediction and evaluation of the formability of tablets obtained from a mixture of actually used drug substances and additives, based on the relationship between the compression load and the hardness, by measuring the hardness of a compression-molded product (tablet) obtained by applying a compression load to a drug substance alone.

Claims

1. A method for evaluating the compactibility of a tablet containing a drug substance, comprising: A compression load in the range of 0 to 200 MPa is applied to the drug substance to compress and mold it, and the hardness of the compressed product is measured; When comparing the compressive loads at any two points within the range of 0 to 200 MPa, When the hardness increases with an increase in the compressive load, the hardness is evaluated as being good. A method for evaluating tablet formability, in which a decrease in hardness with an increase in the compression load is evaluated as poor.

2. The method for evaluating tablet moldability according to claim 1, wherein one of the two compression loads exceeds 100 MPa.

3. When comparing the compressive loads at any three points obtained by adding one additional compressive load to the two compressive loads at any two points within the range of 0 to 200 MPa, When the hardness increases with an increase in the compressive load, the hardness is evaluated as being good. The method for evaluating tablet moldability according to claim 1, wherein the index is that the hardness decreases at at least one of the three compression loads as the compression load increases, and the tablet is evaluated as being defective.

4. The method for evaluating tablet moldability according to claim 3, wherein at least one of the compression loads at any three points exceeds 100 MPa and the other is 100 MPa or less.

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