Solid material consisting of amorphous evocalcet and method for producing the same

Abstract

This provides a solid material consisting of an amorphous form of evocalcet. [Solution] A solid material consisting of an amorphous form of evocalcet is provided.

Description

Technical Field

[0001] The present invention relates to a solid substance composed of an amorphous form of evocalcet and a method for producing the same.

Background Art

[0002] Calcium receptor agonists are known as one of the therapeutic agents for secondary hyperparathyroidism under maintenance dialysis, and among them, evocalcet tablets (trade name: Ocaliva (registered trademark) tablets) have been approved. Evocalcet (4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid) has been reported to be produced as crystals. Patent Documents 1 and 2 describe crystals of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid and a method for producing the same.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0004] Although crystals of evocalcet are known, the use of an amorphous form of evocalcet as a medicine has not been reported so far. An object of the present invention is to provide a solid substance composed of an amorphous form of evocalcet.

Means for Solving the Problems

[0005] The following inventions are provided. [1] A solid substance composed of an amorphous form of evocalcet. [2] The solid substance according to [1], which substantially does not contain crystals of evocalcet. [3] In powder X-ray diffraction measurements, 2θ does not substantially have peaks at 12.7°±0.2°, 14.6°±0.2°, 14.8°±0.2°, 17.3°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 20.5°±0.2°, 22.6°±0.2°, 24.5°±0.2° and 28.1°±0.2°, and The solids described in [1] or [2] that do not substantially have peaks at 2θ = 12.6°±0.2°, 14.4°±0.2°, 15.9°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.7°±0.2°, 21.4°±0.2°, 23.8°±0.2°, 24.3°±0.2° and 28.0°±0.2°. [4] A solid material that exhibits a halo pattern in powder X-ray diffraction measurement, as described in any one of [1] to [3]. [5] A powder, or a solid as described in any one of [1] to [4]. [6] A solution of evocalcet dissolved in an organic solvent is brought into contact with a porous adsorbent; or A solution of evocalcet dissolved in an organic solvent is brought into contact with the polymer. A solid obtained by any one of [1] to [5]. [7] The solid according to [6], wherein the adsorbent having voids is a porous adsorbent or a flake-shaped adsorbent. [8] The solid according to [6] or [7], wherein the adsorbent having voids is substantially composed of a silicon compound. [9] The solid according to any one of [6] to [8], wherein the organic solvent is a mixed solution of dichloromethane and methanol.

[10] A solid according to any one of [6] to [9], wherein the amount of adsorbent having voids used is at least twice the amount of evocalcet used by weight.

[11] The solid according to [6], wherein the polymer is a cellulose polymer, a methacrylic acid polymer, a methacrylic acid ester polymer, or a polyvinylpyrrolidone polymer.

[12] A solid substance according to any one of [1] to

[11] , for use in the treatment of hyperparathyroidism or hypercalcemia associated with parathyroid dysfunction, or for use as a calcium receptor agonist.

[13] A method for producing a solid according to any one of [1] to

[12] , comprising contacting a solution obtained by dissolving evocalcet in an organic solvent with an adsorbent having voids.

[14] The manufacturing method according to

[13] , wherein the adsorbent having voids is a porous adsorbent or a flake-shaped adsorbent.

[15] The method for producing the product according to

[13] or

[14] , wherein the adsorbent having voids is substantially composed of a silicon compound.

[16] The method of production according to any one of

[13] to

[15] , wherein the organic solvent is a mixed solution of dichloromethane and methanol.

[17] A manufacturing method according to any one of

[13] to

[16] , wherein the amount of adsorbent having voids used is at least twice the amount of evocalcet used by weight.

[18] A method for producing a solid according to any one of [1] to

[12] , comprising contacting a polymer with a solution obtained by dissolving evocalcet in an organic solvent.

[19] The method according to

[18] , wherein the polymer is a cellulose polymer, a methacrylic acid polymer, a methacrylic acid ester polymer, or a polyvinylpyrrolidone polymer.

[20] The method of production according to

[18] or

[19] , wherein the organic solvent is a mixed solution of dichloromethane and methanol.

[21] The manufacturing method according to any one of

[18] to

[20] , wherein the amount of polymer used is at least twice the amount of evocalcet used by weight. [Effects of the Invention]

[0006] According to the present invention, an amorphous form of evocalcet is provided that substantially does not contain evocalcet crystals. [Brief explanation of the drawing]

[0007] [Figure 1]Figure 1 shows the measurement results of the X-ray diffraction spectrum when evocalcet is amorphized using AEROSIL 200. [Figure 2] Figure 2 shows the measurement results of the X-ray diffraction spectrum when evocalcet is amorphized using Shin-Etsu AQOAT AS-LF. [Figure 3] Figure 3 shows the measurement results of the X-ray diffraction spectrum when evocalcet is amorphized using AEROSIL 50. [Figure 4] Figure 4 shows the measurement results of the X-ray diffraction spectrum when evocalcet is amorphized using flowrite. [Figure 5] Figure 5 shows the measurement results of the X-ray diffraction spectrum when evocalcet is amorphized using NEUSILIN NS2N. [Figure 6] Figure 6 shows the measurement results of the X-ray diffraction spectrum when evocalcet is amorphized using TC-5. [Figure 7] Figure 7 shows the measurement results of the X-ray diffraction spectrum when evocalcet is amorphized using Eudragit-L100. [Figure 8] Figure 8 shows the measurement results of the X-ray diffraction spectrum when evocalcet is amorphized using povidone 25.

Mode for Carrying Out the Invention

[0008] The present invention will be described in detail below. Each feature of the present invention described below can be arbitrarily combined.

[0009] (Amorphous Body of Evocalcet) One embodiment of the present invention relates to a solid composed of an amorphous body of evocalcet. Evocalcet is a compound represented by the chemical name: 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidin-1-yl)phenylacetic acid.

[0010] The solid material comprising the amorphous form of evocalcet according to the present invention preferably substantially does not contain evocalcet crystals, and more preferably does not contain evocalcet crystals.

[0011] Specifically, the solid material consisting of the amorphous form of evocalcet of the present invention, when measured by powder X-ray diffraction, 2θ does not substantially have peaks at 12.7°±0.2°, 14.6°±0.2°, 14.8°±0.2°, 17.3°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 20.5°±0.2°, 22.6°±0.2°, 24.5°±0.2° and 28.1°±0.2°, and There are virtually no peaks at 2θ = 12.6°±0.2°, 14.4°±0.2°, 15.9°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.7°±0.2°, 21.4°±0.2°, 23.8°±0.2°, 24.3°±0.2°, and 28.0°±0.2°.

[0012] The solid material comprising the amorphous form of evocalcet according to the present invention preferably shows substantially no peaks originating from the crystalline active pharmaceutical ingredient of evocalcet when measured by powder X-ray diffraction, and more preferably shows a halo pattern.

[0013] The form of the solid is not particularly limited and can be powder, granules, fine particles, etc., but is preferably powder. The solid is preferably a dry solid.

[0014] (Manufacturing method) The solid material of the present invention can be obtained by contacting a solution of evocalcet dissolved in an organic solvent with an adsorbent having voids. That is, one embodiment of the present invention relates to a method for producing an amorphous form of evocalcet, which includes contacting a solution of evocalcet dissolved in an organic solvent with an adsorbent having voids (hereinafter referred to as production method (1)). Alternatively, this embodiment may include contacting a solution of evocalcet dissolved in an organic solvent with an adsorbent having voids to adsorb evocalcet onto the adsorbent.

[0015] Furthermore, the solid material of the present invention can be obtained by contacting a polymer with a solution obtained by dissolving evocalcet in an organic solvent. Therefore, one embodiment of the present invention relates to a method for producing an amorphous form of evocalcet, which includes contacting a polymer with a solution obtained by dissolving evocalcet in an organic solvent (hereinafter referred to as production method (2)). This embodiment may also include producing a solid dispersion containing evocalcet by contacting a polymer with a solution obtained by dissolving evocalcet in an organic solvent.

[0016] In the following description of the manufacturing method of the present invention, unless otherwise specified, both manufacturing method (1) and manufacturing method (2) shall be referred to.

[0017] The organic solvent used to dissolve evocalcet can be any solvent capable of dissolving evocalcet. Examples include C1-C5 alcohols, halogenated hydrocarbons, aromatic hydrocarbons, ketones, ethers, esters, and mixed solutions of two or more of these. Specific examples of organic solvents include methanol, dichloromethane, acetic acid, acetone, anisole, 1-butanol, 2-butanol, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, propyl acetate, tetrahydrofuran, and mixed solutions of two or more of these.

[0018] In one embodiment, the organic solvent is a mixed solution of an alcohol having 1 to 5 carbon atoms and a halogenated hydrocarbon, and in a preferred embodiment, it is a mixed solution of methanol and dichloromethane. In these mixed solutions, the volume ratio of the alcohol having 1 to 5 carbon atoms to the halogenated hydrocarbon may be, for example, 10:1 to 1:10, preferably 5:1 to 1:5, more preferably 3:1 to 1:3, even more preferably 2:1 to 1:2, particularly preferably 1.5:1 to 1:1.5, and most preferably 1:1.

[0019] The amount of organic solvent used when dissolving evocalcet may be, for example, 5 times or more by mass relative to the amount of evocalcet used, preferably 10 times or more, more preferably 50 times or more, even more preferably 100 times or more, and even more preferably 200 times or more or more. There is no particular upper limit, but it may be, for example, 1000 times or less by mass relative to the amount of evocalcet used, or 500 times or less.

[0020] In manufacturing method (1), porous adsorbents, flake-shaped adsorbents, etc., can be used as adsorbents having voids, but are not limited to these.

[0021] The material for the adsorbent having voids is preferably a porous silicon compound, such as silica, silicon dioxide (including hydrated silicon dioxide), silicic acid compounds (calcium silicate, magnesium aluminometasilicate, magnesium silicate, aluminum silicate, magnesium aluminum silicate, magnesium aluminometasilicate, synthetic sodium magnesium silicate, colloidal hydrated aluminum silicate, etc.), diatomaceous earth, zeolite, etc.

[0022] The adsorbent having voids is, in one embodiment, substantially composed of a silicon compound, and in a preferred embodiment, substantially composed of one or more selected from silicon dioxide, calcium silicate, and magnesium aluminometasilicate. Here, "substantially composed of X" (where X represents any one or more elements) means that X is present in, for example, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, 99.5% or more, or 99.8% or more.

[0023] Adsorbents having voids may be amorphous or spherical (including elliptical).

[0024] The specific surface area of ​​the adsorbent having voids is preferably 10 to 400 m². 2 It is / g, more preferably 15~350m 2 The value is / g, and more preferably 20-300m 2 It is / g.

[0025] Specific examples of adsorbents with voids include the Aerosil series (Aerosil® 50, Aerosil® 90, Aerosil® 200, Aerosil® 300, etc.) (silicon dioxide) manufactured by Nippon Aerosil Co., Ltd., Neusilin® NS2N (magnesium aluminometasilicate) manufactured by Fuji Chemical Industry Co., Ltd., and Fluorite® (calcium silicate) manufactured by Tomita Pharmaceutical Co., Ltd.

[0026] The amount of porous adsorbent used should be sufficient to adequately adsorb evocalcet. The amount of porous adsorbent used is preferably 2 times or more, more preferably 3 times or more, and even more preferably 4 times or more, by weight ratio to the amount of evocalcet used. There is no particular upper limit to the amount of porous adsorbent used, and it may be, for example, 10 times or less by weight ratio to the amount of evocalcet used.

[0027] Examples of polymers that can be used in manufacturing method (2) include cellulose-based polymers, methacrylic acid-based polymers, methacrylic acid ester-based polymers, and polyvinylpyrrolidone-based polymers. The polymer may be a homopolymer or a copolymer polymerized with any other monomer unit.

[0028] Cellulosic polymers are polymers that contain cellulose as a constituent unit, or cellulose in which one or more hydroxyl groups are substituted with alkyl groups, hydroxyl-containing alkyl groups, carboxyl-containing alkyl groups, acyl groups, carboxyl-containing acyl groups, aryl groups, carboxyl-containing aryl groups, halogens, etc. Specific examples of cellulose polymers include hypromellose, or polymers that contain hypromellose as a constituent unit, in which one or more hydroxyl groups are substituted with alkyl groups, hydroxyl-containing alkyl groups, carboxyl-containing alkyl groups, carboxyl-containing aryl groups, etc. Further specific examples include hypromellose, hypromellose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxymethylcellulose phthalate, hypromellose phthalate, hypromellose acetate maleate, hypromellose trimellitate, carboxymethylethylcellulose, etc. The cellulose polymer preferably contains one or more selected from hypromellose and hypromellose acetate succinate.

[0029] Methacrylic acid polymers and methacrylic acid ester polymers refer to polymers that contain methacrylic acid as a constituent unit, and polymers that contain methacrylic acid in which the carboxyl group is esterified with an alkyl group, alkyl ammonia group, etc., as a constituent unit. Specific examples of methacrylic acid polymers and methacrylic acid ester polymers include methacrylic acid copolymers, aminoalkyl methacrylate copolymers, ammoniaalkyl methacrylate copolymers, and ethyl acrylate / methyl methacrylate copolymers, with methacrylic acid copolymers being preferred.

[0030] Polyvinylpyrrolidone polymers are polymers that use N-vinyl-2-pyrrolidone as a polymerization component. Specific examples of polyvinylpyrrolidone polymers include polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, and vinylpyrrolidone-vinylcaprolactam copolymer. Polyvinylpyrrolidone polymers preferably contain polyvinylpyrrolidone.

[0031] The polymer may be synthesized by methods known to those skilled in the art, or it may be obtained as a commercially available product. Some examples of commercially available products include: Shin-Etsu AQOAT® AS-LF (hypromellose acetate succinate, Shin-Etsu Chemical Co., Ltd.); TC-5 (hypromellose, Shin-Etsu Chemical Co., Ltd.); EUDRAGIT® E100, EUDRAGIT® EPO (aminoalkyl methacrylate copolymer, Evonik); EUDRAGIT® L100, EUDRAGIT® L30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100 (methacrylic acid copolymer, Evonik). Examples include EUDRAGIT® RL100, EUDRAGIT® RLPO, EUDRAGIT® RL30D, EUDRAGIT® RS100, EUDRAGIT® RSPO, EUDRAGIT® RS30D (ammoniaalkyl methacrylate copolymer, Evonik); EUDRAGIT® NE30D (ethyl acrylate / methyl methacrylate copolymer, Evonik); and povidone-25 (polyvinylpyrrolidone, BASF Japan).

[0032] The amount of polymer used should be sufficient to produce a solid dispersion containing evocalcet. The amount of polymer used is preferably 2 times or more, more preferably 3 times or more, even more preferably 5 times or more, and particularly preferably 10 times or more, by weight relative to the amount of evocalcet. There is no particular upper limit to the amount of polymer used, and it may be, for example, 50 times or less, 30 times or less, or 20 times or less, by weight relative to the amount of evocalcet.

[0033] In the manufacturing method of the present invention, contacting a solution of evocalcet dissolved in an organic solvent with a porous adsorbent or polymer may, for example, be made by mixing the solution of evocalcet dissolved in an organic solvent with the porous adsorbent or polymer.

[0034] The manufacturing method of the present invention may further include kneading a mixture obtained by mixing a solution of evocalcet dissolved in an organic solvent with an adsorbent or polymer having voids. The kneading can be carried out according to a conventional method, for example, by placing the mixture in a mortar and kneading it with a pestle.

[0035] When a solution of evocalcet dissolved in an organic solvent is brought into contact with an adsorbent or polymer having voids, the solution may be heated. The temperature at that time is not particularly limited as long as it is within a range that can maintain the state in which evocalcet is dissolved in the organic solvent, and may be, for example, 25°C or higher, 30°C or higher, 35°C or higher, or 40°C or higher, on the other hand, it may be, for example, 200°C or lower, 150°C or lower, 100°C or lower, 90°C or lower, 80°C or lower, or 70°C or lower.

[0036] The manufacturing method of the present invention may further include drying a composite obtained by contacting or adsorbing evocalcet onto the adsorbent or polymer. Drying can be carried out by conventional methods. For example, the mixture can be dried at 30°C to 60°C, preferably 35°C to 45°C, for 1 to 100 hours, preferably 10 to 75 hours. Drying may be carried out under reduced pressure.

[0037] The solid material of the present invention can be used for the manufacture of pharmaceuticals for the treatment of hyperparathyroidism or hypercalcemia associated with parathyroid dysfunction. Hyperparathyroidism may be secondary hyperparathyroidism under maintenance dialysis, primary hyperparathyroidism resulting from parathyroidectomy or postoperative recurrence, etc. Parathyroid dysfunction may be due to parathyroid cancer, or primary hyperparathyroidism resulting from parathyroidectomy or postoperative recurrence.

[0038] The solid material of the present invention can also be used for the manufacture of calcium receptor agonists. Having calcium receptor agonist activity can be evaluated by any method known to those skilled in the art. One example of such a method is Ca + In the presence of fluorescent Ca +The 50% effective concentration (IC) was determined by measuring the fluorescence signal from human calcium receptor-expressing human fetal kidney 293 cells (HEK293 cells) that had incorporated the indicator Fura2. 50 One way to check this is to see if it becomes smaller than a suitable control.

[0039] The solid material of the present invention can be formulated as a pharmaceutical composition by conventional methods. For example, the solid material consisting of the amorphous form of evocalcet of the present invention can be used as a tablet. The tablet can be manufactured by mixing the active ingredient with an additive and compressing the resulting mixture in a tablet press. Examples of additives include excipients, binders, disintegrants, lubricants, coatings, colorants, and flavoring / odorizing agents. Specific examples include lactose, hydroxypropyl cellulose, crystalline cellulose, hypromellose, D-mannitol, polyethylene glycol, croscarmellose sodium, magnesium stearate, titanium dioxide, yellow ferric oxide, carnauba wax, anhydrous calcium hydrogen phosphate, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer, sodium starch glycolate, corn starch, potato starch, talcum, magnesium stearate gelatin, lactose, and rubber.

[0040] Tablets can be manufactured, for example, by a wet granulation method. In a wet granulation method, dry solids (active ingredients, excipients, binders, etc.) are blended and moistened with water or other wetting agents (e.g., alcohol) to form agglomerates or granules from these moistened solids. Wet agglomeration continues until a desired uniform particle size is achieved, after which the granulated product is dried. The solids consisting of the amorphous evocalcet of the present invention are mixed with water and excipients, binders, etc., in a high-shear mixer, for example. After granule formation, these granules may be sieved through a sieve with an appropriate sieve size and dried. The resulting dried granules are then mixed with excipients, lubricants, etc., and the tablets are subsequently compressed. Alternatively, wet granulation of the solids consisting of the amorphous evocalcet of the present invention may be achieved by mixing the granules with appropriate excipients, binders, lubricants, etc.

[0041] The administration route of the pharmaceutical composition containing a solid made of amorphous evocalcet according to the present invention is not particularly limited. For example, it may be administered orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of injections, transdermal agents, suppositories, etc.

[0042] The pharmaceutical composition of the present invention, which contains a solid made of amorphous evocalcet, may be administered daily. It may be administered once a day, or twice a day or more.

[0043] The pharmaceutical composition of the present invention, which contains a solid made of amorphous evocalcet, is preferably administered in a unit dosage form containing an amount of amorphous evocalcet ranging from 0.1 mg to 50 mg. The dosage can be appropriately set considering the age, weight, general condition, metabolic and excretory function, blood calcium concentration, concomitant medications, etc. For example, the total daily dose can be approximately 1-30 mg, approximately 1-24 mg, approximately 1-12 mg, approximately 1-8 mg, or approximately 1-6 mg. Specific examples of daily doses include 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 12 mg, or 24 mg. [Examples]

[0044] The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

[0045] <Powder X-ray diffraction measurement> Equipment: MiniFlex 600 (Rigaku Corporation) Cu, 40 kV × 15 mA Scan range: 3-40° Scan speed: 2° per minute Step width: 0.02° Total: 1 time Detector: High-speed one-dimensional detector (D / tex Ultra) The sample is placed in a circular glass sample plate with a depth of 0.2 mm and measured.

[0046] <Other reagents, equipment, etc.> • Evocalcete • Silicon dioxide AEROSIL 200: Nippon Aerosil Co., Ltd. • Silicon dioxide AEROSIL 50: Nippon Aerosil Co., Ltd. Calcium silicate fluorite: Tomita Pharmaceutical Co., Ltd. Magnesium aluminometasilicate NEUSILIN NS2N: Fuji Chemical Industry Co., Ltd. • Hypromellose acetate succinate Shin-Etsu AQOAT AS-LF: Shin-Etsu Chemical Co., Ltd. • Hypromellose TC-5: Shin-Etsu Chemical Co., Ltd. • Methacrylic acid copolymer Eudragit-L100: Evonik Industries AG • Polyvinylpyrrolidone povidone-25: BASF Japan Co., Ltd. ·methanol • Dichloromethane • Vacuum drying Vacuum dryer: VOS-201SD (Tokyo Rikakikai Co., Ltd.)

[0047] Example 1: Amorphization of evocalcet using AEROSIL 200 (1-1) Preparation of solids consisting of amorphous evocalcet <Method> 100 mg of evocalcet active pharmaceutical ingredient was dissolved in approximately 30 mL of a 1:1 dichloromethane / methanol mixture, and 400 mg of AEROSIL 200 was added to the solution and mixed. The mixture was dried under reduced pressure at 40°C (approximately 17-68 hours). After drying, the X-ray diffraction spectrum was measured. As a control, a 1:1 dichloromethane / methanol solution of evocalcet was dried under reduced pressure, and 10 mg of the dried product was mixed with 40 mg of AEROSIL 200. The X-ray diffraction spectrum was then measured.

[0048] <Result> The X-ray diffraction spectrum showed a halo pattern, and no peaks originating from the crystal were observed (Figure 1).

[0049] (1-2) Confirmation of the crystalline stability of the amorphous form of evocalcet <Method> The solid material consisting of amorphous evocalcet prepared in (1-1) was placed in a glass container and stored at room temperature (at ambient humidity) for 8 months, after which the X-ray diffraction spectrum was measured.

[0050] <Result> No significant changes were observed in the X-ray diffraction spectrum from the time of solid material preparation to 8 months later (Figure 1).

[0051] Example 2: Amorphization of evocalcet using Shin-Etsu AQOAT AS-LF (2-1) Preparation of solids consisting of amorphous evocalcet <Method> 100 mg of evocalcet active pharmaceutical ingredient was dissolved in approximately 30 mL of a 1:1 dichloromethane / methanol mixture. 1000 mg of Shin-Etsu AQOAT AS-LF was then added to this solution and mixed. The mixture was dried under reduced pressure at 40°C for approximately 17-68 hours. After drying, the X-ray diffraction spectrum was measured. As a control, a 1:1 dichloromethane / methanol solution of evocalcet was dried under reduced pressure, and 10 mg of the dried product was mixed with 100 mg of Shin-Etsu AQOAT AS-LF. The X-ray diffraction spectrum was then measured.

[0052] <Result> The X-ray diffraction spectrum showed a halo pattern, and no peaks originating from the crystal were observed (Figure 2).

[0053] (2-2) Confirmation of the crystalline stability of the amorphous form of evocalcet <Method> The solid material consisting of amorphous evocalcet prepared in (2-1) was placed in a glass container and stored at room temperature (at ambient humidity) for one month, after which the X-ray diffraction spectrum was measured.

[0054] <Result> No significant changes were observed in the X-ray diffraction spectrum from the time of solid preparation to one month later (Figure 2).

[0055] Example 3: Amorphization of evocalcet using AEROSIL 50 (3-1) Preparation of solids consisting of amorphous evocalcet <Method> Solids and controls were prepared using AEROSIL 50 in the same manner as in Example 2(2-1), and the X-ray diffraction spectra were measured.

[0056] <Result> The X-ray diffraction spectrum showed a halo pattern, and no peaks originating from the crystal were observed (Figure 3).

[0057] (3-2) Confirmation of the crystalline stability of the amorphous form of evocalcet <Method> The solid material consisting of amorphous evocalcet prepared in (3-1) was placed in a glass container and stored at room temperature (at ambient humidity) for one month, after which the X-ray diffraction spectrum was measured.

[0058] <Result> No significant changes were observed in the X-ray diffraction spectrum from the time of solid preparation to one month later (Figure 3).

[0059] Example 4: Amorphization of evocalcet using fluorite (4-1) Preparation of solids consisting of amorphous evocalcet <Method> Solid materials and controls were prepared using fluorite in the same manner as in Example 2(2-1), and the X-ray diffraction spectra were measured.

[0060] <Result> The X-ray diffraction spectrum showed a pattern similar to that of fluorite, and no peaks originating from the crystalline active pharmaceutical ingredient were observed (Figure 4).

[0061] (4-2) Confirmation of the crystalline stability of the amorphous form of evocalcet <Method> The solid material consisting of amorphous evocalcet prepared in (4-1) was placed in a glass container and stored at room temperature (at ambient humidity) for one month, after which the X-ray diffraction spectrum was measured.

[0062] <Result> No significant changes were observed in the X-ray diffraction spectrum from the time of solid preparation to one month later (Figure 4).

[0063] Example 5: Amorphization of evocalcet using NEUSILIN NS2N (5-1) Preparation of solids consisting of amorphous evocalcet <Method> Solids and controls were prepared using NEUSILIN NS2N in the same manner as in Example 2(2-1), and the X-ray diffraction spectra were measured.

[0064] <Result> The X-ray diffraction spectrum showed a halo pattern, and no peaks originating from the crystal were observed (Figure 5).

[0065] (5-2) Confirmation of the crystalline stability of the amorphous form of evocalcet <Method> The solid material consisting of amorphous evocalcet prepared in (5-1) was placed in a glass container and stored at room temperature (at ambient humidity) for one month, after which the X-ray diffraction spectrum was measured.

[0066] <Result> No significant changes were observed in the X-ray diffraction spectrum from the time of solid preparation to one month later (Figure 5).

[0067] Example 6: Amorphization of evocalcet using TC-5 (6-1) Preparation of solids consisting of amorphous evocalcet <Method> Solids and controls were prepared using TC-5 in the same manner as in Example 2(2-1), and the X-ray diffraction spectra were measured.

[0068] <Result> The X-ray diffraction spectrum showed a halo pattern, and no peaks originating from the crystal were observed (Figure 6).

[0069] (6-2) Confirmation of the crystalline stability of the amorphous form of evocalcet <Method> The solid material consisting of amorphous evocalcet prepared in (6-1) was placed in a glass container and stored at room temperature (at ambient humidity) for one month, after which the X-ray diffraction spectrum was measured.

[0070] <Result> No significant changes were observed in the X-ray diffraction spectrum from the time of solid preparation to one month later (Figure 6).

[0071] Example 7: Amorphization of evocalcet using Eudragit-L100 (7-1) Preparation of solids consisting of amorphous evocalcet <Method> Solids and controls were prepared using Eudragit-L100 in the same manner as in Example 2(2-1), and the X-ray diffraction spectra were measured.

[0072] <Result> The X-ray diffraction spectrum showed a halo pattern, and no peaks originating from the crystal were observed (Figure 7).

[0073] (7-2) Confirmation of the crystalline stability of the amorphous form of evocalcet <Method> The solid material consisting of amorphous evocalcet prepared in (7-1) was placed in a glass container and stored at room temperature (at ambient humidity) for one month, after which the X-ray diffraction spectrum was measured.

[0074] <Result> No significant changes were observed in the X-ray diffraction spectrum from the time of solid preparation to one month later (Figure 7).

[0075] Example 8: Amorphization of evocalcet using povidone-25 (8-1) Preparation of solids consisting of amorphous evocalcet <Method> Solids and controls were prepared using povidone 25 in the same manner as in Example 2(2-1), and the X-ray diffraction spectra were measured.

[0076] <Result> The X-ray diffraction spectrum showed a halo pattern, and no peaks originating from the crystal were observed (Figure 8).

[0077] (8-2) Confirmation of the crystalline stability of the amorphous form of evocalcet <Method> The solid material consisting of amorphous evocalcet prepared in (8-1) was placed in a glass container and stored at room temperature (at ambient humidity) for one month, after which the X-ray diffraction spectrum was measured.

[0078] <Result> No significant changes were observed in the X-ray diffraction spectrum from the time of solid preparation to one month later (Figure 8).

Claims

1. A solid substance consisting of the amorphous form of evocalcet.

2. The solid according to claim 1, which substantially does not contain evocalcet crystals.

3. In powder X-ray diffraction measurements, There are virtually no peaks at 2θ = 12.7°±0.2°, 14.6°±0.2°, 14.8°±0.2°, 17.3°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 20.5°±0.2°, 22.6°±0.2°, 24.5°±0.2° and 28.1°±0.2°, and The solid according to claim 2, wherein 2θ has substantially no peaks at 12.6°±0.2°, 14.4°±0.2°, 15.9°±0.2°, 18.6°±0.2°, 19.1°±0.2°, 19.7°±0.2°, 21.4°±0.2°, 23.8°±0.2°, 24.3°±0.2° and 28.0°±0.2°.

4. The solid material according to claim 2, which exhibits a halo pattern in powder X-ray diffraction measurement.

5. A solid matter according to any one of claims 1 to 4, which is in powder form.

6. A solution of evocalcet dissolved in an organic solvent is brought into contact with an adsorbent having voids; or A solution of evocalcet dissolved in an organic solvent is brought into contact with the polymer. A solid obtained by any one of claims 1 to 4.

7. The solid material according to claim 6, wherein the adsorbent having voids is a porous adsorbent or a flake-shaped adsorbent.

8. The solid according to claim 6, wherein the adsorbent having voids is substantially composed of a silicon compound.

9. The solid according to claim 6, wherein the organic solvent is a mixed solution of dichloromethane and methanol.

10. The solid material according to claim 6, wherein the amount of adsorbent having voids used is at least twice the amount of evocalcet used by weight.

11. The solid according to claim 6, wherein the polymer is a cellulose-based polymer, a methacrylic acid-based polymer, a methacrylic acid ester-based polymer, or a polyvinylpyrrolidone-based polymer.

12. A solid substance according to any one of claims 1 to 4, for use in the treatment of hyperparathyroidism or hypercalcemia associated with parathyroid dysfunction, or for use as a calcium receptor agonist.

13. A method for producing a solid substance according to any one of claims 1 to 4, comprising contacting a solution obtained by dissolving evocalcet in an organic solvent with an adsorbent having voids.

14. The manufacturing method according to claim 13, wherein the adsorbent having voids is a porous adsorbent or a flake-shaped adsorbent.

15. The manufacturing method according to claim 13, wherein the adsorbent having voids is substantially composed of a silicon compound.

16. The manufacturing method according to claim 13, wherein the organic solvent is a mixed solution of dichloromethane and methanol.

17. The manufacturing method according to claim 13, wherein the amount of adsorbent having voids used is at least twice the amount of evocalcet used by weight.

18. A method for producing a solid according to any one of claims 1 to 4, comprising contacting a polymer with a solution obtained by dissolving evocalcet in an organic solvent.

19. The method according to claim 18, wherein the polymer is a cellulose-based polymer, a methacrylic acid-based polymer, a methacrylic acid ester-based polymer, or a polyvinylpyrrolidone-based polymer.

20. The manufacturing method according to claim 18, wherein the organic solvent is a mixed solution of dichloromethane and methanol.

21. The manufacturing method according to claim 18, wherein the amount of polymer used is at least twice the amount of evocalcet used by weight.

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