JP2010133807A - Method of grinding tablet and method of analyzing tablet constituent using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a grinding method for uniformly dissolving or dispersing each kind of constituent that is not dissolved or dispersed easily to a solvent by a normal method and is included in a tablet of which a test precision tends to deteriorate in a quality evaluation test, or the like of a medical product. <P>SOLUTION: The method of grinding a tablet is provided by applying a physical impact to a vessel containing tablets, solvents, and beads by a method, such as shaking, and bringing the tablets into physical contact with the beads. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a grinding method for uniformly dissolving or dispersing various components contained in a tablet in a solvent. Specifically, for example, in quality evaluation tests for pharmaceutical preparations, tablets that are difficult to dissolve or disperse in a solvent by ordinary methods and whose test accuracy is likely to deteriorate (for example, uncoated tablets or film-coated tablets formed under ultrahigh pressure) The tablet is efficiently disintegrated by the action of beads and can be dissolved or dispersed uniformly without altering the components in the tablet.

In pharmaceuticals and health foods, in order to facilitate oral use, in addition to uncoated tablets formed from a small amount of the main component using multiple components such as excipients, masking the taste of the main component For the purpose of improving stability and the like, various tablets such as sugar-coated tablets in which the surface of an uncoated tablet is coated with a saccharide and film-coated tablets coated with a polymer or the like are widely used.
In quality evaluation tests of such tablets (for example, plain tablets, sugar-coated tablets, film-coated tablets, etc.), the content of the main component contained in the tablet and the related substances produced by changing the main component and the moisture in the tablet In general, a liquid in which a tablet is dissolved or dispersed in a solvent or the like (hereinafter, collectively referred to as “sample solution”) is prepared. At that time, if the sample solution is non-uniform or deteriorated, the measurement result is adversely affected. Therefore, it is necessary to set an appropriate method for preparing the sample solution in various measurements.
In general, one of the following wet methods and dry methods is employed as a method for preparing the sample solution. The “wet method” is a method of preparing a uniform sample solution after taking a tablet in a container and adding a solvent before measurement. If the tablet does not disintegrate easily and a uniform sample solution cannot be prepared, the tablet is disintegrated by irradiating with ultrasonic waves after adding a solvent or by shaking with a touch mixer or shaker, and dissolved or dispersed. Prepare a sample solution.
On the other hand, when preparation by a wet method is difficult, a dry method is adopted. The “dry method” is a method in which a tablet is ground in a mortar before adding a solvent, or a sample crusher is used to put a tablet and a hammer for crushing into a container and vibrate to grind the pulverized product. In this method, a sample solution is prepared by dissolving or dispersing in a solvent.

By the way, as a cell crushing treatment method for crushing microorganisms and extracting components such as nucleic acids by crushing techniques other than tablets, in Patent Document 1, 0, such as zirconium, zirconia, etc. in a surfactant / phenol / chloroform mixed solution. A method is disclosed in which cells are physically disrupted by using beads having a diameter of 2 to 5 mm and rotating at several thousand revolutions per minute for about 1 minute. Also, as a continuous pulverization method for drug substances, in Patent Document 2, hard beads made of chemicals and polymer resin (average particle diameter of 1000 μm or less) are continuously introduced into the pulverization chamber, and the rotating body in the pulverization chamber is rotated at high speed. A method is disclosed in which a sample is pulverized by circulating for about 1 hour while rotating (several thousand revolutions per minute).
JP 2006-141292 A JP-A-7-530317

In order to analyze and evaluate pharmaceuticals such as tablets, the components in the tablets are altered by physical and chemical factors such as heat and pressure, regardless of the components and physical properties of the tablets and the presence or absence of a surface coating. There is a need for a technique that can prepare a uniform sample solution without any problems. However, in the wet method generally used for tablets, the tablets may not be completely disintegrated in the solution and may not be uniform. In such a case, the component to be measured in the tablet cannot be completely extracted into the solvent and cannot be measured accurately. Moreover, even if it disintegrates in a solution after being treated for a long time (which may take several hours), in addition to inefficiency, the sample or the solvent itself may be altered by the treatment for a long time. On the other hand, in the dry method, when a component that absorbs moisture is contained in the tablet, there is a problem that moisture or the like cannot be measured accurately, and the sample may be altered due to moisture absorption or the like. Furthermore, in the dry method, a pulverizer or mortar is generally used, but there is a possibility that another remaining sample may be mixed in, and the sample may be altered (change in compound physical properties, crystals, etc.) by pressure and heat during pulverization. Polymorphism, increase of related substances, etc.).
As described above, since various problems may occur in the conventional wet method and the dry method, the components in the tablet are physically and heat-pressure-related regardless of the components and physical properties of the tablet and the presence or absence of a surface film. Therefore, there is a demand for a technique that can easily prepare a uniform sample solution without deteriorating due to general factors or chemical factors.

  The present inventor has focused on beads that have been used for pulverization of very fine samples such as cells and bulk drug substances. Conventionally, these beads have been used to pulverize samples that are very fine or relatively soft compared to beads, but the idea of using them for beads that are larger and relatively harder than beads is conventionally known. It wasn't. The present inventor surprisingly adds a solvent (including water) and commercially available zirconia beads directly to a hard tablet as a sample and stirs using a shaker. The inventors have found that the above problems can be solved, and have completed the invention.

Item 1: A method of pulverizing a tablet by applying a physical impact to a container containing a tablet, a solvent and beads and bringing the tablet and beads into physical contact.
Item 2: The tablet pulverization method according to Item 1, wherein the beads have a diameter of 0.05 to 1 with respect to the major axis of the tablet.
Item 3: The tablet crushing method according to Item 1 or 2, wherein the beads are blended at a ratio of 2 to 200 parts by weight with respect to 1 part by weight of the tablet.
Item 4: The tablet crushing method according to any one of Items 1 to 3, wherein the solvent is blended at a ratio of 10 to 500 parts by volume with respect to 1 part by weight of the tablet.
Item 5: The tablet crushing method according to any one of Items 1 to 4, wherein the solvent is blended at a ratio of 1/10 to 1/2 volume with respect to the total volume of the container.
Item 6: The tablet crushing method according to any one of Items 1 to 5, wherein the physical impact is a method of shaking the container or a method of ultrasonicating the container.
Item 7: The method in which the physical impact is a method of shaking 80 times or more at a shaking distance (D) of about 0.2 to 4 with respect to the length (L) of the container in the shaking direction. The tablet crushing method as described.
Item 8: The tablet crushing method according to Item 7, wherein the shaking direction is a straight line or a curved line in a direction perpendicular to, horizontal to, or inclined with respect to the installation surface.
Item 9: A method for analyzing a component contained in a tablet using the method according to any one of Items 1 to 8.

  According to the present invention, when a pharmaceutical product such as a tablet is analyzed and evaluated, a uniform sample solution can be easily prepared regardless of the components and physical properties of the tablet as the test substance, the presence or absence of a surface film, and the like. Further, if a shaking method is employed as a physical impact method, there is a great advantage that pressure and heat due to friction when beads and a sample are shaken are hardly generated, and it is difficult to alter components and solvents in the sample.

Hereinafter, the present invention will be described in more detail.
The “tablet” in the present invention is not particularly limited, and examples thereof include an uncoated tablet, a sugar-coated tablet, a film-coated tablet, and an orally disintegrating tablet. Furthermore, if the size of the tablet is also circular, it is not particularly limited as long as it has a normal size, for example, a diameter (major axis) of about 5 to 11 mm, and if it is elliptical, it has a major axis of up to about 22 mm. Also, the shape of the tablet is not particularly limited, and examples thereof include a round tablet, a flat tablet, a round tablet, an R tablet, an elliptical tablet, and a scored tablet. The “longer diameter of the tablet” in the present invention means the longest side of the rectangle in contact with the projected image of the tablet.

  The “bead” used in the present invention is not particularly limited in its material, and any bead may be used as long as it has resistance to a solvent and has a hardness necessary for pulverizing a tablet. it can. For example, glass, zirconia, stainless steel, plastic, sand, silicate, etc. can be used as the material, but glass, zirconia, and stainless steel are preferred. The shape is not particularly limited, and examples thereof include a spherical shape, an oblong shape, a spherical shape with protrusions, a cone shape, a rectangular parallelepiped shape, and the like.

As for the hardness of the bead, it is sufficient that it has a hardness necessary for pulverizing the tablet. Specifically, a hardness of about 500 kg / mm ² or more is preferable. When the container to be mixed is made of glass, it is preferable to use glass or zirconia beads having a hardness of about 500 to 1200 kg / mm ² in consideration of safety. Furthermore, it is preferable that the density of the beads is about 2 g / cm ³ or more, and the use of zirconia, which has a higher density than glass, has a larger crushing force in a shaking operation and can be efficiently crushed. .

Although it does not specifically limit regarding the diameter of a bead, It is preferable to use the bead which has a diameter of about 0.05-1 with respect to the long diameter of a tablet, Preferably, it is a diameter of about 0.08-1. Here, the “bead diameter” means the longest side of the rectangle in contact with the projected image, and the shape is not particularly limited, and is spherical, oblong, spherical with protrusions, on a cone, on a cuboid However, it is preferable to use a spherical shape or a nearly spherical shape.
The blending amount of the beads is 2 to 200 parts by weight, preferably about 2 to 25 parts by weight with respect to 1 part by weight of the tablet.

  The “container” used in the present invention is not limited by the material, and may be any material that can withstand impacts such as beads and the solvent to be used, and other than glass, for example, polyethylene (PE), A resin such as polypropylene (PP), polypropylene copolymer, polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), fluorinated ethylene propylene, ethylene tetrafluoroethylene, polysulfone, or polycarbonate is also possible. Moreover, as a shape of a container, a round bottom, a flat bottom, a pitch (a shape with a thin tip), and the like can be used, and a round bottom is preferable.

  The “solvent” used in the present invention is not particularly limited as long as it does not adversely affect the sample and container in the tablet. For example, water, organic solvents (methanol, acetonitrile, chloroform, etc.) can be used. Yes, it can be appropriately selected according to the components in the tablet and the purpose of analysis. These solvents may be used alone or in combination. For example, when the tablet contains a large amount of water-soluble additives and is difficult to disintegrate with an organic solvent, a mixed solvent of water and an organic solvent may be used. About the use ratio of the solvent with respect to a tablet, about 10-500 volume parts of solvent is normally used with respect to 1 weight part of tablets. Or as a quantity of a solvent, you may mix | blend a solvent in the ratio of 1/10-1/2 volume with respect to the whole capacity | capacitance of a container.

  As a method for pulverizing a tablet, for example, first, a tablet, a solvent, and beads are added to a container. The order of addition is not particularly limited. For example, beads and a solvent are added to a container containing tablets and mixed.

  Thereafter, physical impact is applied to the container. Examples of the method of physically bringing the tablet and the beads into contact include a method of shaking the container, a method of ultrasonically treating the container, and the like. According to the method of the present invention, the method of shaking the container is convenient. Tablets can be crushed.

  Examples of the shaking method include a method using a shaker, and examples of the shaker include an apparatus that can shake with a container such as a glass with a stopper fixed. The shaking condition is, for example, a shaking distance of about 0.2 to 4 with respect to the length of the container in the shaking direction, and the shaking direction is linear in a direction perpendicular to the installation surface, horizontal or inclined. Alternatively, shake in a curved line at least 80 times per minute. Preferably, the shaking distance of about 0.3 to 0.4 with respect to the length of the container in the shaking direction is shaken 250 times or more linearly in the vertical direction. Here, the relationship between the length (L) of the container in the shaking direction, the shaking distance (D), and the shaking direction is as shown in FIG. From the left, the figure which shakes in the vertical, horizontal and inclined directions with respect to the installation surface is shown. When the container is shaken in a curved shape, the length (L) of the container is the length in the direction in which the beads move in the container by the movement, and (D) indicates the moving distance of the curve ( (The rightmost figure in FIG. 1). The number of shaking is defined as two round trips. Further, the shaking time is not particularly limited, but according to the method of the present invention, the decay time can be shortened. For example, it can be performed in about 5 to 30 minutes for a tablet that takes 60 minutes or more to completely disintegrate without using beads.

  By carrying out the above method, the tablet is pulverized in the container, and the sample in the tablet can be dissolved or dispersed evenly. The components in the tablet can be analyzed using the obtained sample solution. For example, it is possible to analyze main agents, additives, moisture, related substances, residual solvents, heavy metals, microorganisms, foreign substances, and the like.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
Comparative Example 1 Conventional tablet crushing method Film-coated tablet containing 5 mg of the active ingredient (including hypromellose, titanium oxide, macrogol, carnauba wax as coating components, a round tablet having a diameter of 5.5 mm and a weight of 62 mg) (hereinafter referred to as tablet A) )), And the tablet was pulverized by a dry method, and then the hygroscopicity by pulverization was measured. Tablets were pulverized by a dry method by putting 5 tablets A in an agate mortar and pulverizing with an agate pestle for about 30 seconds.
Then, the change of the weight at the time of storing for 0 to 30 minutes in 25 degreeC / 60% RH was measured using the unmilled product for 1 tablet A, and the said ground product. The result is shown in FIG. In the case of tablet A, the tendency of increasing the weight of the pulverized product was higher than that of the unground product, and increased by about 1% at maximum. Such a change in weight due to moisture absorption causes a decrease in sample collection accuracy and measurement accuracy of moisture in the sample.

Examples 1 and 2 and Comparative Examples 2 and 3 The tablet of the present invention and the conventional tablet crushing method Tablet A was pulverized using the method of the present invention and the conventional method. The following three types of beads were used.
・ Spherical zirconia beads particle size 2mm (outer diameter tolerance ± 0.2mm) (hardness approximately 1200kg / mm ² , density approximately 6.0g / cm ³ )
・ Spherical zirconia beads particle size 3mm (outer diameter tolerance ± 0.3mm) (hardness approximately 1200kg / mm ² , density approximately 6.0g / cm ³ )
・ Spherical zirconia beads particle size 5mm (outer diameter tolerance ± 0.5mm) (hardness approx. 1200kg / mm ² , density approx. 6.0g / cm ³ )
Specifically, about 500 mg (8 tablets) of tablet A and 4, 8 or 12 g of each bead were added to a 50 mL glass tube with a stopper (about 12 cm in length in the shaking direction of the container), and then After adding 20 mL of methanol and sealing, using a shaker (model number SR-2W manufactured by TAITEC), shaking speed of 40 mm and shaking speed of 300 times / minute (Example 1) and 250 times / minute (Example 2) ) In the vertical direction, and the shaking time until the tablet completely disintegrated was evaluated. In addition, it evaluated also in the state without beads as a comparative example (comparative examples 2 and 3).
The results are shown in Tables 1 and 2. When no beads were added, the tablets did not disintegrate completely even after shaking for 60 minutes, but by using zirconia beads, the tablets could be completely disintegrated and the shaking time could be shortened. I was able to.
In addition, the zirconia beads having a particle diameter of 2 mm completely disintegrated in 30 minutes, but the zirconia beads having a particle diameter of 3 mm and 5 mm completely disintegrated in 10 to 30 minutes. Therefore, the larger the particle diameter of the beads, the better the effect. Tended to be. Moreover, the effect tended to improve as the shaking speed increased. Furthermore, when the shaking speed is 300 times / minute, the zirconia beads having a particle size of 3 mm and 5 mm have a shaking time reduced to 8 and 12 g compared to 4 g. Tended to improve.

Example 3 and Comparative Example 4 Comparison of moisture value in sample after pulverization treatment according to the present invention and the conventional method Tablet A was pulverized using the conventional dry method and the method of the present invention, and each of the obtained sample solutions The moisture values were compared.
In the dry method, about 300 mg (5 tablets) of tablet A was pulverized in a mortar in the same manner as described in Comparative Example 1, and about 0.2 g was accurately weighed, and the water content was measured by the Karl Fischer method (volumetric titration). Carried out. Further, as a method of the present invention, about 500 mg (8 tablets) of tablet A in a 50 mL glass tube with a stopper (about 12 cm in length in the shaking direction of the container), and zirconia beads having a particle diameter of 2 mm described in Example 1 4 g was added, 20 mL of methanol was added, and after sealing, the mixture was shaken using a shaker (model number SR-2W manufactured by TAITEC). The shaking conditions were a shaking distance of 40 mm and a speed of 300 times / minute for 40 minutes in the vertical direction, and moisture was quantified by the Karl Fischer method (coulometric titration). As a result, the moisture value in the tablet crushing method of the present invention was 5.3%, and the value in the case of crushing by the conventional dry method was 5.6%. It was considered that the effect of moisture absorption during preparation was improved.

Example 4 and Comparative Example 5
Film-coated tablets containing 40 mg of the active ingredient (including hypromellose, titanium oxide, macrogol, carnauba wax as coating components, round tablets (hereinafter referred to as tablets B) having a diameter of 9 mm and a weight of about 245 mg) and glass beads The tablets were pulverized in the same manner as in 1. The following two types of beads were used.
・ Spherical glass beads particle size 1mm (outer diameter tolerance ± 0.2mm) (hardness approx. 690kg / mm ² , density approx. 2.4g / cm ³ )
・ Spherical glass beads particle size 2mm (outer diameter tolerance ± 0.2mm) (hardness of about 690kg / mm ² , density of about 2.4g / cm ³ )
Specifically, about 50 mg of a stoppered glass tube (about 12 cm in length in the shaking direction of the container), about 500 mg (2 tablets) of tablet B and each bead 1, 2 or 4 g are added, and 20 mL of methanol is added. After the addition, it is sealed and shaken vertically using a shaker (model number SR-2W, manufactured by TAITEC) at a shaking distance of 40 mm at a shaking speed of 300 times / minute, and the tablet completely disintegrates. The shaking time until the evaluation was evaluated. In addition, it evaluated also in the state without beads as a comparative example (comparative example 5).
The results are shown in Table 3. When no beads were added, the tablets did not completely disintegrate even when shaken for 60 minutes. On the other hand, by using glass beads, the tablets could be completely disintegrated, and the shaking time could be shortened. did it. In addition, since the disintegration time was shortened when the glass beads having a particle diameter of 2 mm were 4 g, like the zirconia beads in Example 1, the effect was improved as the particle diameter of the beads was larger and the amount used was larger. there were.

Examples 5-7 and Comparative Examples 6-8
Orally disintegrating tablets containing 200 mg of the active ingredient (including mannitol, corn starch, pregelatinized starch, aspartame, magnesium stearate, 10 mm in diameter and 400 mg in weight (hereinafter referred to as orally disintegrating tablet C)) and An orally disintegrating tablet containing 100 mg of the active ingredient (including mannitol, corn starch, pregelatinized starch, aspartame, magnesium stearate, a round tablet having a diameter of 8 mm and a weight of 200 mg (hereinafter referred to as orally disintegrating tablet D)) Then, the following experiment was conducted. That is, the two types of tablets disintegrate easily in methanol, but do not disintegrate easily in methanol by storing them under high-temperature and high-humidity conditions (for example, temperature 50 ° C./humidity 85% for 1 month or more). A trend was observed.
Specifically, one tablet each of orally disintegrating tablets C and D stored for 2 months at a temperature of 50 ° C./humidity of 85% has a spherical zirconia bead particle size of 5 mm (acceptable outer diameter ± 0.5 mm, hardness of about 1200 kg / mm ² , density about 6.0 g / cm ³ ) 1 or 10 g is weighed into a 15 mL glass tube with a stopper (about 12 cm in length in the shaking direction of the container), and after adding 5 mL of methanol, it is sealed, The sample was shaken in the vertical direction at a shaking distance of 40 mm at a shaking speed of 280 or 300 times / minute, and the shaking time until the tablet completely disintegrated was measured. In addition, it evaluated also in the state without beads as a comparative example (comparative example 6).
The results are shown in Tables 4 and 5. For the orally disintegrating tablet C, at a shaking speed of 280 times / minute, the tablet did not disintegrate completely when no beads were added, whereas the effect was confirmed by using zirconia beads having a particle diameter of 5 mm. . In addition, for the orally disintegrating tablets D having different sizes, the effect was recognized by adding beads at 300 times / min.

  By using the method of the present invention, even a sample that is difficult to dissolve / disperse (for example, a tablet, a film coating agent, a sample that has been altered by storage, etc.) Since the components can be uniformly dissolved and dispersed, it can be applied as a pretreatment method for various tests. Moreover, if it is a molded tablet, the present invention can be applied not only to pharmaceuticals but also to fields such as confectionery and health food.

It is a figure which shows the example of the relationship between the length of the container of a shaking direction, and the shaking distance in the physical impact in this invention. It is a figure which shows the change of the weight at the time of 0-30 minutes preservation | save in the temperature 25 degreeC / 60% RH using the unmilled goods and pulverized goods for 1 tablet A.

Claims (9)

  A method for pulverizing a tablet by applying a physical impact to a container containing a tablet, a solvent and beads and bringing the tablet and beads into physical contact.   The tablet grinding method according to claim 1, wherein the diameter of the beads is 0.05 to 1 with respect to the major axis of the tablet.   The tablet pulverization method according to claim 1 or 2, wherein beads are blended at a ratio of 2 to 200 parts by weight per 1 part by weight of the tablet.   The tablet grinding method according to any one of claims 1 to 3, wherein the solvent is blended at a ratio of 10 to 500 parts by volume with respect to 1 part by weight of the tablet.   The tablet grinding method according to any one of claims 1 to 4, wherein the solvent is blended at a ratio of 1/10 to 1/2 volume with respect to the total volume of the container.   The tablet crushing method according to any one of claims 1 to 5, wherein the physical impact is a method of shaking the container or a method of ultrasonicating the container.   The physical impact is a method of shaking 80 times or more at a shaking distance (D) of a ratio of about 0.2 to 4 with respect to the length (L) of the container in the shaking direction. Tablet crushing method.   The tablet crushing method according to claim 7, wherein the shaking direction is a straight line or a curved line in a vertical, horizontal or inclined direction.   The analysis method of the component contained in the tablet using the method in any one of Claims 1-8.

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