WO2024143236A1 - Crystals of acetate hydrochloride - Google Patents
Crystals of acetate hydrochloride Download PDFInfo
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- WO2024143236A1 WO2024143236A1 PCT/JP2023/046297 JP2023046297W WO2024143236A1 WO 2024143236 A1 WO2024143236 A1 WO 2024143236A1 JP 2023046297 W JP2023046297 W JP 2023046297W WO 2024143236 A1 WO2024143236 A1 WO 2024143236A1
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- powder
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- 239000013078 crystal Substances 0.000 title claims abstract description 150
- HDRXZJPWHTXQRI-BHDTVMLSSA-N diltiazem hydrochloride Chemical compound [Cl-].C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CC[NH+](C)C)C2=CC=CC=C2S1 HDRXZJPWHTXQRI-BHDTVMLSSA-N 0.000 title claims description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 38
- 238000001228 spectrum Methods 0.000 claims abstract description 31
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 16
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 14
- 206010066218 Stress Urinary Incontinence Diseases 0.000 claims description 9
- 238000007915 intraurethral administration Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 230000003449 preventive effect Effects 0.000 claims description 7
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- KVTBRFOQOFIRRM-OEROMNIQSA-N piperidin-4-yl 2-(1,1,2,2,3,3,3-heptadeuteriopropoxy)-2,2-diphenylacetate;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(C=1C=CC=CC=1)(OC([2H])([2H])C([2H])([2H])C([2H])([2H])[2H])C(=O)OC1CCNCC1 KVTBRFOQOFIRRM-OEROMNIQSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 78
- 238000000034 method Methods 0.000 description 21
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- -1 acetate compound Chemical class 0.000 description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
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- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 5
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- 239000008101 lactose Substances 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008368 mint flavor Substances 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 238000001683 neutron diffraction Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960001309 procaine hydrochloride Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000011472 radical prostatectomy Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000002460 vibrational spectroscopy Methods 0.000 description 1
- 238000001845 vibrational spectrum Methods 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
Definitions
- the present disclosure also relates to the following aspects: - Form I crystals of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride, which are produced by a process of recrystallizing 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride with methyl ethyl ketone, and which have peaks in a powder X-ray diffraction spectrum (CuK ⁇ ) at at least one diffraction angle (2 ⁇ 0.2°) selected from the following group (a) and at least one diffraction angle (2 ⁇ 0.2°) selected from the following group (b).
- CuK ⁇ powder X-ray diffraction spectrum
- a stable crystalline form of the above-mentioned compound (I) is provided that is useful as a preventive and/or therapeutic agent for diseases that are expected to be improved by increasing intraurethral pressure. Furthermore, the stable crystalline form of the compound (I) of the present disclosure and its manufacturing method are not currently known.
- type I crystal is a useful form when the compound is used as an active pharmaceutical ingredient for pharmaceuticals from the viewpoints of low hygroscopicity and/or solid stability, etc.
- the values obtained from various patterns may have some errors depending on the crystal growth direction, particle size, measurement conditions, etc. Therefore, in this specification, the values of the diffraction angle (2 ⁇ ) in the powder X-ray diffraction pattern may have a measurement error in the range of about ⁇ 0.2°.
- the type I crystal of compound (I) is a type I crystal of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride having at least one peak selected from the group consisting of 11.3°, 11.4°, and 17.2° as a diffraction angle (2 ⁇ 0.2°) in a powder X-ray diffraction spectrum.
- Coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, white sugar, etc.
- Solvents include water, propylene glycol, and saline.
- Anti-pain agents include procaine hydrochloride and lidocaine.
- Preservatives include ethyl paraoxybenzoate, cresol, and benzalkonium chloride.
- Antioxidants include sodium sulfite, ascorbic acid, and natural vitamin E.
- Coloring agents include titanium oxide, ferric oxide, food blue No. 1, copper chlorophyll, etc.
- Flavoring agents include aspartame, saccharin, sucralose, l-menthol, mint flavor, etc.
- Stabilizers include sodium pyrosulfite, sodium edetate, erythorbic acid, magnesium oxide, and dibutylhydroxytoluene.
- excipients When preparing oral solid preparations, excipients, and if necessary binders, disintegrants, lubricants, colorants, flavorings, odorants, etc., are added to compound (I), and tablets, coated tablets, granules, powders, capsules, etc. can be manufactured by conventional methods.
- each dosage unit varies depending on the symptoms of the patient to whom it is to be administered or on the dosage form, but in general, it is desirable to incorporate about 0.05 to 1000 mg of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate per dosage unit for oral preparations, about 0.1 to 500 mg for injections, and about 1 to 1000 mg for suppositories or external preparations.
- the daily dose of the type I crystal of compound (I) for each dosage form varies depending on the symptoms, body weight, age, sex, etc. of the patient and cannot be determined in general, but usually, for example, about 3 mg, about 6 mg, about 9 mg, or about 18 mg of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate can be administered per day for treatment.
- the daily dosage is about 18 mg of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate.
- Administration of Form I crystals of Compound (I) can be, for example, continuous (7 days per week) or intermittent, depending on the pharmacokinetics and clearance/accumulation of the drug in a particular subject. When administered intermittently, it may be, for example, a 4 day on, 3 day off schedule per week (drug holiday) or other intermittent dosing schedule deemed appropriate using sound medical judgment, although continuous administration is preferred. Administration can be once per day (QD) or two or more times per day (b.i.d., t.i.d., etc.), with a dosage of about 3-18 mg/day QD being preferred. The daily dosage may be a single dose or multiple individual divided doses.
- the morphology of many crystalline grains tends to give the sample a preferred orientation in the sample holder.
- the preferred orientation in the sample affects the intensity of various reflections, which are sometimes observed to be stronger and sometimes weaker than would be expected for a completely unoriented sample.
- DSC measurement Differential scanning calorimetry curve
- Example 1 Preparation of I-type crystals of compound (I) Methyl ethyl ketone (5.5 mL) was added to the crude compound (I) (500 mg) synthesized by the known method disclosed in Patent Document 1, and the mixture was heated to an external temperature of 85° C. or higher to dissolve. The mixture was then cooled and crystallized, stirred at room temperature, and the crystals obtained by filtration were dried under reduced pressure to obtain I-type crystals of compound (1). Yield: 459 mg, yield: 91.8%.
- the powder X-ray diffraction spectrum (CuK ⁇ ) is shown in FIG. 1.
- the differential scanning calorimetry (DSC) curve showed an endothermic peak of 166.1° C.
- Example 2 Preparation of I-type crystals of compound (I) Heptane (1.0 mL) was added to the crude compound (1) (100 mg) synthesized by the known method disclosed in Patent Document 1, and the mixture was heated to an external temperature of 120° C. or higher and stirred in suspension. The mixture was then cooled and stirred at room temperature, after which the crystals obtained by filtration were dried under reduced pressure and heat to obtain I-type crystals of compound (1). Yield: 78 mg, yield: 78.0%.
- Example 3 Preparation of I-type crystals of compound (I) Butyl acetate (3.5 mL) was added to the crude compound (1) (250 mg) synthesized by the known method disclosed in Patent Document 1, and dissolved by heating to an external temperature of 130° C. or higher. After cooling, a small amount of I-type crystals of compound (I) was added, and crystallization was performed at an external temperature of 35° C., and the crystals obtained by filtration were dried under reduced pressure and heat to obtain I-type crystals of compound (1). Yield: 230 mg, yield: 92.0%.
- the Form II crystal does not have peaks at 11.3 °, 11.4 °, and 17.2 ° as diffraction angles (2 ⁇ ⁇ 0.2 °) in the powder X-ray diffraction spectrum (CuK ⁇ ).
- 1H-NMR (DMSO-d6) ⁇ ppm 1.62-1.71 (2H,m), 1.90-1.98 (2H,m), 2.78-2.85 (2H,m), 2.95-3.04 (2H,m), 5.01-5.08 (1H,m), 7.30-7.40 (10H,m), 8.72 (1H,brs)
- Test Example 1 Solid Stability Test The storage stability of the type I crystal of Compound (I) obtained by the method described in Example 1 above was tested under the following conditions.
- Test condition 1 Storage conditions: 25°C ⁇ 2°C / 60% RH ⁇ 5% Measurement points: 12, 24, 36 months Storage amount: approx. 5g
- Test condition 2 Storage conditions: 40°C ⁇ 2°C / 75% RH ⁇ 5% Measurement points: 1, 3, 6 months Storage amount: approx. 4g
- the amount of related substances in type I crystals was small after storage, and no change in appearance was observed.
- the powder X-ray diffraction pattern after storage was the same as the initial value.
- a VTI-SA+ (TA Instruments) was used. Approximately 10 mg of I-type crystals of compound (I) were weighed and placed in a pan. The temperature was raised to 60°C at 1 degree per minute while confirming that the weight fluctuation was within 0.0100% in 5 minutes. If the weight fluctuated, the temperature was maintained for a maximum of 5 hours before proceeding to the next step. The temperature was then lowered to 25°C, and the humidity was raised from 5% RH to 95% RH, and then lowered to 5% RH. At that time, the humidity was increased by 5% RH while confirming that the weight fluctuation was within 0.00100% in 5 minutes. If the weight fluctuated, the humidity was maintained for a maximum of 2 hours before proceeding to the next step.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Urology & Nephrology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention provides I form crystals of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7)acetate hydrochloride having at least one diffraction angle (2θ±0.2°) selected from group (a) below and at least one diffraction angle (2θ±0.2°) selected from group (b) below in a powder x-ray diffraction spectrum (CuKα). (a) 11.3°, 11.4°, and 17.2° (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4°
Description
本開示は、酢酸エステル塩酸塩の結晶、並びに当該結晶を含む医薬組成物に関する。
The present disclosure relates to crystals of acetate ester hydrochloride and pharmaceutical compositions containing the crystals.
一般的に、医薬品の有効活性成分として化合物が使用されるとき、品質を安定に保持するために及び／又は保管管理を容易にするために、化合物の化学的及び物理学的な安定性が必要である。
Generally, when a compound is used as an active ingredient in a pharmaceutical product, the chemical and physical stability of the compound is required to maintain stable quality and/or to facilitate storage and management.
特許文献１には、酢酸エステル化合物又はその塩、及びこれらを有効成分とする尿道内圧の上昇により改善が見込まれる疾患、例えば腹圧性尿失禁の予防剤及び／又は治療剤を提供する化合物として、下記式（Ｉ）
Patent Document 1 describes an acetate compound or its salt, and a compound containing the compound as an active ingredient, which provides a preventive and/or therapeutic agent for diseases that are expected to be improved by increasing intraurethral pressure, such as stress urinary incontinence, and which is represented by the following formula (I):
しかしながら、特許文献１には、本開示の結晶形について記載されておらず、化合物（Ｉ）の安定形結晶、及びその製法については現在のところ知られていない。
However, Patent Document 1 does not describe the crystal form of the present disclosure, and stable crystals of compound (I) and a method for producing the same are currently unknown.
本開示は、医薬品又は医薬品原薬として有用な化合物（Ｉ）の結晶を提供することを目的とする。
The present disclosure aims to provide crystals of compound (I) that are useful as a pharmaceutical or active pharmaceutical ingredient.
上記の課題を解決すべく鋭意研究を行ったところ、化合物（Ｉ）として２つの結晶形（Ｉ形結晶及びＩＩ形結晶）を見出した。これらの結晶のうちI形結晶は優れた固体安定性及び／又は低い吸湿性を有することを見出した。
As a result of intensive research aimed at solving the above problems, two crystal forms (form I crystal and form II crystal) of compound (I) were found. Of these crystals, it was found that form I crystal has excellent solid stability and/or low hygroscopicity.
すなわち、本開示は、以下〔１〕～〔９〕を提供するものである。
〔１〕
粉末Ｘ線回折スペクトル（ＣｕＫα）において、以下の（ａ）群から選ばれる少なくとも１つの回折角（２θ±０．２°）並びに以下の（ｂ）群から選択される少なくとも１つの回折角（２θ±０．２°）にピークを有する４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩のI形結晶。（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜
〔２〕
粉末Ｘ線回折スペクトル（ＣｕＫα）において、以下の（ａ）群から選ばれる少なくとも２つの回折角（２θ±０．２°）並びに以下の（ｂ）群から選択される少なくとも１つの回折角（２θ±０．２°）にピークを有する〔１〕に記載の結晶。
（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜
〔３〕
粉末Ｘ線回折スペクトル（ＣｕＫα）において、回折角（２θ±０．２°）として、１１．３゜、１１．４゜、１２．７゜、１５．９゜、１６．１゜、１７．２゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜にピークを有する〔１〕又は〔２〕に記載の結晶。
〔４〕
図１に示される粉末Ｘ線回折スペクトル（ＣｕＫα）を有する結晶である、〔１〕乃至〔３〕のいずれかに記載の結晶。
〔５〕
示差走査熱量測定において、１６６℃付近に吸熱ピークを有する〔１〕乃至〔４〕のいずれかに記載の結晶。
〔６〕
４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩をメチルエチルケトンで再結晶化する工程を含む、〔１〕乃至〔５〕のいずれかに記載のＩ型結晶の製造方法。
〔７〕
〔１〕乃至〔５〕のいずれかに記載の結晶を含有する医薬組成物。
〔８〕
〔１〕乃至〔５〕のいずれか１項に記載の結晶を含有する尿道内圧の上昇により改善が見込まれる疾患の予防及び／又は治療剤。
〔９〕
〔１〕乃至〔５〕のいずれかに記載の結晶を含有する腹圧性尿失禁予防及び／又は治療剤。 That is, the present disclosure provides the following [1] to [9].
[1]
A type I crystal of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride having peaks in a powder X-ray diffraction spectrum (CuKα) at at least one diffraction angle (2θ±0.2°) selected from the following group (a) and at least one diffraction angle (2θ±0.2°) selected from the following group (b): (a) 11.3°, 11.4°, and 17.2° (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4° [2]
The crystal according to [1], which has peaks in a powder X-ray diffraction spectrum (CuKα) at at least two diffraction angles (2θ±0.2°) selected from the following group (a) and at least one diffraction angle (2θ±0.2°) selected from the following group (b):
(a) 11.3°, 11.4° and 17.2°; (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9° and 28.4°. [3]
The crystal according to [1] or [2], which has peaks at diffraction angles (2θ±0.2°) of 11.3°, 11.4°, 12.7°, 15.9°, 16.1°, 17.2°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4° in a powder X-ray diffraction spectrum (CuKα).
[4]
The crystal according to any one of [1] to [3], which is a crystal having the powder X-ray diffraction spectrum (CuKα) shown in FIG. 1.
[5]
The crystal according to any one of [1] to [4], which has an endothermic peak at about 166° C. in differential scanning calorimetry.
[6]
A method for producing the I-type crystal according to any one of [1] to [5], comprising a step of recrystallizing 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride from methyl ethyl ketone.
[7]
A pharmaceutical composition comprising the crystal according to any one of [1] to [5].
[8]
A preventive and/or therapeutic agent for a disease expected to be improved by increasing intraurethral pressure, comprising the crystal according to any one of [1] to [5].
[9]
A preventive and/or therapeutic agent for stress urinary incontinence, comprising the crystal according to any one of [1] to [5].
〔１〕
粉末Ｘ線回折スペクトル（ＣｕＫα）において、以下の（ａ）群から選ばれる少なくとも１つの回折角（２θ±０．２°）並びに以下の（ｂ）群から選択される少なくとも１つの回折角（２θ±０．２°）にピークを有する４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩のI形結晶。（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜
〔２〕
粉末Ｘ線回折スペクトル（ＣｕＫα）において、以下の（ａ）群から選ばれる少なくとも２つの回折角（２θ±０．２°）並びに以下の（ｂ）群から選択される少なくとも１つの回折角（２θ±０．２°）にピークを有する〔１〕に記載の結晶。
（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜
〔３〕
粉末Ｘ線回折スペクトル（ＣｕＫα）において、回折角（２θ±０．２°）として、１１．３゜、１１．４゜、１２．７゜、１５．９゜、１６．１゜、１７．２゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜にピークを有する〔１〕又は〔２〕に記載の結晶。
〔４〕
図１に示される粉末Ｘ線回折スペクトル（ＣｕＫα）を有する結晶である、〔１〕乃至〔３〕のいずれかに記載の結晶。
〔５〕
示差走査熱量測定において、１６６℃付近に吸熱ピークを有する〔１〕乃至〔４〕のいずれかに記載の結晶。
〔６〕
４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩をメチルエチルケトンで再結晶化する工程を含む、〔１〕乃至〔５〕のいずれかに記載のＩ型結晶の製造方法。
〔７〕
〔１〕乃至〔５〕のいずれかに記載の結晶を含有する医薬組成物。
〔８〕
〔１〕乃至〔５〕のいずれか１項に記載の結晶を含有する尿道内圧の上昇により改善が見込まれる疾患の予防及び／又は治療剤。
〔９〕
〔１〕乃至〔５〕のいずれかに記載の結晶を含有する腹圧性尿失禁予防及び／又は治療剤。 That is, the present disclosure provides the following [1] to [9].
[1]
A type I crystal of 4-
The crystal according to [1], which has peaks in a powder X-ray diffraction spectrum (CuKα) at at least two diffraction angles (2θ±0.2°) selected from the following group (a) and at least one diffraction angle (2θ±0.2°) selected from the following group (b):
(a) 11.3°, 11.4° and 17.2°; (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9° and 28.4°. [3]
The crystal according to [1] or [2], which has peaks at diffraction angles (2θ±0.2°) of 11.3°, 11.4°, 12.7°, 15.9°, 16.1°, 17.2°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4° in a powder X-ray diffraction spectrum (CuKα).
[4]
The crystal according to any one of [1] to [3], which is a crystal having the powder X-ray diffraction spectrum (CuKα) shown in FIG. 1.
[5]
The crystal according to any one of [1] to [4], which has an endothermic peak at about 166° C. in differential scanning calorimetry.
[6]
A method for producing the I-type crystal according to any one of [1] to [5], comprising a step of recrystallizing 4-
[7]
A pharmaceutical composition comprising the crystal according to any one of [1] to [5].
[8]
A preventive and/or therapeutic agent for a disease expected to be improved by increasing intraurethral pressure, comprising the crystal according to any one of [1] to [5].
[9]
A preventive and/or therapeutic agent for stress urinary incontinence, comprising the crystal according to any one of [1] to [5].
また、本開示は以下の態様にも関する 。
・４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩をメチルエチルケトンで再結晶化する工程により生産される、粉末Ｘ線回折スペクトル（ＣｕＫα）において、以下の（ａ）群から選ばれる少なくとも１つの回折角（２θ±０．２°）並びに以下の（ｂ）群から選択される少なくとも１つの回折角（２θ±０．２°）にピークを有する、４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩のI形結晶。
（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜
・医薬（尿道内圧の上昇により改善が見込まれる疾患ないし腹圧性尿失禁の予防及び／又は治療に用いるものも含む）の製造における〔１〕乃至〔５〕のいずれかの結晶の使用。
・疾患（尿道内圧の上昇により改善が見込まれる疾患ないし腹圧性尿失禁）の予防及び／又は治療するための〔１〕乃至〔５〕のいずれかの結晶の使用。
・〔１〕乃至〔５〕のいずれかの結晶を用いた疾患（尿道内圧の上昇により改善が見込まれる疾患ないし腹圧性尿失禁）の予防及び／又は治療方法。例えば、それを必要とする対象に対し〔１〕乃至〔５〕のいずれかの結晶を投与することを含む、疾患（尿道内圧の上昇により改善が見込まれる疾患ないし腹圧性尿失禁）の予防及び／又は治療方法。 The present disclosure also relates to the following aspects:
- Form I crystals of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride, which are produced by a process of recrystallizing 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride with methyl ethyl ketone, and which have peaks in a powder X-ray diffraction spectrum (CuKα) at at least one diffraction angle (2θ±0.2°) selected from the following group (a) and at least one diffraction angle (2θ±0.2°) selected from the following group (b).
(a) 11.3°, 11.4°, and 17.2° (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4°. Use of a crystal of any of [1] to [5] in the manufacture of a medicine (including those used for the prevention and/or treatment of diseases expected to be improved by increasing intraurethral pressure or stress urinary incontinence).
Use of a crystal of any of [1] to [5] for the prevention and/or treatment of a disease (a disease expected to be improved by increasing intraurethral pressure or stress urinary incontinence).
- A method for preventing and/or treating a disease (diseases that are expected to be improved by increasing intraurethral pressure or stress urinary incontinence) using any of the crystals of [1] to [5]. For example, a method for preventing and/or treating a disease (diseases that are expected to be improved by increasing intraurethral pressure or stress urinary incontinence) comprising administering any of the crystals of [1] to [5] to a subject in need thereof.
・４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩をメチルエチルケトンで再結晶化する工程により生産される、粉末Ｘ線回折スペクトル（ＣｕＫα）において、以下の（ａ）群から選ばれる少なくとも１つの回折角（２θ±０．２°）並びに以下の（ｂ）群から選択される少なくとも１つの回折角（２θ±０．２°）にピークを有する、４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩のI形結晶。
（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜
・医薬（尿道内圧の上昇により改善が見込まれる疾患ないし腹圧性尿失禁の予防及び／又は治療に用いるものも含む）の製造における〔１〕乃至〔５〕のいずれかの結晶の使用。
・疾患（尿道内圧の上昇により改善が見込まれる疾患ないし腹圧性尿失禁）の予防及び／又は治療するための〔１〕乃至〔５〕のいずれかの結晶の使用。
・〔１〕乃至〔５〕のいずれかの結晶を用いた疾患（尿道内圧の上昇により改善が見込まれる疾患ないし腹圧性尿失禁）の予防及び／又は治療方法。例えば、それを必要とする対象に対し〔１〕乃至〔５〕のいずれかの結晶を投与することを含む、疾患（尿道内圧の上昇により改善が見込まれる疾患ないし腹圧性尿失禁）の予防及び／又は治療方法。 The present disclosure also relates to the following aspects:
- Form I crystals of 4-
(a) 11.3°, 11.4°, and 17.2° (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4°. Use of a crystal of any of [1] to [5] in the manufacture of a medicine (including those used for the prevention and/or treatment of diseases expected to be improved by increasing intraurethral pressure or stress urinary incontinence).
Use of a crystal of any of [1] to [5] for the prevention and/or treatment of a disease (a disease expected to be improved by increasing intraurethral pressure or stress urinary incontinence).
- A method for preventing and/or treating a disease (diseases that are expected to be improved by increasing intraurethral pressure or stress urinary incontinence) using any of the crystals of [1] to [5]. For example, a method for preventing and/or treating a disease (diseases that are expected to be improved by increasing intraurethral pressure or stress urinary incontinence) comprising administering any of the crystals of [1] to [5] to a subject in need thereof.
本開示によれば、尿道内圧の上昇により改善が見込まれる疾患の予防及び／又は治療剤として有用な上記化合物（Ｉ）の安定結晶形が提供される。また、本開示の化合物（Ｉ）の安定結晶形及びその製法については現在のところ知られていない。本開示において、化合物（Ｉ）の結晶形（Ｉ形結晶及びＩＩ形結晶）のうち、I形結晶は低い吸湿性及び／又は固体安定性等の観点から、該化合物を医薬品用の原薬として使用する際の有用な形態である。
According to the present disclosure, a stable crystalline form of the above-mentioned compound (I) is provided that is useful as a preventive and/or therapeutic agent for diseases that are expected to be improved by increasing intraurethral pressure. Furthermore, the stable crystalline form of the compound (I) of the present disclosure and its manufacturing method are not currently known. In the present disclosure, of the crystalline forms of compound (I) (type I crystal and type II crystal), type I crystal is a useful form when the compound is used as an active pharmaceutical ingredient for pharmaceuticals from the viewpoints of low hygroscopicity and/or solid stability, etc.
本明細書中で単に「化合物（Ｉ）」と記載した場合は、４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩を意味し、「非晶質体」、「結晶」のいずれをも含む意味で用いられる。また、本開示の結晶形態は、溶媒和物（例えば、水和物等）であっても、非溶媒和物であってもよい。
When simply referred to as "Compound (I)" in this specification, it means 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride, and is used in the sense of including both "amorphous form" and "crystal." In addition, the crystalline form of the present disclosure may be a solvate (e.g., a hydrate, etc.) or a non-solvate.
化合物（Ｉ）は、例えば国際公開第２０１３／１１５０７７号公報に記載の方法に従って合成することができるが、この方法に限定されるものではない。
Compound (I) can be synthesized, for example, according to the method described in WO 2013/115077, but is not limited to this method.
本明細書中、「結晶」、「非晶質体」なる語は、通常の意味で用いられる。本明細書中、用語「結晶」と、本明細書中で用いられる関連する用語、例えば「結晶形」「結晶形態」とは、互換的に用いられる。また本明細書中、用語「非晶質」と、本明細書中で用いられる関連する用語、例えば「非晶質体」「非晶質形態」とは、互換的に用いられる。
In this specification, the terms "crystal" and "amorphous body" are used in their usual sense. In this specification, the term "crystal" and related terms used herein, such as "crystalline form" and "crystalline morphology," are used interchangeably. In addition, in this specification, the term "amorphous" and related terms used herein, such as "amorphous body" and "amorphous form," are used interchangeably.
本開示の結晶は、再結晶化、結晶化、蒸留及びカラムクロマトグラフィーなどの周知の分離精製技術により、単離及び精製することができる。
The crystals of the present disclosure can be isolated and purified by well-known separation and purification techniques such as recrystallization, crystallization, distillation, and column chromatography.
本明細書中で用いられる場合で、かつ別途明記しない限り、用語「結晶」及び本明細書中で用いられる関連する用語は、化合物、物質、修飾、材料、成分又は生成物を描写するために用いる際には、化合物、物質、修飾、材料、成分又は生成物が、Ｘ線回折により決定される場合に実質的に結晶であることを意味する。例えば、Ｒｅｍｉｎｇｔｏｎ：Ｔｈｅ Ｓｃｉｅｎｃｅ ａｎｄ Ｐｒａｃｔｉｃｅ ｏｆ Ｐｈａｒｍａｃｙ，第２１版，Ｌｉｐｐｉｎｃｏｔｔ，Ｗｉｌｌｉａｍｓ ａｎｄ Ｗｉｌｋｉｎｓ，Ｂａｌｔｉｍｏｒｅ，ＭＤ（２００５）；米国薬局方、第２３版、１８４３－１８４４（１９９５）を参照されたい。
As used herein, and unless otherwise specified, the term "crystalline" and related terms used herein, when used to describe a compound, substance, modification, material, component, or product, means that the compound, substance, modification, material, component, or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott, Williams and Wilkins, Baltimore, MD (2005); United States Pharmacopeia, 23rd ed., 1843-1844 (1995).
本明細書中で用いられる場合で、かつ別途明記しない限り、用語「結晶形態」及び本明細書中の関連する用語は、結晶である固体形態を意味する。結晶形態としては、単一成分結晶形態及び複数成分結晶形態が挙げられ、任意により、限定するものではないが、共結晶、塩（製薬上許容される塩を含む）、多形体、溶媒和物、水和物、及び／又は他の分子複合体を含むことができる。特定の実施形態では、物質の結晶形態は、非晶質形態及び／又は他の結晶形態を実質的に含まないことができる。特定の実施形態では、物質の結晶形態は、重量基準で約０．１、０．５、１、２、３、４、５、６、７、８、９、１０、１１、１２、１３、１４、１５、２０、２５、３０、３５、４０、４５又は５０％未満の１種以上の非晶質形態及び／又は他の結晶形態を含有することができる。
As used herein, and unless otherwise specified, the term "crystalline form" and related terms herein refer to a solid form that is crystalline. Crystalline forms include single-component and multi-component crystalline forms, and can optionally include, but are not limited to, cocrystals, salts (including pharma- ceutically acceptable salts), polymorphs, solvates, hydrates, and/or other molecular complexes. In certain embodiments, the crystalline form of the substance can be substantially free of amorphous forms and/or other crystalline forms. In certain embodiments, the crystalline form of the substance can contain less than about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50% by weight of one or more amorphous forms and/or other crystalline forms.
本明細書中で用いられる場合で、かつ別途明記しない限り、用語「多形体」、「多形形態」及び本明細書中の関連する用語は、実質的に同じ分子、分子群及び／又はイオンからなる2種以上の結晶形態を意味する。異なる結晶形態同士と同様に、異なる多形体は、例えば、融点、融解熱、溶解度、溶解特性及び／又は振動スペクトル（結晶格子中の分子及び／もしくはイオンの配置又はコンホメーションの結果として）などの異なる物性を有することができる。物性の差異は、貯蔵安定性、圧縮性及び密度（製剤化及び製品製造において重要である）、及び溶解速度（バイオアベイラビリティにおいて重要な因子である）などの薬学的パラメータに影響する場合がある。安定性の違いは、化学的反応性での変化（例えば、投与剤形が、別の多形体から構成される場合よりも、ある多形体から構成される場合に、より速く変色するような、示差的酸化）もしくは機械的変化（例えば、動力学上は好ましい多形体が、熱動態学上はより安定な多形体へと変質すると、貯蔵中に錠剤が崩壊する）又はその両方（例えば、ある多形体の錠剤は、高湿度ではより分解し易い）により生じ得る。可溶性／溶解性の差異の結果として、極端なケースでは、一部の固体遷移が、効力の欠損を生じる場合があり、他の極端なケースでは、毒性を生じる場合がある。加えて、物性は、加工において重要であり得る（例えば、ある多形体は、溶媒和物を比較的形成し易い可能性があり、又は不純物を除去するために濾過及び洗浄することが困難であり得、かつ粒子の形状及びサイズ分布は多形体同士で異なり得るであろう）。
As used herein, and unless otherwise specified, the terms "polymorph," "polymorphic form," and related terms herein refer to two or more crystalline forms of substantially the same molecule, molecular groups, and/or ions. As with different crystalline forms, different polymorphs can have different physical properties, such as, for example, melting points, heats of fusion, solubilities, dissolution characteristics, and/or vibrational spectra (as a result of the arrangement or conformation of the molecules and/or ions in the crystal lattice). Differences in physical properties can affect pharmaceutical parameters, such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form changes color faster when composed of one polymorph than another) or mechanical changes (e.g., tablets disintegrate during storage when a kinetically favored polymorph transforms into a thermokinetically more stable polymorph), or both (e.g., tablets of one polymorph are more susceptible to degradation at high humidity). As a result of solubility/dissolution differences, in extreme cases some solid state transitions may result in loss of efficacy and in other extreme cases toxicity. In addition, physical properties may be important in processing (e.g., one polymorph may be more prone to forming solvates or may be difficult to filter and wash to remove impurities, and particle shape and size distribution may differ between polymorphs).
本明細書中で用いられる場合で、かつ別途明記しない限り、用語「非晶質」、「非晶質形態」、及び本明細書中で用いられる関連する用語は、当該物質、成分又は生成物が、Ｘ線回折により決定される場合に実質的に結晶でないことを意味する。特に、用語「非晶質形態」は、不規則な固体形態、すなわち長距離にわたる結晶秩序を欠く固体形態を説明する。
As used herein, and unless otherwise specified, the terms "amorphous," "amorphous form," and related terms used herein mean that the substance, component, or product is substantially not crystalline as determined by X-ray diffraction. In particular, the term "amorphous form" describes a solid form that is disordered, i.e., lacks long-range crystalline order.
結晶形態及び非晶質形態を特性決定するための技術としては、限定するものではないが、熱重量分析（ＴＧＡ）、示差走査熱量測定（ＤＳＣ）、Ｘ線粉末回折（ＸＲＰＤ）、単結晶Ｘ線回折、振動分光法、例えば、赤外（ＩＲ）及びラマン分光法、固体核磁気共鳴（ＮＭＲ）分光法、光学顕微鏡観察、ホットステージ光学顕微鏡観察、走査型電子顕微鏡観察（ＳＥＭ）、電子線結晶学及び定量分析、溶解度測定等が挙げられる。特徴的な単位格子パラメータは、限定するものではないが、単結晶回折及び粉末回折をはじめとする、Ｘ線回折及び中性子回折などの、１種以上の技術を用いて決定することができる。粉末回折データを解析するために有用な技術としては、リートベルト精密化などのプロファイル精密化が挙げられ、これは、例えば、２種以上の固相を含むサンプル中の単一相に関連する回折ピークを解析するために用いることができる。粉末回折データを解析するために有用な他の方法としては、単位格子インデックス化が挙げられ、この方法は、当業者が、結晶粉末を含有するサンプルから単位格子パラメータを決定することを可能にする。
Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy such as infrared (IR) and Raman spectroscopy, solid-state nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, solubility measurements, and the like. Characteristic unit cell parameters can be determined using one or more techniques, such as, but not limited to, X-ray diffraction and neutron diffraction, including single crystal diffraction and powder diffraction. Techniques useful for analyzing powder diffraction data include profile refinement, such as Rietveld refinement, which can be used, for example, to analyze diffraction peaks associated with a single phase in a sample containing two or more solid phases. Other methods useful for analyzing powder diffraction data include unit cell indexing, which allows one of skill in the art to determine unit cell parameters from a sample containing a crystalline powder.
尚、粉末Ｘ線回折パターンは、データの性質上、結晶の同一性を認定する際は、回折角及び全体的なパターンが重要である。粉末Ｘ線回折パターンの相対強度は結晶成長の方向、粒子の大きさ、測定条件によって多少変動し得るものであるから、厳密に解されるべきではない。
When determining the identity of a crystal, due to the nature of the data, the diffraction angle and overall pattern of the powder X-ray diffraction pattern are important. The relative intensities of the powder X-ray diffraction pattern can vary somewhat depending on the direction of crystal growth, particle size, and measurement conditions, so they should not be interpreted strictly.
各種パターンから得られる数値は、その結晶成長の方向、粒子の大きさ、測定条件等によって多少の誤差が生じる場合がある。したがって、本明細書中、粉末Ｘ線回折パターンにおける回折角（２θ）の数値は、±０．２°程度の範囲で測定誤差を有し得る。
The values obtained from various patterns may have some errors depending on the crystal growth direction, particle size, measurement conditions, etc. Therefore, in this specification, the values of the diffraction angle (2θ) in the powder X-ray diffraction pattern may have a measurement error in the range of about ±0.2°.
また、示差走査熱量（ＤＳＣ）曲線における吸熱ピークは、１分あたりの昇温の幅、試料の純度等により測定温度が変化することがある。本明細書においてＤＳＣ測定温度値における「付近」という用語はその値の±２、３、４又は５℃以内の温度値を意味する。温度範囲としては好ましくは±５℃であり、より好ましくは±４℃であり、さらに好ましくは±３℃であり、特に好ましくは±２℃である。
In addition, the measurement temperature of the endothermic peak in a differential scanning calorimetry (DSC) curve may change depending on the rate of temperature rise per minute, the purity of the sample, etc. In this specification, the term "near" the DSC measurement temperature value means a temperature value within ±2, 3, 4, or 5°C of that value. The temperature range is preferably ±5°C, more preferably ±4°C, even more preferably ±3°C, and particularly preferably ±2°C.
ある実施様態では、本明細書中に開示される化合物（Ｉ）の結晶形態は、空間的に規則的な原子配置を有する複数の結晶（結晶多形体）を含むことができ、かつ異なる物理化学的特性を生じ得る。ある実施様態では、本明細書中に開示される結晶形態は、結晶多形体を含有する混合物であり得る。
In some embodiments, the crystalline form of compound (I) disclosed herein may include multiple crystals having a spatially regular arrangement of atoms (crystalline polymorphs) and may result in different physicochemical properties. In some embodiments, the crystalline form disclosed herein may be a mixture containing crystalline polymorphs.
本開示の化合物（Ｉ）の結晶形態は、以下に記載の実施形態の組み合わせにより特徴付けられる場合があり、これらは互いに矛盾しない。例えば、化合物（Ｉ）の結晶形態は、Ｘ線回折パターンの本明細書に記載のピーク及びＤＳＣにより測定される本明細書に記載の吸熱ピークの組み合わせにより特徴付けられる場合がある。
The crystalline form of compound (I) of the present disclosure may be characterized by a combination of the embodiments described below, which are not mutually exclusive. For example, the crystalline form of compound (I) may be characterized by a combination of the peaks described herein in an X-ray diffraction pattern and the endothermic peaks described herein as measured by DSC.
化合物（Ｉ）のＩ形結晶は、例えば、図１に示される粉末Ｘ線回折スペクトル（ＣｕＫα）を有し、また、図２に示される示差走査熱量（ＤＳＣ）曲線を有する。
The type I crystal of compound (I) has, for example, the powder X-ray diffraction spectrum (CuKα) shown in Figure 1, and the differential scanning calorimetry (DSC) curve shown in Figure 2.
ここで、化合物（Ｉ）のＩ形結晶の粉末Ｘ線回折スペクトル（ＣｕＫα）における特徴的なピークとしては、例えば、回折角（２θ±０．２°）として、５．７゜、１１．３゜、１１．４゜、１２．７゜、１５．９゜、１６．１゜、１７．２゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜、２８．４゜を挙げることができる。
Here, characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of type I crystals of compound (I) include, for example, diffraction angles (2θ±0.2°) of 5.7°, 11.3°, 11.4°, 12.7°, 15.9°, 16.1°, 17.2°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4°.
本開示のＩ型結晶は、上記ピーク群から選択される少なくとも２つのピークを有する結晶であり、好ましくは上記ピーク群から選択される少なくとも３つのピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも４つのピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも５つのピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも６つのピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも７つのピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも８つのピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも９つのピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも１０個のピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも１１個のピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも１２個のピークを有する結晶であり、より好ましくは上記ピーク群から選択される少なくとも１３個のピークを有する結晶であり、特に好ましくは上記ピークの全てを有する結晶である。
The type I crystal of the present disclosure is a crystal having at least two peaks selected from the above peak group, preferably a crystal having at least three peaks selected from the above peak group, more preferably a crystal having at least four peaks selected from the above peak group, more preferably a crystal having at least five peaks selected from the above peak group, more preferably a crystal having at least six peaks selected from the above peak group, more preferably a crystal having at least seven peaks selected from the above peak group, more preferably a crystal having at least eight peaks selected from the above peak group, more preferably a crystal having at least nine peaks selected from the above peak group, more preferably a crystal having at least ten peaks selected from the above peak group, more preferably a crystal having at least eleven peaks selected from the above peak group, more preferably a crystal having at least twelve peaks selected from the above peak group, more preferably a crystal having at least thirteen peaks selected from the above peak group, and particularly preferably a crystal having all of the above peaks.
本開示の一実施形態において、化合物（Ｉ）のＩ型結晶は、粉末Ｘ線回折スペクトルにおいて、回折角（２θ±０．２°）として、１１．３゜、１１．４゜及び１７．２゜からなる群より選択される少なくとも１つのピークを有する４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩のI形結晶である。
In one embodiment of the present disclosure, the type I crystal of compound (I) is a type I crystal of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride having at least one peak selected from the group consisting of 11.3°, 11.4°, and 17.2° as a diffraction angle (2θ±0.2°) in a powder X-ray diffraction spectrum.
本開示の一実施形態において、化合物（Ｉ）のＩ型結晶は、粉末Ｘ線回折スペクトル（ＣｕＫα）において、以下の（ａ）からなる群より選ばれる少なくとも１つの回折角（２θ±０．２°）並びに以下の（ｂ）からなる群より選択される少なくとも１つの回折角（２θ±０．２°）にピークを有する４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩のI形結晶である。
（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜ In one embodiment of the present disclosure, the type I crystal of compound (I) is a type I crystal of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride having a peak in a powder X-ray diffraction spectrum (CuKα) at at least one diffraction angle (2θ±0.2°) selected from the group consisting of the following (a) and at least one diffraction angle (2θ±0.2°) selected from the group consisting of the following (b):
(a) 11.3°, 11.4° and 17.2° (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9° and 28.4°
（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜ In one embodiment of the present disclosure, the type I crystal of compound (I) is a type I crystal of 4-
(a) 11.3°, 11.4° and 17.2° (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9° and 28.4°
本開示の好ましい実施態様における化合物（Ｉ）のＩ形結晶は、粉末Ｘ線回折スペクトルにおいて、回折角（２θ±０．２°）が、上記（ａ）の群から少なくとも１つ有し、かつ上記（ｂ）から少なくとも１つ、好ましくは少なくとも２つ、より好ましくは少なくとも３つ、より好ましくは少なくとも４つ、より好ましくは少なくとも５つ、より好ましくは少なくとも６つ、より好ましくは少なくとも７つ、より好ましくは少なくとも８つ、特に好ましくは全てのピークを有する。
In a preferred embodiment of the present disclosure, the type I crystal of compound (I) has, in a powder X-ray diffraction spectrum, at least one diffraction angle (2θ±0.2°) from group (a) above, and at least one, preferably at least two, more preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, and particularly preferably all, from group (b) above.
他の実施態様において、本開示の好ましい実施態様における化合物（Ｉ）のＩ形結晶は、粉末Ｘ線回折スペクトルにおいて、回折角（２θ±０．２°）が、上記（ａ）の群から少なくとも２つ有し、かつ上記（ｂ）から少なくとも１つ、好ましくは少なくとも２つ、より好ましくは少なくとも３つ、より好ましくは少なくとも４つ、より好ましくは少なくとも５つ、より好ましくは少なくとも６つ、より好ましくは少なくとも７つ、より好ましくは少なくとも８つ、特に好ましくは全てのピークを有する。
In another embodiment, the type I crystal of compound (I) in the preferred embodiment of the present disclosure has, in a powder X-ray diffraction spectrum, at least two diffraction angles (2θ±0.2°) from group (a) above, and at least one, preferably at least two, more preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, and particularly preferably all, from group (b) above.
他の実施態様において、本開示の好ましい実施態様における化合物（Ｉ）のＩ形結晶は、粉末Ｘ線回折スペクトルにおいて、回折角（２θ±０．２°）が、上記（ａ）の群から少なくとも３つ有し、かつ上記（ｂ）から少なくとも１つ、好ましくは少なくとも２つ、より好ましくは少なくとも３つ、より好ましくは少なくとも４つ、より好ましくは少なくとも５つ、より好ましくは少なくとも６つ、より好ましくは少なくとも７つ、より好ましくは少なくとも８つ、特に好ましくは全てのピークを有する。
In another embodiment, the type I crystal of compound (I) in the preferred embodiment of the present disclosure has, in a powder X-ray diffraction spectrum, at least three diffraction angles (2θ±0.2°) from group (a) above, and at least one, preferably at least two, more preferably at least three, more preferably at least four, more preferably at least five, more preferably at least six, more preferably at least seven, more preferably at least eight, and particularly preferably all, from group (b) above.
本開示の一実施形態において、化合物（Ｉ）のＩ形結晶の粉末Ｘ線回折スペクトル（ＣｕＫα）における特徴的なピークは、回折角（２θ±０．２°）として、５．７゜、１１．３°、１１．４゜、２０．５゜、２０．７゜及び２３．１゜を有する。
また、化合物（Ｉ）のＩ形結晶は、粉末Ｘ線回折スペクトル（ＣｕＫα）における特徴的なピークとして、回折角（２θ±０．２°）で、１１．３゜、１１．４゜、１２．７゜、１５．９゜、１６．１゜、１７．２゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜、２８．４゜にピークを有することが好ましい。 In one embodiment of the present disclosure, characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the type I crystal of compound (I) have diffraction angles (2θ±0.2°) of 5.7°, 11.3°, 11.4°, 20.5°, 20.7°, and 23.1°.
In addition, the type I crystal of compound (I) preferably has characteristic peaks in a powder X-ray diffraction spectrum (CuKα) at diffraction angles (2θ±0.2°) of 11.3°, 11.4°, 12.7°, 15.9°, 16.1°, 17.2°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4°.
また、化合物（Ｉ）のＩ形結晶は、粉末Ｘ線回折スペクトル（ＣｕＫα）における特徴的なピークとして、回折角（２θ±０．２°）で、１１．３゜、１１．４゜、１２．７゜、１５．９゜、１６．１゜、１７．２゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜、２８．４゜にピークを有することが好ましい。 In one embodiment of the present disclosure, characteristic peaks in the powder X-ray diffraction spectrum (CuKα) of the type I crystal of compound (I) have diffraction angles (2θ±0.2°) of 5.7°, 11.3°, 11.4°, 20.5°, 20.7°, and 23.1°.
In addition, the type I crystal of compound (I) preferably has characteristic peaks in a powder X-ray diffraction spectrum (CuKα) at diffraction angles (2θ±0.2°) of 11.3°, 11.4°, 12.7°, 15.9°, 16.1°, 17.2°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4°.
本開示の一実施形態において、化合物（Ｉ）のＩ形結晶は図１に示される粉末Ｘ線回折スペクトル（ＣｕＫα）を有する。なお、反射法で測定した場合、配向の影響により５．７°のピークが検出されない場合があるが、図１に示される粉末Ｘ線回折スペクトル（ＣｕＫα）のうち、当該ピークが検出されないとしても図１に示される粉末Ｘ線回折スペクトル（ＣｕＫα）を有する結晶と同一であるといえる。また、透過法において、－２°～２°の範囲で入射角度を変えることにより、いずれかの入射角度で当該ピークを検出することが可能である。そのため、反射法で測定した場合に当該ピークが検出されない場合、透過法により、当該ピークの有無を確認することができる。
In one embodiment of the present disclosure, the type I crystal of compound (I) has the powder X-ray diffraction spectrum (CuKα) shown in FIG. 1. When measured by the reflection method, the peak at 5.7° may not be detected due to the influence of orientation, but even if this peak is not detected in the powder X-ray diffraction spectrum (CuKα) shown in FIG. 1, it can be said that the crystal is the same as the crystal having the powder X-ray diffraction spectrum (CuKα) shown in FIG. 1. In addition, by changing the incident angle in the range of -2° to 2° in the transmission method, it is possible to detect the peak at any incident angle. Therefore, if the peak is not detected when measured by the reflection method, the presence or absence of the peak can be confirmed by the transmission method.
ここで、本開示にかかる結晶が有する「ピーク」としては、例えば、粉末Ｘ線回折スペクトル（ＣｕＫα）により得られる強度ピークのうち最大ピークの強度の５％以上、１０％以上、１５％以上、２０％以上、２５％以上、あるいは３０％以上の強度を有するもの等が挙げられる。より好ましくは、得られる強度ピークのうち最大ピークの強度の５％以上であり、より好ましくは得られる強度ピークのうち最大ピークの強度の１０％以上であり、より好ましくは得られる強度ピークのうち最大ピークの強度の１５％以上であり、より好ましくは得られる強度ピークのうち最大ピークの強度の２０％以上であり、さらに好ましくは得られる強度ピークのうち最大ピークの強度の２５％以上であり、特に好ましくは得られる強度ピークのうち最大ピークの強度の３０％以上のピークを有するものを選択する場合である。本開示にかかる結晶は、粉末Ｘ線回折スペクトル（ＣｕＫα）において上記回折角にピークを有するものであればよい。従って、上記に規定する上記回折角にピークを有するものであれば上記回折角以外にもピークを有していても本開示の結晶に包含され得る。
Here, examples of the "peak" possessed by the crystal according to the present disclosure include those having an intensity of 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, or 30% or more of the maximum peak intensity among the intensity peaks obtained by powder X-ray diffraction spectrum (CuKα). More preferably, the peak has an intensity of 5% or more of the maximum peak intensity among the obtained intensity peaks, more preferably, an intensity of 10% or more of the maximum peak intensity among the obtained intensity peaks, more preferably, an intensity of 15% or more of the maximum peak intensity among the obtained intensity peaks, more preferably, an intensity of 20% or more of the maximum peak intensity among the obtained intensity peaks, even more preferably, an intensity of 25% or more of the maximum peak intensity among the obtained intensity peaks, and particularly preferably, an intensity of 30% or more of the maximum peak intensity among the obtained intensity peaks. The crystal according to the present disclosure may have a peak at the above diffraction angle in the powder X-ray diffraction spectrum (CuKα). Therefore, as long as the crystal has a peak at the above diffraction angle specified above, it may be included in the crystal according to the present disclosure even if it has a peak other than the above diffraction angle.
また、化合物（Ｉ）の示差走査熱量曲線における吸熱ピークは１６１℃～１７１℃付近、好ましくは１６４℃～１６８℃付近、より好ましくは１６６℃付近を挙げることができる。
The endothermic peak in the differential scanning calorimetry curve of compound (I) is around 161°C to 171°C, preferably around 164°C to 168°C, and more preferably around 166°C.
化合物（Ｉ）のＩ形結晶は、化合物（Ｉ）の化学純度が９０％以上であり、高速液体クロマトグラフィー（ＨＰＬＣ）で測定することができる。好ましくは、化合物（Ｉ）の化学純度が９５％以上のＩ形結晶であり、より好ましくは９９％以上がＩ形結晶である。特に好ましくは、９９．９％以上がＩ形結晶である。
The type I crystals of compound (I) have a chemical purity of 90% or more of compound (I) and can be measured by high performance liquid chromatography (HPLC). Preferably, the chemical purity of compound (I) is 95% or more of type I crystals, more preferably 99% or more of type I crystals. Particularly preferably, the chemical purity of compound (I) is 99.9% or more of type I crystals.
化合物（Ｉ）のＩ形結晶は、Ｉ形結晶を含むものであればよく、Ｉ形結晶の単一結晶であってもそれ以外の結晶を含む多形混合物であってもよい。好ましくは９０％以上がＩ形結晶であり、より好ましくは９５％以上がＩ形結晶である。
The type I crystal of compound (I) may be any type that contains type I crystal, and may be a single type I crystal or a polymorphic mixture containing other crystals. Preferably, 90% or more of the crystal is type I crystal, and more preferably, 95% or more of the crystal is type I crystal.
本開示に係る化合物（Ｉ）のI形結晶は、例えば溶媒として、酢酸ブチル、メチルエチルケトン又はヘプタンに溶解させた後、析出させる方法により製造することができる。前記溶媒として、好ましくはメチルエチルケトン又はヘプタンであり、特に好ましくはメチルエチルケトンである。なお、これらの溶媒に対して、ごく微量（例えば、５％以下、１％以下、０．１％以下等）の他の溶媒が混ざっていても良い。
The type I crystals of compound (I) according to the present disclosure can be produced, for example, by dissolving in a solvent such as butyl acetate, methyl ethyl ketone, or heptane, followed by precipitation. The solvent is preferably methyl ethyl ketone or heptane, and particularly preferably methyl ethyl ketone. These solvents may contain very small amounts (e.g., 5% or less, 1% or less, 0.1% or less, etc.) of other solvents.
化合物（Ｉ）のＩ形結晶を製造するために用いるメチルエチルケトンの量は、５～２０倍量であり、より好ましくは１０～１５倍量である。
本開示の一実施形態において、化合物（Ｉ）のＩ形結晶を製造するために用いるメチルエチルケトンの量は、５倍量以上であり、より好ましくは１０倍量以上であり、より好ましくは１５倍量以上である。 The amount of methyl ethyl ketone used to produce the type I crystals of compound (I) is 5 to 20 times, more preferably 10 to 15 times.
In one embodiment of the present disclosure, the amount of methyl ethyl ketone used to produce type I crystals of compound (I) is 5 times or more, more preferably 10 times or more, and more preferably 15 times or more.
本開示の一実施形態において、化合物（Ｉ）のＩ形結晶を製造するために用いるメチルエチルケトンの量は、５倍量以上であり、より好ましくは１０倍量以上であり、より好ましくは１５倍量以上である。 The amount of methyl ethyl ketone used to produce the type I crystals of compound (I) is 5 to 20 times, more preferably 10 to 15 times.
In one embodiment of the present disclosure, the amount of methyl ethyl ketone used to produce type I crystals of compound (I) is 5 times or more, more preferably 10 times or more, and more preferably 15 times or more.
I形結晶の晶析を促すため、種晶として適当量の化合物（Ｉ）のI形結晶を加えても加えなくてもよい。
In order to promote the crystallization of type I crystals, an appropriate amount of type I crystals of compound (I) may or may not be added as seed crystals.
I形結晶を製造する際の溶媒として酢酸ブチルを使用する場合は、種晶として適当量の化合物（Ｉ）のI形結晶を加える。
When butyl acetate is used as a solvent in producing type I crystals, an appropriate amount of type I crystals of compound (I) is added as seed crystals.
析出した結晶は、例えば、ろ過、水による洗浄、減圧乾燥等の公知の分離精製手段によって、前記結晶を含む懸濁液から単離精製することができる。
The precipitated crystals can be isolated and purified from the suspension containing the crystals by known separation and purification means, such as filtration, washing with water, and drying under reduced pressure.
化合物（Ｉ）のＩＩ形結晶は、例えば、図３に示される粉末Ｘ線回折スペクトル（ＣｕＫα）を有し、また、図４に示される示差走査熱量（ＤＳＣ）曲線を有する。
The type II crystal of compound (I) has, for example, the powder X-ray diffraction spectrum (CuKα) shown in Figure 3, and the differential scanning calorimetry (DSC) curve shown in Figure 4.
また、化合物（Ｉ）のＩＩ形結晶の示差走査熱量曲線における吸熱ピークは１６３℃～１６７℃付近、好ましくは１６５℃付近を挙げることができる。
The endothermic peak in the differential scanning calorimetry curve of the type II crystal of compound (I) is around 163°C to 167°C, preferably around 165°C.
本開示に係る化合物（Ｉ）のII形結晶は、例えば溶媒として、酢酸ブチルやキシレンに溶解させた後、析出させる方法により製造することができる。前記溶媒として、特に好ましくはキシレンである．
The type II crystal of compound (I) according to the present disclosure can be produced, for example, by dissolving the compound in a solvent such as butyl acetate or xylene, followed by precipitation. Xylene is particularly preferred as the solvent.
また、上記のようにして得られたＩＩ形結晶は、化合物（Ｉ）の化学純度が９０％以上であり、高速液体クロマトグラフィー（ＨＰＬＣ）で測定することができる。好ましくは、化合物（Ｉ）の化学純度が９５％以上のＩＩ形結晶であり、より好ましくは９９％以上がＩＩ形結晶である。
Furthermore, the type II crystal obtained as described above has a chemical purity of compound (I) of 90% or more, which can be measured by high performance liquid chromatography (HPLC). Preferably, the type II crystal has a chemical purity of compound (I) of 95% or more, more preferably 99% or more.
化合物（Ｉ）のＩＩ形結晶は、ＩＩ形結晶を含むものであればよく、ＩＩ形結晶の単一結晶であってもそれ以外の結晶を含む多形混合物であってもよい。好ましくは９０％以上がＩＩ形結晶であり、より好ましくは９５％以上がＩＩ形結晶である。
The type II crystal of compound (I) may be any type containing type II crystal, and may be a single type II crystal or a polymorphic mixture containing other crystals. Preferably, 90% or more of the type II crystal is a type II crystal, and more preferably, 95% or more of the type II crystal is a type II crystal.
後記実施例に示すとおり、本開示に係る化合物（Ｉ）のＩ形結晶は、低い吸湿性で優れた固体安定性（保存安定性等）を有する。医薬品の原薬や医薬品中の有効成分が固体安定性を備えることは、工業上の操作においても、品質を保つ上でも重要である。
As shown in the Examples below, the type I crystals of compound (I) according to the present disclosure have low hygroscopicity and excellent solid-state stability (storage stability, etc.). It is important for pharmaceutical raw materials and active ingredients in pharmaceuticals to have solid-state stability both in industrial operations and in maintaining quality.
また、医薬品の製造に用いられる溶媒は毒性を有していることがあり、安全性の観点から、製造工程で残留してしまう溶媒はできるだけ少ないことが望ましいところ、化合物（Ｉ）のＩ形結晶は、残留溶媒をＩＣＨ（日米ＥＵ医薬品規制調和国際会議）ガイドラインの規制値以上含まない。
In addition, solvents used in the manufacture of pharmaceuticals can be toxic, and from a safety standpoint, it is desirable for as little solvent to remain in the manufacturing process as possible. Form I crystals of compound (I) do not contain residual solvents in amounts greater than the limit stipulated by the ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines.
本開示に係る化合物（Ｉ）のＩ形結晶は、尿道内圧の上昇により改善が見込まれる疾患の治療又は予防に有用である。例えば本開示に係る化合物（Ｉ）のＩ形結晶を含有する薬剤で治療、予防又は改善される疾患としては、腹圧性尿失禁、切迫性尿失禁、混合性尿失禁、前立腺全摘手術後の尿失禁が挙げられる。さらに神経因性膀胱、神経性膀胱、不安定膀胱，膀胱刺激状態（慢性膀胱炎、慢性前立腺炎）等における頻尿・尿失禁や、過活動膀胱における尿意切迫感、頻尿及び心血管疾患、過敏性腸症候群、更年期障害にも有用である。本開示に係る化合物（Ｉ）のＩ形結晶を含有する薬剤で治療、予防又は改善される疾患として好ましくは腹圧性尿失禁である。
The I-type crystal of compound (I) according to the present disclosure is useful for treating or preventing diseases that are expected to improve by increasing intraurethral pressure. For example, diseases that can be treated, prevented, or improved with a drug containing the I-type crystal of compound (I) according to the present disclosure include stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, and urinary incontinence after radical prostatectomy. It is also useful for frequent urination and incontinence in neurogenic bladder, neurogenic bladder, unstable bladder, bladder irritation state (chronic cystitis, chronic prostatitis), etc., urgency and frequent urination in overactive bladder, and cardiovascular disease, irritable bowel syndrome, and menopausal disorders. A preferred disease that can be treated, prevented, or improved with a drug containing the I-type crystal of compound (I) according to the present disclosure is stress urinary incontinence.
化合物（Ｉ）のＩ形結晶を医薬として用いるにあたっては、当該結晶を粉砕するか又は粉砕することなく、予防又は治療目的に応じて各種の投与形態を採用可能であり、該形態としては、例えば、錠剤、カプセル剤、顆粒剤、細粒剤、散剤、ドライシロップ剤等の経口剤；及び坐剤、吸入剤、点鼻剤、軟膏剤、貼付剤、注射剤等の非経口剤のいずれでもよく、経口剤に利用することが好ましい。これらの医薬組成物は、薬学的に許容される担体を用いて、当業者に公知慣用の製剤方法により製造できる。
When using the type I crystal of compound (I) as a medicine, various administration forms can be adopted depending on the preventive or therapeutic purpose, with or without crushing the crystal. The forms may be, for example, oral preparations such as tablets, capsules, granules, fine granules, powders, dry syrups, etc.; and parenteral preparations such as suppositories, inhalants, nasal drops, ointments, patches, injections, etc., and it is preferable to use it as an oral preparation. These pharmaceutical compositions can be manufactured by a formulation method known and commonly used by those skilled in the art using a pharma-
ceutical acceptable carrier.
薬学的担体としては、製剤素材として慣用の各種有機或いは無機担体物質が用いられ、固形製剤における賦形剤、結合剤、崩壊剤、滑沢剤、コーティング剤、液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等として配合される。また、必要に応じて防腐剤、抗酸化剤、着色剤、甘味剤、安定化剤等の製剤添加物を用いることもできる。
As pharmaceutical carriers, various organic or inorganic carrier substances commonly used as formulation materials are used, and are compounded as excipients, binders, disintegrants, lubricants, coating agents in solid preparations, and solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations. In addition, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers, etc. can also be used as necessary.
賦形剤としては、乳糖、白糖、Ｄ－マンニトール、デンプン、結晶セルロース、ケイ酸カルシウム等が挙げられる。
Excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, calcium silicate, etc.
結合剤としては、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルピロリドン、アメ粉、ヒプロメロース等が挙げられる。
Binders include hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, candy powder, hypromellose, etc.
崩壊剤としては、デンプングリコール酸ナトリウム、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドン、低置換度ヒドロキシプロピルセルロース、部分アルファー化デンプン等が挙げられる。
Disintegrants include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, etc.
滑沢剤としては、タルク、ステアリン酸マグネシウム、ショ糖脂肪酸エステル、ステアリン酸、フマル酸ステアリルナトリウム等が挙げられる。
Lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearic acid, sodium stearyl fumarate, etc.
コーティング剤としては、エチルセルロース、アミノアルキルメタクリレートコポリマーＲＳ、ヒプロメロース、白糖等が挙げられる。
Coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, white sugar, etc.
溶剤としては、水、プロピレングリコール、生理食塩液が挙げられる。
Solvents include water, propylene glycol, and saline.
溶解補助剤としては、ポリエチレングリコール、エタノール、α－シクロデキストリン、マクロゴール４００、ポリソルベート８０等が挙げられる。
Solubilizing agents include polyethylene glycol, ethanol, α-cyclodextrin, macrogol 400, polysorbate 80, etc.
懸濁化剤としては、カラギーナン、結晶セルロース・カルメロースナトリウム、ポリオキシエチレン硬化ヒマシ油が挙げられる。
Suspending agents include carrageenan, crystalline cellulose/carmellose sodium, and polyoxyethylene hydrogenated castor oil.
等張化剤としては、塩化ナトリウム、グリセリン、塩化カリウム等が挙げられる。
Isotonicity agents include sodium chloride, glycerin, potassium chloride, etc.
ｐＨ調節剤・緩衝剤としては、クエン酸ナトリウム、塩酸、乳酸、リン酸、リン酸二水素ナトリウム等が挙げられる。
pH adjusters and buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate, etc.
無痛化剤としては、プロカイン塩酸塩、リドカイン等が挙げられる。
Anti-pain agents include procaine hydrochloride and lidocaine.
防腐剤としては、パラオキシ安息香酸エチル、クレゾール、ベンザルコニウム塩化物等が挙げられる。
Preservatives include ethyl paraoxybenzoate, cresol, and benzalkonium chloride.
抗酸化剤としては、亜硫酸ナトリウム、アスコルビン酸、天然ビタミンＥ等が挙げられる。
Antioxidants include sodium sulfite, ascorbic acid, and natural vitamin E.
着色剤としては、酸化チタン、三二酸化鉄、食用青色１号、銅クロロフィル等が挙げられる。
Coloring agents include titanium oxide, ferric oxide, food blue No. 1, copper chlorophyll, etc.
矯味・矯臭剤としてはアスパルテーム、サッカリン、スクラロース、ｌ－メントール、ミントフレーバー等が挙げられる。
Flavoring agents include aspartame, saccharin, sucralose, l-menthol, mint flavor, etc.
安定化剤としては、ピロ亜硫酸ナトリウム、エデト酸ナトリウム、エリソルビン酸、酸化マグネシウム、ジブチルヒドロキシトルエン等が挙げられる。
Stabilizers include sodium pyrosulfite, sodium edetate, erythorbic acid, magnesium oxide, and dibutylhydroxytoluene.
経口用固形製剤を調製する場合は、化合物（Ｉ）に賦形剤、必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味・矯臭剤等を加えた後、常法により錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤等を製造することができる。
When preparing oral solid preparations, excipients, and if necessary binders, disintegrants, lubricants, colorants, flavorings, odorants, etc., are added to compound (I), and tablets, coated tablets, granules, powders, capsules, etc. can be manufactured by conventional methods.
各投与単位形態中に配合されるべき化合物（Ｉ）は、これを適用すべき患者の症状により、或いはその剤形等により一定ではないが、一般に投与単位形態あたり、経口剤では４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテートとして約０．０５～１０００ｍｇ、注射剤では約０．１～５００ｍｇ、坐剤又は外用剤では約１～１０００ｍｇとするのが望ましい。
The amount of compound (I) to be incorporated into each dosage unit varies depending on the symptoms of the patient to whom it is to be administered or on the dosage form, but in general, it is desirable to incorporate about 0.05 to 1000 mg of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate per dosage unit for oral preparations, about 0.1 to 500 mg for injections, and about 1 to 1000 mg for suppositories or external preparations.
また、各投与形態を有する薬剤の化合物（Ｉ）のＩ形結晶の１日あたりの投与量は、患者の症状、体重、年齢、性別等によって異なり一概には決定できないが、通常、１日あたり例えば、４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテートとして約３ｍｇ、約６ｍｇ、約９ｍｇ、約１８ｍｇで治療することができる。
本開示の一態様において、４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテートとしての一日あたりの投与量は約１８ｍｇである。 In addition, the daily dose of the type I crystal of compound (I) for each dosage form varies depending on the symptoms, body weight, age, sex, etc. of the patient and cannot be determined in general, but usually, for example, about 3 mg, about 6 mg, about 9 mg, or about 18 mg of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate can be administered per day for treatment.
In one embodiment of the present disclosure, the daily dosage is about 18 mg of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate.
本開示の一態様において、４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテートとしての一日あたりの投与量は約１８ｍｇである。 In addition, the daily dose of the type I crystal of compound (I) for each dosage form varies depending on the symptoms, body weight, age, sex, etc. of the patient and cannot be determined in general, but usually, for example, about 3 mg, about 6 mg, about 9 mg, or about 18 mg of 4-
In one embodiment of the present disclosure, the daily dosage is about 18 mg of 4-
化合物（Ｉ）のＩ形結晶投与は、薬物動態及び特定の被験者の薬剤のクリアランス／蓄積に応じて、例えば連続的（１週間で７日間投与）又は断続的とすることができる。断続的に投与する場合、例えば、１週間に４日投与して３日休む（休薬する）スケジュールでもよいし、健全な医学的判断を用いて適切と考えられる他の断続的投与スケジュールであってもよいが、連続投与が好ましい。投与は、１日１回（ＱＤ）又は１日２回以上（ｂ．ｉ．ｄ．，ｔ．ｉ．ｄ．など）行うことができ、約３～１８ｍｇ／日ＱＤの用量が好ましい。日用量は、単回投与でもよいし、複数の個別分割投与でもよい。
Administration of Form I crystals of Compound (I) can be, for example, continuous (7 days per week) or intermittent, depending on the pharmacokinetics and clearance/accumulation of the drug in a particular subject. When administered intermittently, it may be, for example, a 4 day on, 3 day off schedule per week (drug holiday) or other intermittent dosing schedule deemed appropriate using sound medical judgment, although continuous administration is preferred. Administration can be once per day (QD) or two or more times per day (b.i.d., t.i.d., etc.), with a dosage of about 3-18 mg/day QD being preferred. The daily dosage may be a single dose or multiple individual divided doses.
化合物（Ｉ）のＩ形結晶の投与スケジュールの一態様として、７日間の連続投与を１サイクルとして、４サイクル、８サイクル、又は１２サイクル実施することが好ましい。投与スケジュールの一態様として、好ましいサイクル数としては、１２サイクルである。
As an embodiment of the administration schedule for the type I crystal of compound (I), it is preferable to administer 4, 8, or 12 cycles, with 7 days of continuous administration as one cycle. As an embodiment of the administration schedule, the preferred number of cycles is 12 cycles.
一般的には、多くの結晶粒子の形態は試料ホルダー中で試料に選択配向性を与える傾向がある。試料中の選択配向は種々の反射強度に影響を与え、その結果、完全な無配向な試料で予測される反射に比べ、ある場合には強く、ある場合には弱く観察される。
Generally, the morphology of many crystalline grains tends to give the sample a preferred orientation in the sample holder. The preferred orientation in the sample affects the intensity of various reflections, which are sometimes observed to be stronger and sometimes weaker than would be expected for a completely unoriented sample.
以下、実施例を挙げて本開示を更に具体的に説明するが、本開示発明はこれらによって何ら限定されるものではない。本開示は実施例により十分に説明されているが、当業者により種々の変更及び／又は修飾が可能であろうことは理解される。したがって、そのような変更及び／又は修飾が本開示の範囲を逸脱するものでない限り、それらは本開示に包含される。
The present disclosure will be explained in more detail below with reference to examples, but the present disclosure is not limited to these in any way. Although the present disclosure has been fully explained with reference to examples, it will be understood that various changes and/or modifications may be made by those skilled in the art. Therefore, as long as such changes and/or modifications do not deviate from the scope of the present disclosure, they are included in the present disclosure.
＜試薬及び測定法＞
実施例で用いた各種試薬は、特に記載の無い限り市販品を使用した。ＮＭＲスペクトルは、ＡＬ４００（４００ＭＨｚ；日本電子（ＪＥＯＬ））を使用し、重溶媒中にテトラメチルシランを含む場合は内部基準としてテトラメチルシランを用い、それ以外の場合には内部基準として、ＮＭＲ溶媒に残存する非重水素化プロトンピークを用いて測定し、全δ値をｐｐｍで示した。 <Reagents and Measurement Method>
Unless otherwise specified, the various reagents used in the examples were commercially available products. NMR spectra were measured using an AL400 (400 MHz; JEOL) with tetramethylsilane as the internal standard when the deuterated solvent contained tetramethylsilane, and with the non-deuterated proton peak remaining in the NMR solvent as the internal standard otherwise, and the total δ value was expressed in ppm.
実施例で用いた各種試薬は、特に記載の無い限り市販品を使用した。ＮＭＲスペクトルは、ＡＬ４００（４００ＭＨｚ；日本電子（ＪＥＯＬ））を使用し、重溶媒中にテトラメチルシランを含む場合は内部基準としてテトラメチルシランを用い、それ以外の場合には内部基準として、ＮＭＲ溶媒に残存する非重水素化プロトンピークを用いて測定し、全δ値をｐｐｍで示した。 <Reagents and Measurement Method>
Unless otherwise specified, the various reagents used in the examples were commercially available products. NMR spectra were measured using an AL400 (400 MHz; JEOL) with tetramethylsilane as the internal standard when the deuterated solvent contained tetramethylsilane, and with the non-deuterated proton peak remaining in the NMR solvent as the internal standard otherwise, and the total δ value was expressed in ppm.
略号の意味を以下に示す。
ｓ：シングレット
ｄ：ダブレット
ｔ：トリプレット
ｄｄ：ダブル ダブレット
ｍ：マルチプレット
ｂｒｓ：ブロードシングレット
ＤＭＳＯ－ｄ6：重ジメチルスルホキシド
ＣＤＣｌ3：重クロロホルム The meanings of the abbreviations are as follows:
s: singlet d: doublet t: triplet dd: double doublet m: multiplet brs: broad singlet DMSO-d 6 : deuterated dimethylsulfoxide CDCl 3 : deuterated chloroform
ｓ：シングレット
ｄ：ダブレット
ｔ：トリプレット
ｄｄ：ダブル ダブレット
ｍ：マルチプレット
ｂｒｓ：ブロードシングレット
ＤＭＳＯ－ｄ6：重ジメチルスルホキシド
ＣＤＣｌ3：重クロロホルム The meanings of the abbreviations are as follows:
s: singlet d: doublet t: triplet dd: double doublet m: multiplet brs: broad singlet DMSO-d 6 : deuterated dimethylsulfoxide CDCl 3 : deuterated chloroform
粉末Ｘ線回折測定
粉末Ｘ線回折は、試験物質適量を必要に応じてメノウ製乳鉢で軽く粉砕した後、次のいずれかの試験条件に従って測定した。 Powder X-ray Diffraction Measurement Powder X-ray diffraction was measured according to any of the following test conditions after lightly grinding an appropriate amount of the test substance in an agate mortar as necessary.
粉末Ｘ線回折は、試験物質適量を必要に応じてメノウ製乳鉢で軽く粉砕した後、次のいずれかの試験条件に従って測定した。 Powder X-ray Diffraction Measurement Powder X-ray diffraction was measured according to any of the following test conditions after lightly grinding an appropriate amount of the test substance in an agate mortar as necessary.
装置：パナリティカル Ａｅｒｉｓ
ターゲット：Ｃｕ
Ｘ線出力設定：１５ｍＡ，４０ｋＶ
走査範囲：５．０～４０．０°
ステップサイズ：０．０２２０°
スキャンステップ時間：１８．８７ｓ
発散スリットサイズ：０．４５８４°
測定方法：反射法 Equipment: PANalytical Aeris
Target: Cu
X-ray output settings: 15mA, 40kV
Scanning range: 5.0 to 40.0°
Step size: 0.0220°
Scan step time: 18.87 s
Divergence slit size: 0.4584°
Measurement method: Reflection method
ターゲット：Ｃｕ
Ｘ線出力設定：１５ｍＡ，４０ｋＶ
走査範囲：５．０～４０．０°
ステップサイズ：０．０２２０°
スキャンステップ時間：１８．８７ｓ
発散スリットサイズ：０．４５８４°
測定方法：反射法 Equipment: PANalytical Aeris
Target: Cu
X-ray output settings: 15mA, 40kV
Scanning range: 5.0 to 40.0°
Step size: 0.0220°
Scan step time: 18.87 s
Divergence slit size: 0.4584°
Measurement method: Reflection method
装置：リガク Ｕｌｔｉｍａ＋
ターゲット：Ｃｕ
Ｘ線出力設定：４０ｍＡ，４０ｋＶ
走査範囲：６．０～４０．０°
ステップサイズ：０．０１０°
スキャンスピード：５．００°／ｍｉｎ.
発散スリット：１／２°
散乱スリット：３．００ｍｍ
測定方法：反射法 Equipment: Rigaku Ultima+
Target: Cu
X-ray output settings: 40mA, 40kV
Scanning range: 6.0 to 40.0°
Step size: 0.010°
Scan speed: 5.00°/min.
Divergence slit: 1/2°
Scattering slit: 3.00 mm
Measurement method: Reflection method
ターゲット：Ｃｕ
Ｘ線出力設定：４０ｍＡ，４０ｋＶ
走査範囲：６．０～４０．０°
ステップサイズ：０．０１０°
スキャンスピード：５．００°／ｍｉｎ.
発散スリット：１／２°
散乱スリット：３．００ｍｍ
測定方法：反射法 Equipment: Rigaku Ultima+
Target: Cu
X-ray output settings: 40mA, 40kV
Scanning range: 6.0 to 40.0°
Step size: 0.010°
Scan speed: 5.00°/min.
Divergence slit: 1/2°
Scattering slit: 3.00 mm
Measurement method: Reflection method
データ処理を含む装置の取り扱いは、各装置で指示された方法及び手順にしたがった。
The handling of equipment, including data processing, was in accordance with the methods and procedures specified for each piece of equipment.
なお、各種スペクトルから得られる数値は、その結晶成長の方向、粒子の大きさ、測定条件等によって多少変動する場合がある。したがって、それらの数値は厳密に解されるべきではない。
The values obtained from various spectra may vary slightly depending on the crystal growth direction, particle size, measurement conditions, etc. Therefore, these values should not be interpreted strictly.
示差走査熱量曲線（ＤＳＣ測定）
ＤＳＣ測定は、次の試験条件に従って測定した。 Differential scanning calorimetry curve (DSC measurement)
The DSC measurement was performed under the following test conditions.
ＤＳＣ測定は、次の試験条件に従って測定した。 Differential scanning calorimetry curve (DSC measurement)
The DSC measurement was performed under the following test conditions.
装置：ＴＡインスツルメント Ｑ１０００
試料：およそ５ｍｇ
試料容器：アルミニウム製
昇温速度：３００℃まで１０℃／分で昇温
雰囲気ガス：空気
窒素ガス流量：１００ｍＬ／分
データ処理を含む装置の取り扱いは、各装置で指示された方法及び手順にしたがった。 Equipment: TA Instruments Q1000
Sample: Approximately 5 mg
Sample container: made of aluminum Heating rate: heating up to 300° C. at 10° C./min. Atmospheric gas: air Nitrogen gas flow rate: 100 mL/min. The handling of the apparatus including data processing was performed according to the method and procedure specified for each apparatus.
試料：およそ５ｍｇ
試料容器：アルミニウム製
昇温速度：３００℃まで１０℃／分で昇温
雰囲気ガス：空気
窒素ガス流量：１００ｍＬ／分
データ処理を含む装置の取り扱いは、各装置で指示された方法及び手順にしたがった。 Equipment: TA Instruments Q1000
Sample: Approximately 5 mg
Sample container: made of aluminum Heating rate: heating up to 300° C. at 10° C./min. Atmospheric gas: air Nitrogen gas flow rate: 100 mL/min. The handling of the apparatus including data processing was performed according to the method and procedure specified for each apparatus.
実施例１ 化合物（Ｉ）のＩ形結晶の製造
特許文献１に開示されている公知の手法で合成した化合物（Ｉ）の粗体（５００ｍｇ）にメチルエチルケトン（５．５ｍＬ）を加え、外温８５℃以上に加熱し溶解させた。その後、冷却晶析させ、室温下で攪拌した後、ろ取し得られた結晶を減圧加熱乾燥を行い、化合物（１）のＩ形結晶を得た。収量；４５９ｍｇ、収率；９１．８％。粉末Ｘ線回折スペクトル（ＣｕＫα）を図１に示す。また、示差走査熱量（ＤＳＣ）曲線を図２に示すとおり、吸熱ピークは１６６．１℃であった。
１Ｈ－ＮＭＲ （ＤＭＳＯ－ｄ６）：δppm １．６２－１．７１ (２Ｈ，ｍ)， １．９０－１．９９ (２Ｈ，ｍ)， ２．７８－２．８５ (２Ｈ，ｍ)， ２．９５－３．０４ (２Ｈ，ｍ)， ５．０１－５．０８ (１Ｈ，ｍ) ，７．３０－７．４０ (１０Ｈ，ｍ)， ８．９９ (１Ｈ，ｂｒｓ)
特徴的な回折角は以下の通りである。
特徴的な回折角（２θ±０．２°）：５．７゜、１１．３゜、１１．４゜、１２．７゜、１５．９゜、１６．１゜、１７．２゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜、２８．４゜。また、各ピーク及び強度は下表の通りであった。 Example 1: Preparation of I-type crystals of compound (I) Methyl ethyl ketone (5.5 mL) was added to the crude compound (I) (500 mg) synthesized by the known method disclosed in Patent Document 1, and the mixture was heated to an external temperature of 85° C. or higher to dissolve. The mixture was then cooled and crystallized, stirred at room temperature, and the crystals obtained by filtration were dried under reduced pressure to obtain I-type crystals of compound (1). Yield: 459 mg, yield: 91.8%. The powder X-ray diffraction spectrum (CuKα) is shown in FIG. 1. In addition, as shown in FIG. 2, the differential scanning calorimetry (DSC) curve showed an endothermic peak of 166.1° C.
1H-NMR (DMSO-d6): δppm 1.62-1.71 (2H,m), 1.90-1.99 (2H,m), 2.78-2.85 (2H,m), 2.95-3.04 (2H,m), 5.01-5.08 (1H,m), 7.30-7.40 (10H,m), 8.99 (1H,brs)
The characteristic diffraction angles are as follows:
Characteristic diffraction angles (2θ±0.2°): 5.7°, 11.3°, 11.4°, 12.7°, 15.9°, 16.1°, 17.2°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, 28.4°. The peaks and intensities are as shown in the table below.
特許文献１に開示されている公知の手法で合成した化合物（Ｉ）の粗体（５００ｍｇ）にメチルエチルケトン（５．５ｍＬ）を加え、外温８５℃以上に加熱し溶解させた。その後、冷却晶析させ、室温下で攪拌した後、ろ取し得られた結晶を減圧加熱乾燥を行い、化合物（１）のＩ形結晶を得た。収量；４５９ｍｇ、収率；９１．８％。粉末Ｘ線回折スペクトル（ＣｕＫα）を図１に示す。また、示差走査熱量（ＤＳＣ）曲線を図２に示すとおり、吸熱ピークは１６６．１℃であった。
１Ｈ－ＮＭＲ （ＤＭＳＯ－ｄ６）：δppm １．６２－１．７１ (２Ｈ，ｍ)， １．９０－１．９９ (２Ｈ，ｍ)， ２．７８－２．８５ (２Ｈ，ｍ)， ２．９５－３．０４ (２Ｈ，ｍ)， ５．０１－５．０８ (１Ｈ，ｍ) ，７．３０－７．４０ (１０Ｈ，ｍ)， ８．９９ (１Ｈ，ｂｒｓ)
特徴的な回折角は以下の通りである。
特徴的な回折角（２θ±０．２°）：５．７゜、１１．３゜、１１．４゜、１２．７゜、１５．９゜、１６．１゜、１７．２゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜、２８．４゜。また、各ピーク及び強度は下表の通りであった。 Example 1: Preparation of I-type crystals of compound (I) Methyl ethyl ketone (5.5 mL) was added to the crude compound (I) (500 mg) synthesized by the known method disclosed in Patent Document 1, and the mixture was heated to an external temperature of 85° C. or higher to dissolve. The mixture was then cooled and crystallized, stirred at room temperature, and the crystals obtained by filtration were dried under reduced pressure to obtain I-type crystals of compound (1). Yield: 459 mg, yield: 91.8%. The powder X-ray diffraction spectrum (CuKα) is shown in FIG. 1. In addition, as shown in FIG. 2, the differential scanning calorimetry (DSC) curve showed an endothermic peak of 166.1° C.
1H-NMR (DMSO-d6): δppm 1.62-1.71 (2H,m), 1.90-1.99 (2H,m), 2.78-2.85 (2H,m), 2.95-3.04 (2H,m), 5.01-5.08 (1H,m), 7.30-7.40 (10H,m), 8.99 (1H,brs)
The characteristic diffraction angles are as follows:
Characteristic diffraction angles (2θ±0.2°): 5.7°, 11.3°, 11.4°, 12.7°, 15.9°, 16.1°, 17.2°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, 28.4°. The peaks and intensities are as shown in the table below.
実施例２ 化合物（Ｉ）のＩ形結晶の製造
特許文献１に開示されている公知の手法で合成した化合物（１）の粗体（１００ｍｇ）にヘプタン（１．０ｍＬ）を加え、外温１２０℃以上に加熱し、懸濁攪拌させた。その後、冷却させ、室温下で攪拌した後、ろ取し得られた結晶を減圧加熱乾燥を行い、化合物（１）のＩ形結晶を得た。収量；７８ｍｇ、収率；７８．０％。 Example 2: Preparation of I-type crystals of compound (I) Heptane (1.0 mL) was added to the crude compound (1) (100 mg) synthesized by the known method disclosed in Patent Document 1, and the mixture was heated to an external temperature of 120° C. or higher and stirred in suspension. The mixture was then cooled and stirred at room temperature, after which the crystals obtained by filtration were dried under reduced pressure and heat to obtain I-type crystals of compound (1). Yield: 78 mg, yield: 78.0%.
特許文献１に開示されている公知の手法で合成した化合物（１）の粗体（１００ｍｇ）にヘプタン（１．０ｍＬ）を加え、外温１２０℃以上に加熱し、懸濁攪拌させた。その後、冷却させ、室温下で攪拌した後、ろ取し得られた結晶を減圧加熱乾燥を行い、化合物（１）のＩ形結晶を得た。収量；７８ｍｇ、収率；７８．０％。 Example 2: Preparation of I-type crystals of compound (I) Heptane (1.0 mL) was added to the crude compound (1) (100 mg) synthesized by the known method disclosed in Patent Document 1, and the mixture was heated to an external temperature of 120° C. or higher and stirred in suspension. The mixture was then cooled and stirred at room temperature, after which the crystals obtained by filtration were dried under reduced pressure and heat to obtain I-type crystals of compound (1). Yield: 78 mg, yield: 78.0%.
実施例３ 化合物（Ｉ）のＩ形結晶の製造
特許文献１に開示されている公知の手法で合成した化合物（１）の粗体（２５０ｍｇ）に酢酸ブチル（３．５ｍＬ）を加え、外温１３０℃以上に加熱し溶解させた。その後、冷却し、化合物（Ｉ）のＩ形結晶を少量加え、外温３５℃晶析させた後、ろ取し得られた結晶を減圧加熱乾燥を行い、化合物（１）のＩ形結晶を得た。収量；２３０ｍｇ、収率；９２．０％。 Example 3: Preparation of I-type crystals of compound (I) Butyl acetate (3.5 mL) was added to the crude compound (1) (250 mg) synthesized by the known method disclosed in Patent Document 1, and dissolved by heating to an external temperature of 130° C. or higher. After cooling, a small amount of I-type crystals of compound (I) was added, and crystallization was performed at an external temperature of 35° C., and the crystals obtained by filtration were dried under reduced pressure and heat to obtain I-type crystals of compound (1). Yield: 230 mg, yield: 92.0%.
特許文献１に開示されている公知の手法で合成した化合物（１）の粗体（２５０ｍｇ）に酢酸ブチル（３．５ｍＬ）を加え、外温１３０℃以上に加熱し溶解させた。その後、冷却し、化合物（Ｉ）のＩ形結晶を少量加え、外温３５℃晶析させた後、ろ取し得られた結晶を減圧加熱乾燥を行い、化合物（１）のＩ形結晶を得た。収量；２３０ｍｇ、収率；９２．０％。 Example 3: Preparation of I-type crystals of compound (I) Butyl acetate (3.5 mL) was added to the crude compound (1) (250 mg) synthesized by the known method disclosed in Patent Document 1, and dissolved by heating to an external temperature of 130° C. or higher. After cooling, a small amount of I-type crystals of compound (I) was added, and crystallization was performed at an external temperature of 35° C., and the crystals obtained by filtration were dried under reduced pressure and heat to obtain I-type crystals of compound (1). Yield: 230 mg, yield: 92.0%.
比較例１ 化合物（Ｉ）のＩＩ形結晶の製造
特許文献１に開示されている公知の手法で合成した化合物（Ｉ）の粗体（１００ｍｇ）に酢酸ブチル（１ｍＬ）を加え、外温１４０℃以上に加熱し溶解させた。その後、冷却晶析させ、室温下で攪拌した後、ろ取し得られた結晶を減圧加熱乾燥を行い、化合物（Ｉ）のＩＩ形結晶を得た。収量；９５．５ｍｇ、収率；９５．５％。粉末Ｘ線回折スペクトル（ＣｕＫα）を図３に示す。また、示差走査熱量（ＤＳＣ）曲線を図４に示すとおり、吸熱ピークは１６４．９℃であった。図３にから分かるように、ＩＩ形結晶は、粉末Ｘ線回折スペクトル（ＣｕＫα）において、回折角（２θ±０．２°）として、１１．３゜、１１．４゜、及び１７．２゜のピークを有さない。
１Ｈ－ＮＭＲ （ＤＭＳＯ－ｄ６）：δppm １．６２－１．７１ (２Ｈ，ｍ)， １．９０－１．９８ (２Ｈ，ｍ)， ２．７８－２．８５ (２Ｈ，ｍ)， ２．９５－３．０４ (２Ｈ，ｍ)， ５．０１－５．０８ (１Ｈ，ｍ) ，７．３０－７．４０ (１０Ｈ，ｍ)， ８．７２ (１Ｈ，ｂｒｓ) Comparative Example 1 Preparation of Form II Crystal of Compound (I) Butyl acetate (1 mL) was added to the crude compound (I) (100 mg) synthesized by the known method disclosed in Patent Document 1, and the mixture was heated to an external temperature of 140 ° C. or higher to dissolve. Thereafter, the mixture was cooled and crystallized, stirred at room temperature, and the crystals obtained by filtration were dried under reduced pressure to obtain Form II crystal of Compound (I). Yield: 95.5 mg, yield: 95.5%. Powder X-ray diffraction spectrum (CuKα) is shown in FIG. 3. In addition, as shown in FIG. 4, the differential scanning calorimetry (DSC) curve, the endothermic peak was 164.9 ° C. As can be seen from FIG. 3, the Form II crystal does not have peaks at 11.3 °, 11.4 °, and 17.2 ° as diffraction angles (2θ ± 0.2 °) in the powder X-ray diffraction spectrum (CuKα).
1H-NMR (DMSO-d6): δppm 1.62-1.71 (2H,m), 1.90-1.98 (2H,m), 2.78-2.85 (2H,m), 2.95-3.04 (2H,m), 5.01-5.08 (1H,m), 7.30-7.40 (10H,m), 8.72 (1H,brs)
特許文献１に開示されている公知の手法で合成した化合物（Ｉ）の粗体（１００ｍｇ）に酢酸ブチル（１ｍＬ）を加え、外温１４０℃以上に加熱し溶解させた。その後、冷却晶析させ、室温下で攪拌した後、ろ取し得られた結晶を減圧加熱乾燥を行い、化合物（Ｉ）のＩＩ形結晶を得た。収量；９５．５ｍｇ、収率；９５．５％。粉末Ｘ線回折スペクトル（ＣｕＫα）を図３に示す。また、示差走査熱量（ＤＳＣ）曲線を図４に示すとおり、吸熱ピークは１６４．９℃であった。図３にから分かるように、ＩＩ形結晶は、粉末Ｘ線回折スペクトル（ＣｕＫα）において、回折角（２θ±０．２°）として、１１．３゜、１１．４゜、及び１７．２゜のピークを有さない。
１Ｈ－ＮＭＲ （ＤＭＳＯ－ｄ６）：δppm １．６２－１．７１ (２Ｈ，ｍ)， １．９０－１．９８ (２Ｈ，ｍ)， ２．７８－２．８５ (２Ｈ，ｍ)， ２．９５－３．０４ (２Ｈ，ｍ)， ５．０１－５．０８ (１Ｈ，ｍ) ，７．３０－７．４０ (１０Ｈ，ｍ)， ８．７２ (１Ｈ，ｂｒｓ) Comparative Example 1 Preparation of Form II Crystal of Compound (I) Butyl acetate (1 mL) was added to the crude compound (I) (100 mg) synthesized by the known method disclosed in Patent Document 1, and the mixture was heated to an external temperature of 140 ° C. or higher to dissolve. Thereafter, the mixture was cooled and crystallized, stirred at room temperature, and the crystals obtained by filtration were dried under reduced pressure to obtain Form II crystal of Compound (I). Yield: 95.5 mg, yield: 95.5%. Powder X-ray diffraction spectrum (CuKα) is shown in FIG. 3. In addition, as shown in FIG. 4, the differential scanning calorimetry (DSC) curve, the endothermic peak was 164.9 ° C. As can be seen from FIG. 3, the Form II crystal does not have peaks at 11.3 °, 11.4 °, and 17.2 ° as diffraction angles (2θ ± 0.2 °) in the powder X-ray diffraction spectrum (CuKα).
1H-NMR (DMSO-d6): δppm 1.62-1.71 (2H,m), 1.90-1.98 (2H,m), 2.78-2.85 (2H,m), 2.95-3.04 (2H,m), 5.01-5.08 (1H,m), 7.30-7.40 (10H,m), 8.72 (1H,brs)
試験例１ 固体安定性試験
上記実施例１に記載の方法に準じて製造した方法により得られた化合物（Ｉ）のＩ形結晶の保存安定性を以下の条件により試験した。
・試験条件１
保存条件：２５℃±２℃／６０％ＲＨ±５％
測定ポイント：１２，２４，３６箇月
保存量：約５ｇ
・試験条件２
保存条件：４０℃±２℃／７５％ＲＨ±５％
測定ポイント：１，３，６箇月
保存量：約４ｇ Test Example 1 Solid Stability Test The storage stability of the type I crystal of Compound (I) obtained by the method described in Example 1 above was tested under the following conditions.
Test condition 1
Storage conditions: 25°C ±2°C / 60% RH ±5%
Measurement points: 12, 24, 36 months Storage amount: approx. 5g
Test condition 2
Storage conditions: 40°C ± 2°C / 75% RH ± 5%
Measurement points: 1, 3, 6 months Storage amount: approx. 4g
上記実施例１に記載の方法に準じて製造した方法により得られた化合物（Ｉ）のＩ形結晶の保存安定性を以下の条件により試験した。
・試験条件１
保存条件：２５℃±２℃／６０％ＲＨ±５％
測定ポイント：１２，２４，３６箇月
保存量：約５ｇ
・試験条件２
保存条件：４０℃±２℃／７５％ＲＨ±５％
測定ポイント：１，３，６箇月
保存量：約４ｇ Test Example 1 Solid Stability Test The storage stability of the type I crystal of Compound (I) obtained by the method described in Example 1 above was tested under the following conditions.
Test condition 1
Storage conditions: 25°C ±2°C / 60% RH ±5%
Measurement points: 12, 24, 36 months Storage amount: approx. 5g
Storage conditions: 40°C ± 2°C / 75% RH ± 5%
Measurement points: 1, 3, 6 months Storage amount: approx. 4g
カラム：ＩｎｅｒｔＳｕｓｔａｉｎ Ｃ１８，３．０×１００ｍｍ，３μｍ
カラム温度：４０℃
カラム流速：０．５ｍＬ／ｍｉｎ
移動相：Ａ；１０ｍmol/Lリン酸塩緩衝液（ｐＨ３．０）／アセトニトリル（９：１），Ｂ；アセトニトリル
検出ＵＶ：２２０ｎｍ
グラディエント：
Ｔｉｍｅ（ｍｉｎ） Ａ Ｂ
０～１８ １００％→２５％ ０％→７５％
１８～３５ ２５％ ７５％
３５～３６ ２５％→１００％ ７５％→０％
３６～４６ １００％ ０％ Column: InertSustain C18, 3.0 x 100 mm, 3 μm
Column temperature: 40°C
Column flow rate: 0.5 mL/min
Mobile phase: A: 10 mmol/L phosphate buffer (pH 3.0)/acetonitrile (9:1), B: acetonitrile Detection UV: 220 nm
gradient:
Time (min) A B
0-18 100% → 25% 0% → 75%
18-35 25% 75%
35-36 25% → 100% 75% → 0%
36-46 100% 0%
カラム温度：４０℃
カラム流速：０．５ｍＬ／ｍｉｎ
移動相：Ａ；１０ｍmol/Lリン酸塩緩衝液（ｐＨ３．０）／アセトニトリル（９：１），Ｂ；アセトニトリル
検出ＵＶ：２２０ｎｍ
グラディエント：
Ｔｉｍｅ（ｍｉｎ） Ａ Ｂ
０～１８ １００％→２５％ ０％→７５％
１８～３５ ２５％ ７５％
３５～３６ ２５％→１００％ ７５％→０％
３６～４６ １００％ ０％ Column: InertSustain C18, 3.0 x 100 mm, 3 μm
Column temperature: 40°C
Column flow rate: 0.5 mL/min
Mobile phase: A: 10 mmol/L phosphate buffer (pH 3.0)/acetonitrile (9:1), B: acetonitrile Detection UV: 220 nm
gradient:
Time (min) A B
0-18 100% → 25% 0% → 75%
18-35 25% 75%
35-36 25% → 100% 75% → 0%
36-46 100% 0%
その結果、下表のとおり、Ｉ形結晶は保存後の類縁物質量が少なく、外観の変化も見られなかった。また、保存後の粉末X線回折パターンは初期値と同様であった。
As a result, as shown in the table below, the amount of related substances in type I crystals was small after storage, and no change in appearance was observed. In addition, the powder X-ray diffraction pattern after storage was the same as the initial value.
試験例２ 動的水分吸脱着試験
試験には、ＶＴＩ－ＳＡ＋（ＴＡ Ｉｎｓｔｒｕｍｅｎｔｓ）を用いた。化合物（Ｉ）のＩ形結晶約１０ｍｇ秤量してパンに入れた。５分間で重量変動が０．０１００％以内であることを確認しながら１分間に１度毎６０℃まで昇温させた。重量が変動する場合には、最大５時間その温度を保持した後、次ステップへ進めた。その後、２５℃へ降温させ、湿度を５％ＲＨから９５％ＲＨまで上げ、その後５％ＲＨまで下げた。その際、５分間で重量変動が０．００１００％以内であることを確認しながら５％ＲＨずつ湿度をかけた。重量が変動する場合には、最大２時間その湿度を保持した後、次ステップへと進めた。 Test Example 2 Dynamic Moisture Adsorption/Desorption Test For the test, a VTI-SA+ (TA Instruments) was used. Approximately 10 mg of I-type crystals of compound (I) were weighed and placed in a pan. The temperature was raised to 60°C at 1 degree per minute while confirming that the weight fluctuation was within 0.0100% in 5 minutes. If the weight fluctuated, the temperature was maintained for a maximum of 5 hours before proceeding to the next step. The temperature was then lowered to 25°C, and the humidity was raised from 5% RH to 95% RH, and then lowered to 5% RH. At that time, the humidity was increased by 5% RH while confirming that the weight fluctuation was within 0.00100% in 5 minutes. If the weight fluctuated, the humidity was maintained for a maximum of 2 hours before proceeding to the next step.
試験には、ＶＴＩ－ＳＡ＋（ＴＡ Ｉｎｓｔｒｕｍｅｎｔｓ）を用いた。化合物（Ｉ）のＩ形結晶約１０ｍｇ秤量してパンに入れた。５分間で重量変動が０．０１００％以内であることを確認しながら１分間に１度毎６０℃まで昇温させた。重量が変動する場合には、最大５時間その温度を保持した後、次ステップへ進めた。その後、２５℃へ降温させ、湿度を５％ＲＨから９５％ＲＨまで上げ、その後５％ＲＨまで下げた。その際、５分間で重量変動が０．００１００％以内であることを確認しながら５％ＲＨずつ湿度をかけた。重量が変動する場合には、最大２時間その湿度を保持した後、次ステップへと進めた。 Test Example 2 Dynamic Moisture Adsorption/Desorption Test For the test, a VTI-SA+ (TA Instruments) was used. Approximately 10 mg of I-type crystals of compound (I) were weighed and placed in a pan. The temperature was raised to 60°C at 1 degree per minute while confirming that the weight fluctuation was within 0.0100% in 5 minutes. If the weight fluctuated, the temperature was maintained for a maximum of 5 hours before proceeding to the next step. The temperature was then lowered to 25°C, and the humidity was raised from 5% RH to 95% RH, and then lowered to 5% RH. At that time, the humidity was increased by 5% RH while confirming that the weight fluctuation was within 0.00100% in 5 minutes. If the weight fluctuated, the humidity was maintained for a maximum of 2 hours before proceeding to the next step.
図５に示すように、Ｉ形結晶の吸湿性が低いことが確認できた。
As shown in Figure 5, it was confirmed that type I crystals have low hygroscopicity.
Claims (9)
- 粉末Ｘ線回折スペクトル（ＣｕＫα）において、以下の（ａ）群から選ばれる少なくとも１つの回折角（２θ±０．２°）並びに以下の（ｂ）群から選択される少なくとも１つの回折角（２θ±０．２°）にピークを有する４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩のI形結晶。（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜ A type I crystal of 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride having peaks in a powder X-ray diffraction spectrum (CuKα) at at least one diffraction angle (2θ±0.2°) selected from the following group (a) and at least one diffraction angle (2θ±0.2°) selected from the following group (b): (a) 11.3°, 11.4°, and 17.2°; (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4°. - 粉末Ｘ線回折スペクトル（ＣｕＫα）において、以下の（ａ）群から選ばれる少なくとも２つの回折角（２θ±０．２°）並びに以下の（ｂ）群から選択される少なくとも１つの回折角（２θ±０．２°）にピークを有する請求項１に記載の結晶。
（ａ）１１．３゜、１１．４゜及び１７．２゜
（ｂ）１２．７゜、１５．９゜、１６．１゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜ The crystal according to claim 1, which has peaks in a powder X-ray diffraction spectrum (CuKα) at at least two diffraction angles (2θ±0.2°) selected from the following group (a) and at least one diffraction angle (2θ±0.2°) selected from the following group (b):
(a) 11.3°, 11.4° and 17.2° (b) 12.7°, 15.9°, 16.1°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9° and 28.4° - 粉末Ｘ線回折スペクトル（ＣｕＫα）において、回折角（２θ±０．２°）として、１１．３゜、１１．４゜、１２．７゜、１５．９゜、１６．１゜、１７．２゜、２０．５゜、２０．７゜、２３．１゜、２３．２゜、２５．９゜及び２８．４゜にピークを有する結晶である請求項１に記載の結晶。 The crystal according to claim 1, which has peaks at diffraction angles (2θ±0.2°) of 11.3°, 11.4°, 12.7°, 15.9°, 16.1°, 17.2°, 20.5°, 20.7°, 23.1°, 23.2°, 25.9°, and 28.4° in a powder X-ray diffraction spectrum (CuKα).
- 図１に示される粉末Ｘ線回折スペクトル（ＣｕＫα）を有する結晶である、請求項１に記載の結晶。 The crystal described in claim 1, which has the powder X-ray diffraction spectrum (CuKα) shown in Figure 1.
- 示差走査熱量測定において、１６６℃付近に吸熱ピークを有する請求項１に記載の結晶。 The crystal described in claim 1 has an endothermic peak at about 166°C in differential scanning calorimetry.
- ４－ピペリジニル ２，２－ジフェニル－２－（プロポキシ－１，１，２，２，３，３，３－ｄ７）アセテート塩酸塩をメチルエチルケトンで再結晶化する工程を含む、請求項１乃至５のいずれか１項に記載のＩ型結晶の製造方法。 A method for producing type I crystals according to any one of claims 1 to 5, comprising a step of recrystallizing 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7) acetate hydrochloride from methyl ethyl ketone.
- 請求項１乃至５のいずれか１項に記載の結晶を含有する医薬組成物。 A pharmaceutical composition containing the crystal described in any one of claims 1 to 5.
- 請求項１乃至５のいずれか１項に記載の結晶を含有する尿道内圧の上昇により改善が見込まれる疾患の予防及び／又は治療剤。 A preventive and/or therapeutic agent for a disease expected to be improved by increasing intraurethral pressure, comprising the crystal according to any one of claims 1 to 5.
- 請求項１乃至５のいずれか１項に記載の結晶を含有する腹圧性尿失禁予防及び／又は治療剤。 A preventive and/or therapeutic agent for stress urinary incontinence, comprising the crystal according to any one of claims 1 to 5.
Applications Claiming Priority (2)
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| JP2022208804 | 2022-12-26 | ||
| JP2022-208804 | 2022-12-26 |
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| WO2024143236A1 true WO2024143236A1 (en) | 2024-07-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/JP2023/046297 WO2024143236A1 (en) | 2022-12-26 | 2023-12-25 | Crystals of acetate hydrochloride |
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| WO (1) | WO2024143236A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS6239567A (en) * | 1985-08-14 | 1987-02-20 | Taiho Yakuhin Kogyo Kk | 4-piperidyl benzilate |
| WO2013115077A1 (en) * | 2012-01-30 | 2013-08-08 | 大鵬薬品工業株式会社 | Novel acetic acid ester compound or salt thereof |
| WO2017047791A1 (en) * | 2015-09-17 | 2017-03-23 | 大鵬薬品工業株式会社 | New crystal of piperazine compound |
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2023
- 2023-12-25 WO PCT/JP2023/046297 patent/WO2024143236A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6239567A (en) * | 1985-08-14 | 1987-02-20 | Taiho Yakuhin Kogyo Kk | 4-piperidyl benzilate |
| WO2013115077A1 (en) * | 2012-01-30 | 2013-08-08 | 大鵬薬品工業株式会社 | Novel acetic acid ester compound or salt thereof |
| WO2017047791A1 (en) * | 2015-09-17 | 2017-03-23 | 大鵬薬品工業株式会社 | New crystal of piperazine compound |
Non-Patent Citations (4)
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| 2002, non-official translation (ASHIZAWA, Kazuhide. Polymorph Phenomena in Drugs Agents, Science of Crystallization) pp.273,278,305-317 * |
| HIRAYAMA NORIAKI: "Handbook of Organic Compound Crystal Manufacture", 1 January 2008, MARUZEN CO., LTD., JP , ISBN: 978-4-621-07991-1, article NORIAKI HIRAYAMA: "Passage; Handbook of Organic Compound Crystal Manufacture", pages: 17-23, 37-40, 45 - 51,57-65, XP009508206 * |
| MITSUHISA YAMANO: "Approach to Crystal Polymorph in Process Research of New Drug", YUKI GOSEI KAGAKU KYOKAISHI - JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY, YUKI GOSEI KAGAKU KYOKAI, JP, vol. 65, no. 9, 1 September 2007 (2007-09-01), JP , pages 907 - 913, XP055358201, ISSN: 0037-9980, DOI: 10.5059/yukigoseikyokaishi.65.907 * |
| NORIYUKI TAKATA: "Soyaku Dankai ni Okeru Gen'yaku Form Screening to Sentaku - API form screening and selection in drug discovery stage", PHARM STAGE, TECHNICAL INFORMATION INSTITUTE, JP, vol. 6, no. 10, 1 January 2007 (2007-01-01), JP , pages 20 - 25, XP008145548, ISSN: 1346-3918 * |
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