Method for improving aggregation behavior of dapagliflozin propylene glycol hydrate and method for producing pharmaceutical comprising dapagliflozin propylene glycol hydrate

Abstract

To provide a method for improving the aggregation behavior of dapagliflozin propylene glycol hydrate.SOLUTION: A method for improving the aggregation behavior of dapagliflozin propylene glycol hydrate according to the present disclosure comprises a step of mixing or co-milling dapagliflozin propylene glycol hydrate with a pharmaceutical additive under application of shear stress.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for improving the aggregation property of dapagliflozin propylene glycol hydrate and a method for producing a medicine containing dapagliflozin propylene glycol hydrate. [Background technology]

[0002] Dapagliflozin is known as a sodium-dependent glucose transporter 2 (SGLT2) inhibitor and is used, for example, as a therapeutic drug for type II diabetes, etc. Patent Document 1 discloses a pharmaceutical preparation containing dapagliflozin propylene glycol hydrate and a pharma- ceutical acceptable carrier. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Special Publication No. 2010-522244 Summary of the Invention [Problem to be solved by the invention]

[0004] The present inventors have independently found that dapagliflozin propylene glycol hydrate has a strong tendency to aggregate and does not dissolve quickly. In the above-mentioned conventional techniques, the aggregation tendency of dapagliflozin propylene glycol hydrate has not been considered at all.

[0005] One aspect of the present invention aims to provide a method for improving the cohesiveness of dapagliflozin propylene glycol hydrate. [Means for solving the problem]

[0006] The present invention includes the following aspects. <1> A method for improving the cohesiveness of dapagliflozin propylene glycol hydrate, comprising a step of mixing or co-grinding dapagliflozin propylene glycol hydrate with a pharmaceutical excipient while applying shear stress. <2> The dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and crushed using an apparatus equipped with a fixed container and a rotor capable of applying shear stress. <1> The method for improving cohesion according to claim 1. <3> A granulator, a granulator, or a pulverizer is used for mixing or mixing and pulverizing the dapagliflozin propylene glycol hydrate and the pharmaceutical additive; <1> or <2> The method for improving cohesion according to claim 1. <4> The dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and ground using an apparatus equipped with a vessel and a stirring blade. <1> ~ <3> 2. The method for improving cohesion according to claim 1 . <5> The dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and crushed using an apparatus equipped with a pin disc; <1> ~ <3> 2. The method for improving cohesion according to claim 1 . <6> The dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and pulverized using an apparatus equipped with a screen and a rotor. <1> ~ <3> 2. The method for improving cohesion according to claim 1 . <7> A method for producing a pharmaceutical containing dapagliflozin propylene glycol hydrate, comprising a step of mixing or co-pulverizing dapagliflozin propylene glycol hydrate with a pharmaceutical additive while applying shear stress to improve the cohesiveness of dapagliflozin propylene glycol hydrate. <8> The dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and crushed using an apparatus equipped with a fixed container and a rotor capable of applying shear stress. <7> The manufacturing method described in <9> A granulator, a granulator, or a pulverizer is used for mixing or mixing and pulverizing the dapagliflozin propylene glycol hydrate and the pharmaceutical additive; <7> or <8> The manufacturing method described in <10> The dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and ground using an apparatus equipped with a vessel and a stirring blade. <7> ~ <9> 13. The method for producing a semiconductor device according to claim 12, wherein the semiconductor device is a semiconductor device. <11> The dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and crushed using an apparatus equipped with a pin disc; <7> ~ <9> 13. The method for producing a semiconductor device according to claim 12, wherein the semiconductor device is a semiconductor device. <12> The dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and pulverized using an apparatus equipped with a screen and a rotor. <7> ~ <9> 13. The method for producing a semiconductor device according to claim 12, wherein the semiconductor device is a semiconductor device. Effect of the Invention

[0007] According to one aspect of the present invention, there is provided a method for improving the coagulation property of dapagliflozin propylene glycol hydrate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] An embodiment of the present invention will be described below. However, the present invention is not limited to each of the configurations described below. Unless otherwise specified in this specification, "A to B" representing a numerical range means "A or more and B or less."

[0009] 1. Method for improving the aggregation properties of dapagliflozin propylene glycol hydrate The method for improving the coagulation of dapagliflozin propylene glycol hydrate according to one embodiment of the present invention includes a step of mixing or co-grinding dapagliflozin propylene glycol hydrate and a pharmaceutical additive while applying shear stress. The reason for the improvement in coagulation is believed to be that dapagliflozin propylene glycol hydrate is uniformly dispersed. The improvement in coagulation can be evaluated, for example, by the improvement in dissolution behavior. In this specification, co-grinding means grinding while mixing. Hereinafter, dapagliflozin propylene glycol hydrate and a pharmaceutical additive may be collectively referred to as "raw material".

[0010] Dapagliflozin propylene glycol hydrate according to one embodiment of the present invention is a crystal. The crystal form of dapagliflozin propylene glycol hydrate is not limited, but includes, for example, SC-3 type having peaks at 2θ=3.8°±0.2°, 7.6°±0.2°, 8.1°±0.2°, 8.7°±0.2°, 15.2°±0.2°, 15.7°±0.2°, 17.1°±0.2°, 18.9°±0.2° and 20.1°±0.2° in powder X-ray diffraction measurement.

[0011] The average particle size (D50) of the dapagliflozin propylene glycol hydrate according to one embodiment of the present invention before mixing or co-pulverization is preferably 1 to 30 μm, more preferably 2 to 20 μm, and even more preferably 5 to 15 μm. The average particle size is calculated from the particle size distribution measured by a dry method using a laser diffraction particle size distribution measuring device.

[0012] An apparatus may be used as a means for mixing or mixing and grinding the raw materials while applying shear stress. For example, such an apparatus may be an apparatus equipped with a fixed container and a rotor capable of applying shear stress. With such an apparatus, shear stress can be efficiently applied to the raw materials.

[0013] In this specification, a fixed container means a container capable of containing raw materials and fixed to an apparatus. A fixed container is distinguished from a container that rotates or vibrates itself for mixing or stirring (e.g., a Bohle container mixer, a container blender, etc.). In other words, a fixed container can also be said to be a container that does not rotate or vibrate itself for mixing or stirring. A fixed container may be sealable, or may have a part open as a path for inputting or discharging raw materials.

[0014] The rotating body is a member that is provided in a vessel and can apply shear stress to the raw material. The shape of the rotating body is not limited, but examples include blade type, impeller type, hammer type, comb type, and disk type with pins. Specific examples of the rotating body include stirring blades, impellers, hammers, and pin disks.

[0015] The device may be a granulator, a sieving machine, or a pulverizer. A granulator generally means a device used to compact powdered raw materials and form them into larger diameter particles. A sieving machine generally means a device used to make the size of particles uniform. A pulverizer generally means a device used to crush or pulverize raw materials into smaller diameter particles. Any of these devices can be used for mixing or mixed pulverization while applying shear stress. Any of these devices may be devices equipped with a fixed container and a rotor capable of applying shear stress. The device may be a device that combines two or more functions of a granulator, a sieving machine, and a pulverizer.

[0016] The granulator may be a wet granulator or a dry granulator, preferably a wet granulator, more preferably an agitation granulator. The device may be a device equipped with a vessel and an agitation blade. Such a device may be an agitation granulator. The vessel corresponds to a fixed container. The agitation blade corresponds to a rotating body capable of applying shear stress.

[0017] The device may be equipped with a screen and a rotor. Such a device may be a granulator. The screen is a member having holes of a desired diameter for regulating the size of the particles, and corresponds to the fixed vessel. The rotor corresponds to a rotating body capable of applying a shear stress.

[0018] The crusher may be an impact crusher. The device may be an impact crusher. The device may be equipped with a pin disk. Such a device may be an impact crusher. The device may be equipped with a suitable fixed container in addition to the pin disk. The pin disk corresponds to a rotating body capable of applying a shear stress.

[0019] The rotation speed of the rotor is not particularly limited, but is preferably 100 rpm or more, more preferably 400 rpm or more, and even more preferably 700 rpm or more. The rotation speed of the rotor is preferably 30,000 rpm or less, and more preferably 20,000 rpm or less. For example, in the case of a granulator, the rotation speed is preferably 1,000 to 5,000 rpm, and more preferably 2,000 to 4,000 rpm. In the case of an agitation granulator, the rotation speed is preferably 100 to 2,000 rpm, more preferably 400 to 1,500 rpm, and even more preferably 700 to 1,000 rpm. In the case of an impact mill, the rotation speed is preferably 500 to 30,000 rpm, and more preferably 1,000 to 20,000 rpm.

[0020] The shear stress applied to the raw material is, for example, 20N / mm 2 or more, 40 to 600N / mm 2 60 to 400N / mm 2 may be also possible.

[0021] The temperature in the device in the mixing or mixed grinding step is not particularly limited, but is preferably less than 45°C, more preferably 35°C or less, and even more preferably 25°C or less. At this temperature, the raw material can be prevented from melting and adhering to the device, and the medicine can be produced stably. For example, the device may be equipped with a cooling mechanism to control the temperature. Such a cooling mechanism is not particularly limited, and examples thereof include a water-cooled jacket. The temperature may be, for example, 10°C or more, 15°C or more, or 20°C or more.

[0022] Pharmaceutical excipients include fillers and / or excipients, binders, disintegrants, lubricants, coating agents, glidants and / or anti-adherents, emulsifiers, stabilizers, colorants and / or light-blocking agents, and flavoring agents.

[0023] Examples of fillers and / or excipients include cellulose derivatives (e.g., crystalline cellulose, wood cellulose), lactose, sucrose, glucose, mannitol, fructose, xylitol, sorbitol, dextrose, starch, pregelatinized starch, corn starch, dextrin, maltodextrin, dextran, pullulan, gum arabic, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminometasilicate, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, and the like.

[0024] Binders include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gum arabic, ethyl cellulose, cellulose acetate, carnauba wax, paraffin, spermaceti, polyethylene glycol, polyethylene, and microcrystalline wax.

[0025] Disintegrants include, for example, croscarmellose sodium, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose and the like.

[0026] Lubricants include, for example, stearic acid, magnesium stearate, zinc stearate, calcium stearate, talc, palmitic acid, fumaric acid, sodium stearyl fumarate, sodium lauryl sulfate, magnesium lauryl sulfate, glyceryl palmitostearate, palmitic acid, myristic acid, boric acid, adipic acid, sodium sulfate, glycol, sucrose fatty acid esters, sodium benzoate, leucine, hydrogenated vegetable oils and fats.

[0027] Glidants and / or anti-adherents include silicon dioxide, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, and the like.

[0028] Emulsifiers include colloidal clays (e.g., bentonite, veegum), metal hydroxides (e.g., magnesium hydroxide, aluminum hydroxide), anionic surfactants, cationic surfactants (e.g., benzalkonium chloride), nonionic surfactants (e.g., polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters), and the like.

[0029] Stabilizers include paraoxybenzoic acid esters (eg, methylparaben, propylparaben), alcohols (eg, chlorobutanol, benzyl alcohol, phenylethyl alcohol), phenols (eg, phenol, cresol), thimerosal, dehydroacetic acid, sorbic acid, and the like.

[0030] The coating agent can be appropriately selected from pharma- ceutically acceptable ones depending on the application of the coating. Examples of the coating agent include hypromellose, ethyl cellulose, talc, titanium oxide, silicic acid, hydroxypropyl cellulose, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer, polyvinyl alcohol, polyvinyl alcohol diethylaminoacetate, polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, hypromellose phthalate, methacrylic acid copolymer, copolymer of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate. The coating agent may be one kind or two or more kinds in combination. It may also be combined with a colorant described later.

[0031] Examples of colorants include ferric oxide, yellow ferric oxide, titanium oxide, aluminum lake, and Yellow No. 5. The colorants may be used alone or in combination of two or more.

[0032] Flavoring agents include sweeteners (e.g., saccharin sodium, aspartame), acidulants (e.g., citric acid, malic acid, tartaric acid), flavors (e.g., menthol, lemon, orange), and the like.

[0033] 2. Method for producing a drug containing dapagliflozin propylene glycol hydrate The method for producing a dapagliflozin propylene glycol hydrate-containing drug according to one embodiment of the present invention includes a step of improving the cohesiveness of dapagliflozin propylene glycol hydrate by mixing or co-pulverizing dapagliflozin propylene glycol hydrate and a pharmaceutical additive while applying shear stress. This makes it possible to produce a dapagliflozin propylene glycol hydrate-containing drug with improved cohesiveness. As a means for applying shear stress, the above-mentioned various devices can be used. The matters already explained in [1. Method for improving the cohesiveness of dapagliflozin propylene glycol hydrate] will not be explained here.

[0034] The medicine obtained by the above-mentioned manufacturing method may contain dapagliflozin propylene glycol hydrate and pharmaceutical additives. The dosage form of the medicine is not particularly limited. Examples of the dosage form include capsules, tablets, orally disintegrating tablets, granular tablets, granules, powders, etc. In addition, the tablets and orally disintegrating tablets may be appropriately selected as necessary from the form of layered tablets or dry-coated tablets.

[0035] The water content of the medicine obtained by the above-mentioned manufacturing method is not particularly limited, but is preferably 3% by mass or less, more preferably 2% by mass or less. The lower limit of the water content is not particularly limited, and may be 0% by mass, but the water content can be, for example, 0.2% by mass or more. The water content can be measured, for example, by loss on drying method.

[0036] When the pharmaceutical agent obtained by the above-mentioned production method is dispersed or dissolved in water, the pH of the resulting dispersion or solution is in the range of 3-9, and preferably 4-8.

[0037] The shape of the present tablet can be appropriately selected from round tablets, irregular tablets, etc., and can be, for example, round, elliptical, spherical, rod-like, donut-like, etc. When the present tablet is a round tablet, the diameter is not particularly limited, but is, for example, 4 to 12 mm, preferably 6 to 10 mm. The thickness of the present tablet is not particularly limited, but is, for example, 3 to 12 mm, preferably 4 to 10 mm. When the present tablet is an irregular tablet, the size is not particularly limited, but is, for example, a major axis of 10 to 15 mm, a minor axis of 4 to 8 mm, and a thickness of 3 to 10 mm.

[0038] The tableting pressure in this manufacturing method can be appropriately adjusted depending on the formulation and tablet shape, but is preferably in the range of 4 to 16 kN, for example. The tablet hardness can also be appropriately adjusted depending on the purpose, but is preferably in the range of 20 to 200 N, for example. Furthermore, the tablet hardness can be appropriately adjusted depending on the diameter of the tablet. For example, when the tablet diameter is 4 to 6 mm, the tablet hardness is preferably 20 N or more, more preferably 25 N or more, and even more preferably 30 N or more. When the tablet diameter is 6 to 9 mm, the tablet hardness is preferably 40 N or more, more preferably 45 N or more, and even more preferably 50 N or more. When the tablet diameter is 9 to 11 mm, the tablet hardness is preferably 50 N or more, more preferably 60 N or more, and even more preferably 70 N or more. When the tablet diameter is 11 to 15 mm, the tablet hardness is preferably 70 N or more, more preferably 85 N or more, and even more preferably 100 N or more. For tablets with a diameter of 15 mm or more, the tablet hardness is preferably 100N or more, more preferably 125N or more, and even more preferably 150N or more.

[0039] The tablet may be further coated as necessary. A known coating method may be used for the coating. For example, a pan coating method, a fluidized bed coating method, etc. may be used. In addition, a multi-layer coating may be provided as necessary, for example, an intermediate layer and a release control layer may be provided on the tablet. For the intermediate layer, the above-mentioned coating agent may be appropriately selected according to the purpose of the coating.

[0040] The tablet preferably has a dissolution rate of dapagliflozin of 70% or more when allowed to dissolve for 15 minutes according to the paddle method of the dissolution test (second fluid) described in the Japanese Pharmacopoeia.

[0041] Examples of materials for the PTP (Press Through Package) packaging in which the tablet according to this embodiment is housed include resins such as polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene, polyethylene, polystyrene, or polycarbonate, and metals such as aluminum. These materials may be used alone or in combination of two or more. Examples of combinations include laminating polyvinyl chloride and polyvinylidene chloride, and laminating polyvinyl chloride and polychlorotrifluoroethylene. The above resins are molded by a known method, and the tablet is placed in a molded pocket of the resin sheet, and the tablet is covered with aluminum foil to form a PTP package. In addition, from the viewpoint of improving light stability, PTP packaging using a material that can block a specific wavelength of light may be used. Examples of the 90% absorption wavelength of the light transmittance of the material include 390 nm, 480 nm, 550 nm, 560 nm, and 600 nm. Examples of the color of the material include clear (transparent color), persimmon, orange, red, and yellow.

[0042] The PTP package may further be packaged in an aluminum pillow or a packaging bag made of a material capable of blocking a specific wavelength of light. The aluminum pillow or the packaging bag made of a material capable of blocking a specific wavelength of light may further contain a desiccant. Examples of desiccant include calcium chloride, calcium oxide, magnesium oxide, silica gel, and zeolite, and zeolite is preferred when the amount of moisture inside the package is to be significantly reduced.

[0043] [3. Prescription Examples]

[0044] [Table 1]

[0045] The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope of the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention. EXAMPLES

[0046] An embodiment of the present invention will now be described.

[0047] [Dissolution test] Dissolution tests were performed in accordance with the 18th edition of the Japanese Pharmacopoeia. The powder obtained as described below was used in an amount equivalent to 10 mg of dapagliflozin (12.3 mg of dapagliflozin propylene glycol hydrate). The specific test method was the paddle method, and the paddle rotation speed was 50 rpm. The test liquid used was the second dissolution test liquid (solvent pH: 6.8), the test liquid volume was 900 mL, and the temperature during the test was 37±0.5°C. Sampling times were 5 minutes, 10 minutes, and 15 minutes after the start of the test.

[0048] [Example 1: Dry granulator] Dapagliflozin propylene glycol hydrate and crystalline cellulose were mixed and passed through a dry granulator (Powrex, Comil). The device was equipped with a round impeller (rotor) and a round-hole screen. Although the device is a dry granulator, it can also be called a granulator because it is equipped with a screen. The impeller rotation speed was 2393 rpm, and the diameter of the holes in the round-hole screen was 475 μm. The obtained mixed dispersion powder was mixed with fast-disintegrating granules and then passed through a sieve with an opening of 710 μm. The composition of the fast-disintegrating granules is as shown in the above-mentioned formulation example (Table 1). The formulation amounts in Example 1 are shown in Table 2.

[0049] [Example 2: Wet high shear granulator] Dapagliflozin propylene glycol hydrate and crystalline cellulose were charged into a wet high shear granulator (Powrex Corporation, Vertical Granulator) and mixed for 60 minutes at a blade rotation speed of 732 rpm and a cross screw rotation speed of 3000 rpm. The device corresponds to an agitation granulator equipped with an agitation blade and a vessel. The obtained mixed dispersion powder was mixed with fast-disintegrating granules and then passed through a sieve with an opening of 710 μm. The formulation amounts in Example 2 are shown in Table 2.

[0050] [Examples 3 to 5: Impact Crusher] Dapagliflozin propylene glycol hydrate and crystalline cellulose were mixed, and the mixed powder was passed through an impact mill (Hosokawa Micron Corporation, Fine Impact Mill). The mill was equipped with a pin disk and a fixed container. The pin disk rotation speed was 1000 rpm in Example 3, 5000 rpm in Example 4, and 18000 rpm in Example 5. The obtained mixed dispersion powder was mixed with fast-disintegrating granules, and then passed through a sieve with an opening of 710 μm. The formulation amounts in Examples 3 to 5 are shown in Table 2.

[0051] [Table 2]

[0052] [Examples 6 to 8: Wet high shear granulator] Dapagliflozin propylene glycol hydrate, D-mannitol, and croscarmellose sodium were charged into a wet high shear granulator (Powrex Corporation, Vertical Granulator) and mixed for 60 minutes at a blade rotation speed of 140 rpm in Example 6, 488 rpm in Example 7, and 732 rpm in Example 8, and a cross screw rotation speed of 3000 rpm. The temperature inside the device was about 23°C. The obtained mixed dispersion powder was mixed with the fast-disintegrating granules and then passed through a sieve with an opening of 710 μm. The formulation amounts in Examples 6 to 8 are shown in Table 3.

[0053] [Table 3]

[0054] [Evaluation results] Table 4 shows the results of the dissolution test of Examples 1 to 5. Table 4 also shows the results of the dissolution test of the drug substance (dapagliflozin propylene glycol hydrate) for comparison. The drug substance refers to one that does not contain any pharmaceutical additives and has not been subjected to mixing or mixing pulverization under shear stress. As can be seen from Table 4, Examples 1 to 5 were dissolved more quickly than the drug substance, which means that the cohesiveness was improved. In particular, Example 2 showed a satisfactory improvement in cohesiveness.

[0055] [Table 4]

[0056] Table 5 shows the results of the dissolution test of Examples 6 to 8. Table 5 also shows the results of the dissolution test of the drug substance (dapagliflozin propylene glycol hydrate) for comparison. As can be seen from Table 5, Examples 6 to 8 were dissolved more quickly than the drug substance, and therefore it can be said that the coagulation property was improved. Since the coagulation property was improved in both Examples 1 to 5 and Examples 6 to 8, it can be seen that the coagulation property is improved regardless of the use of any pharmaceutical additive. Furthermore, it can be seen from Examples 6 to 8 that the coagulation property is improved regardless of the rotation speed.

[0057] [Table 5] [Industrial Applicability]

[0058] The present invention can be utilized in the production of a medicine containing dapagliflozin propylene glycol hydrate.

Claims

1. A method for improving the cohesiveness of dapagliflozin propylene glycol hydrate, comprising a step of mixing or co-grinding dapagliflozin propylene glycol hydrate with a pharmaceutical excipient while applying shear stress.

2. The method for improving cohesiveness according to claim 1, wherein the dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and crushed using an apparatus equipped with a fixed container and a rotor capable of applying shear stress.

3. The method for improving cohesiveness according to claim 1, wherein a granulator, a granulator, or a pulverizer is used for mixing or mixing and pulverizing the dapagliflozin propylene glycol hydrate and the pharmaceutical additive.

4. The method for improving cohesiveness according to claim 1, wherein an apparatus equipped with a vessel and a stirring blade is used for mixing or mix-grinding the dapagliflozin propylene glycol hydrate and the pharmaceutical additive.

5. The method for improving cohesiveness according to claim 1, wherein an apparatus equipped with a pin disc is used for mixing or mix-grinding the dapagliflozin propylene glycol hydrate and the pharmaceutical additive.

6. The method for improving cohesiveness according to claim 1, wherein an apparatus equipped with a screen and a rotor is used for mixing or mix-grinding the dapagliflozin propylene glycol hydrate and the pharmaceutical additive.

7. A method for producing a pharmaceutical containing dapagliflozin propylene glycol hydrate, comprising a step of mixing or co-pulverizing dapagliflozin propylene glycol hydrate with a pharmaceutical additive while applying shear stress to improve the cohesiveness of dapagliflozin propylene glycol hydrate.

8. The method according to claim 7, wherein the dapagliflozin propylene glycol hydrate and the pharmaceutical additive are mixed or mixed and crushed using an apparatus equipped with a fixed container and a rotor capable of applying shear stress.

9. The method according to claim 7, wherein a granulator, a granulator, or a pulverizer is used for mixing or mixing and pulverizing the dapagliflozin propylene glycol hydrate and the pharmaceutical additive.

10. The method according to claim 7, wherein an apparatus equipped with a vessel and a stirring blade is used for mixing or mixing and grinding the dapagliflozin propylene glycol hydrate and the pharmaceutical additive.

11. The method according to claim 7, wherein an apparatus equipped with a pin disc is used for mixing or co-grinding the dapagliflozin propylene glycol hydrate and the pharmaceutical additive.

12. The method according to claim 7, wherein an apparatus equipped with a screen and a rotor is used for mixing or co-grinding the dapagliflozin propylene glycol hydrate and the pharmaceutical additive.

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