CN117700354A - Crystal form of raffinancin and preparation method thereof - Google Patents
Crystal form of raffinancin and preparation method thereof Download PDFInfo
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- CN117700354A CN117700354A CN202311699179.XA CN202311699179A CN117700354A CN 117700354 A CN117700354 A CN 117700354A CN 202311699179 A CN202311699179 A CN 202311699179A CN 117700354 A CN117700354 A CN 117700354A
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- 239000013078 crystal Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 69
- 238000001816 cooling Methods 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 239000012046 mixed solvent Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 6
- 230000008018 melting Effects 0.000 claims description 6
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims 2
- 229960002009 naproxen Drugs 0.000 claims 2
- 230000001747 exhibiting effect Effects 0.000 claims 1
- 238000001757 thermogravimetry curve Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 11
- 239000012458 free base Substances 0.000 abstract description 7
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 241000234479 Narcissus Species 0.000 abstract description 4
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 abstract 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 abstract 1
- 229960002930 sirolimus Drugs 0.000 abstract 1
- 238000001228 spectrum Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229940041682 inhalant solution Drugs 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 230000004584 weight gain Effects 0.000 description 5
- 235000019786 weight gain Nutrition 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229940110339 Long-acting muscarinic antagonist Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 101710202365 Napin Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- -1 1- [2- [4- [ (4-carbamoyl-1-piperidinyl) methyl ] -N-methylbenzamido ] ethyl ] -4-piperidinyl 2-biphenylyl carbamate Chemical compound 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 235000017274 Diospyros sandwicensis Nutrition 0.000 description 1
- 241000282838 Lama Species 0.000 description 1
- VHKXXVVRRDYCIK-CWCPJSEDSA-N Narasin Chemical compound C[C@H]1C[C@H](C)[C@H]([C@@H](CC)C(O)=O)O[C@H]1[C@@H](C)[C@H](O)[C@H](C)C(=O)[C@H](CC)[C@@H]1[C@@H](C)C[C@@H](C)[C@@]2(C=C[C@@H](O)[C@@]3(O[C@@](C)(CC3)[C@@H]3O[C@@H](C)[C@@](O)(CC)CC3)O2)O1 VHKXXVVRRDYCIK-CWCPJSEDSA-N 0.000 description 1
- VHKXXVVRRDYCIK-UHFFFAOYSA-N Narasin Natural products CC1CC(C)C(C(CC)C(O)=O)OC1C(C)C(O)C(C)C(=O)C(CC)C1C(C)CC(C)C2(C=CC(O)C3(OC(C)(CC3)C3OC(C)C(O)(CC)CC3)O2)O1 VHKXXVVRRDYCIK-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical class OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- FYDWDCIFZSGNBU-UHFFFAOYSA-N [1-[2-[[4-[(4-carbamoylpiperidin-1-yl)methyl]benzoyl]-methylamino]ethyl]piperidin-4-yl] n-(2-phenylphenyl)carbamate Chemical compound C=1C=C(CN2CCC(CC2)C(N)=O)C=CC=1C(=O)N(C)CCN(CC1)CCC1OC(=O)NC1=CC=CC=C1C1=CC=CC=C1 FYDWDCIFZSGNBU-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960001851 narasin Drugs 0.000 description 1
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C[C@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 description 1
- 229960003255 natamycin Drugs 0.000 description 1
- 235000010298 natamycin Nutrition 0.000 description 1
- 239000004311 natamycin Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011780 sodium chloride Substances 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
- 230000001502 supplementing effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a crystal form VI of a novel free base of rapamycin and a preparation method thereof. The Lei Fen narcissus crystal form VI has better chemical stability and lower moisture absorption under the condition of higher humidity, and an X-ray powder diffraction spectrum of the narcissus crystal form VI is expressed by 2 theta (°), and has characteristic peaks of 4.95+/-0.2 degrees, 7.46+/-0.2 degrees, 10.00+/-0.2 degrees, 12.93+/-0.2 degrees, 14.81+/-0.2 degrees, 17.63 +/-0.2 degrees, 18.66+/-0.2 degrees, 19.74+/-0.2 degrees, 20.44+/-0.2 degrees, 21.34+/-0.2 degrees, 22.69+/-0.2 degrees and 25.34+/-0.2 degrees.
Description
Technical Field
The invention belongs to the field of drug crystal forms, and relates to a crystal form of raffinancin and a preparation method thereof.
Background
Lei Fen Nacine (revhenacin) was developed by Theravance biopharmaceutical company in combination with Mylan pharmaceutical company, U.S. for the treatment of Chronic Obstructive Pulmonary Disease (COPD) as a long-acting muscarinic antagonist (long-acting muscarinic antagonist, LAMA). In 11 months 2018, the U.S. Food and Drug Administration (FDA) approved Lei Fen that was marketed under the trade name YUPELRI in the form of an inhalation solution at a concentration of 175 μg/3 mL. Lei Fen the chemical name of the octyl is 1- [2- [4- [ (4-carbamoyl-1-piperidinyl) methyl ] -N-methylbenzamido ] ethyl ] -4-piperidinyl 2-biphenylyl carbamate, which has the following structural formula:
patent CN101163677B discloses the free base, diphosphate, monosulfate, hydrogen oxalate salt of Lei Fen nacin crystalline form, their preparation and characterization, crude Lei Fen nacin acetonitrile: recrystallisation from a water=1:1 mixed solvent gives the free base form I (melting point 102.7 ℃). Lei Fen nataxin was crystallized from acetonitrile and methyl tert-butyl ether system to give the free base form II (melting point 98 ℃ 6 ℃). The crystal form I has stronger hygroscopicity and poor stability. Wherein the diffraction angle in the X-ray powder diffraction pattern of Lei Fen narsin free alkali crystal form I is expressed as 2 theta, and has characteristic peaks of 4.7+/-0.2 degrees, 9.6+/-0.2 degrees, 12.7+/-0.2 degrees, 13.7+/-0.2 degrees, 16.7+/-0.2 degrees, 17.4+/-0.2 degrees, 18.5+/-0.2 degrees, 19.4+/-0.2 degrees, 20.8+/-0.2 degrees, 21.4+/-0.2 degrees, 24.2+/-0.2 degrees and 25.6+/-0.2 degrees. The diffraction angle in the X-ray powder diffraction pattern of Lei Fen narsin free base crystal form II is expressed as 2 theta, and the diffraction angle has characteristic peaks of 4.6+/-0.2 degrees, 9.3+/-0.2 degrees, 12.90+/-0.2 degrees, 13.6+/-0.2 degrees, 14.0+/-0.2 degrees, 14.6+/-0.2 degrees, 16.5+/-0.2 degrees, 18.6+/-0.2 degrees, 19.1+/-0.2 degrees, 20.9+/-0.2 degrees, 22.1+/-0.2 degrees and 22.7+/-0.2 degrees.
Patent CN102470130B discloses Lei Fen nacin form III and form iv, wherein the biphosphate of Lei Fen nacin is dissociated by NaOH in a mixed solvent of isopropyl acetate and water, and then recrystallized in isopropyl acetate or toluene to obtain Lei Fen nacin free base form III (melting point: 125 ℃). Form IV was further prepared by crystallization of form III in acetonitrile (melting point: 119 ℃). Wherein the diffraction angle in the X-ray powder diffraction pattern of Lei Fen narcissus crystal form III is expressed as 2 theta, and the diffraction angle has characteristic peaks of 6.6+/-0.1 degrees, 11.4+/-0.1 degrees, 13.1+/-0.1 degrees, 16.1+/-0.1 degrees, 17.5+/-0.1 degrees, 18.2+/-0.1 degrees, 18.6+/-0.1 degrees, 19.3+/-0.1 degrees, 19.7+/-0.1 degrees, 19.9+/-0.1 degrees, 20.2+/-0.1 degrees, 20.8+/-0.1 degrees, 21.1+/-0.1 degrees, 21.7+/-0.1 degrees and 22.3+/-0.1 degrees. The diffraction angle in the X-ray powder diffraction pattern of Lei Fen narsin free base form IV is expressed as 2 theta, and has characteristic peaks of 6.6+/-0.1 DEG, 13.1+/-0.1 DEG, 15.0+/-0.1 DEG, 17.3+/-0.1 DEG, 17.7+/-0.1 DEG, 18.6+/-0.1 DEG, 19.7+/-0.1 DEG, 20.2+/-0.1 DEG, 20.9+/-0.1 DEG, 21.4+/-0.1 DEG and 22.6+/-0.1 deg.
Patent CN114276290a discloses another Lei Fen na Xin Moshui crystal form and a preparation method thereof in a toluene-containing mixed solvent, wherein the diffraction angle in the X-ray powder diffraction pattern is expressed as 2θ, and the diffraction angles have characteristic peaks of 7.05±0.2°, 9.36±0.2°, 11.10±0.2°, 12.90±0.2°, 17.56±0.2°, 18.56±0.2°, 20.00±0.2°, 21.27±0.2°, and 24.15±0.2°.
Disclosure of Invention
In the research process, the invention unexpectedly discovers a novel crystal form different from the crystal form, and the crystal form has good stability (especially lower content of degraded impurity X) and small hygroscopicity, and the preparation process is simple and easy to amplify.
The technical scheme adopted for solving the technical problems is as follows:
in one aspect of the present invention, there is provided a crystalline form of raffinacine (form VI), wherein the Lei Fen narciscine form VI has characteristic peaks in terms of 2θ diffraction angles of 4.95±0.2°, 7.46±0.2°, 10.00±0.2°, 12.93±0.2°, 14.81±0.2°, 17.63 ±0.2°, 18.66±0.2°, 19.74±0.2°, 20.44±0.2°, 21.34±0.2°, 22.69±0.2°, 25.34±0.2°.
The melting point is 106.8-110.5 ℃.
The peak value of the differential scanning calorimeter heat absorption is about 100-115 ℃.
The invention provides a preparation method of Lei Fen nacin crystal form VI, which is characterized in that Lei Fen nacin is dissolved in an organic solvent (1) by recrystallization, the temperature is raised to 40-60 ℃ and the mixture is stirred to be completely dissolved, the temperature is reduced for crystallization, or another organic solvent (2) is added for crystallization, the temperature is reduced to 0-30 ℃ and then crystallization is continued, suction filtration is carried out, and vacuum drying is carried out at the temperature of 40-50 ℃ to obtain Lei Fen nacin crystal form VI.
Preferably, the organic solvent (1) is acetonitrile, and the ratio of Lei Fen that is octyl to the organic solvent (1) is 1: 5-50 g/mL.
Preferably, the organic solvent (2) can be one or more mixed solvents selected from ethyl acetate, isopropyl acetate, methyl acetate, n-propyl acetate, butyl acetate, ethyl formate, propyl formate and isopropyl ether, and the volume ratio of the organic solvent (1) to the organic solvent (2) is 1:0.1-20. The ratio of Lei Fen narasin to the mixed solvent is 1: 5-100 g/mL. Preferably, the mixed solvent of the organic solvent (1) and the organic solvent (2) is acetonitrile and isopropyl ether, the ratio is 1:1, and the dosage of the mixed solvent is 10 times of the mass of Lei Fen natamycin.
Lei Fen nacin form VI obtained according to the above method, having an X-ray powder diffraction pattern, in terms of diffraction angle 2θ (°), as shown in fig. 1, with HPLC purity >99.5% as shown in fig. 2.
The crystal form VI has the characteristics of good stability, high purity, difficult moisture absorption and the like. After stability inspection of the crystal form VI at 40+/-2 ℃ and relative humidity RH 75+/-5%, degrading impurity X is less than 0.5% after 180 days, and the structural formula of the impurity X is as follows:
the invention Lei Fen, xin Jiejing VI and at least one pharmaceutically acceptable carrier provide a pharmaceutical composition.
The Lei Fen and Xin Jiejing VI of the invention have a faster dissolution rate in the preparation process.
The 175 mu g/3mL inhalation solution prepared by the Lei Fen nacin crystal form VI has better stability, thereby improving the production quality of medicines.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of Lei Fen cina form VI obtained in example 3 of the present invention
FIG. 2 is an HPLC chart of Lei Fen nacin form VI obtained in example 3 of the present invention
FIG. 3 is a DSC chart of crystal form VI of Lei Fen that is obtained in example 3 of the present invention
FIG. 4 is an X-ray powder diffraction pattern of the crystalline form I obtained in comparative example 1
Detailed Description
The following describes the invention in further detail by way of specific examples, but is not intended to limit the invention thereto.
The instrument and the method for collecting data are as follows:
x-ray powder diffraction (XRPD): model SmartLab SE intelligent multifunctional X-ray diffractometer, D/teX Ultra 250 detector, cuK alpha radiation, power 40kV,50mA, step width 0.02 DEG, scanning speed 10.00 DEG/min, scanning range 3-40 deg.
Differential scanning calorimetric analysis (DSC) model NETZSCH DSC 3500, nitrogen 60mL/min, heating rate 10 ℃/min, temperature range: room temperature to 280 ℃.
Example 1
Taking Lei Fen nacin 1g, adding 5mL of acetonitrile, heating to 40-50 ℃, stirring until the acetonitrile is completely dissolved, slowly cooling, cooling to 0-30 ℃, standing for crystallization for 2 hours, heating to 40-50 ℃, adding 5mL of ethyl acetate, stirring for 2 hours, cooling to 20-30 ℃, carrying out suction filtration, and drying in a vacuum oven (40-50 ℃) to obtain Lei Fen nacin crystal form VI0.85g with HPLC purity of 99.5%.
Example 2
Taking Lei Fen nacin 1g, adding 5mL of acetonitrile, heating to 40-50 ℃, stirring until the acetonitrile is completely dissolved, slowly cooling, cooling to 0-30 ℃, standing for crystallization for 2 hours, heating to 40-50 ℃, adding 5mL of isopropyl ether, stirring for 2 hours, cooling to 0-10 ℃, carrying out suction filtration, and drying in a vacuum oven (40-50 ℃) to obtain 0.8g Lei Fen nacin crystal form VI with HPLC purity of more than 99.5%.
Example 3
Taking Lei Fen nacin 1g, adding 5mL of acetonitrile and 5mL of isopropyl ether, heating to 40-50 ℃, stirring until the components are completely dissolved, slowly cooling, cooling to 0-30 ℃, standing for crystallization for 2 hours, heating to 40-50 ℃, stirring for 2 hours, cooling to 10-25 ℃, carrying out suction filtration, and drying in a vacuum oven (40-50 ℃) to obtain 0.83g Lei Fen nacin crystal form VI with HPLC purity of more than 99.5%.
Example 4
Taking Lei Fen nacin 1g, adding 5mL of acetonitrile, heating to 50-60 ℃, stirring to completely dissolve, slowly cooling, cooling to 0-30 ℃, standing for crystallization for 2 hours, heating to 50-60 ℃, stirring for 2 hours, cooling to 0-10 ℃, carrying out suction filtration, and drying in a vacuum oven (40-50 ℃) to obtain 0.8g Lei Fen nacin crystal form VI with HPLC purity of more than 99.5%.
Example 5
Taking Lei Fen nacin 1g, adding 5mL of acetonitrile and 5mL of isopropyl ether, heating to 40-50 ℃, stirring for 15 hours, slowly cooling, cooling to 0-30 ℃, carrying out suction filtration, and placing in a vacuum oven (40-50 ℃) for drying to obtain 0.78g Lei Fen nacin crystal form VI, wherein the HPLC purity is more than 99.5%.
Example 6
Adding 5mL of acetonitrile and 5mL of isopropyl acetate into 1g of Lei Fen napin, heating to 40-50 ℃, stirring until the mixture is completely dissolved, slowly cooling, cooling to 0-30 ℃, standing for crystallization for 2 hours, heating to 40-50 ℃, stirring for 2 hours, cooling to 0-30 ℃, slowly stirring for 15 hours, suction filtering, and drying in a vacuum oven (40-50 ℃) to obtain 0.88g Lei Fen napin crystal form VI, wherein the HPLC purity is more than 99.5%.
Example 7
Taking Lei Fen that 10g of acetonitrile, adding 50mL of acetonitrile, heating to 40-50 ℃, stirring until the acetonitrile is completely dissolved, slowly cooling, cooling to 0-30 ℃, standing for crystallization for 2 hours, heating to 40-50 ℃, adding 50mL of isopropyl ether, stirring for 2 hours, cooling to 0-30 ℃, carrying out suction filtration, drying in a vacuum oven (40-50 ℃) to obtain 0.9g Lei Fen that of the crystal form VI, wherein the purity measured by HPLC is more than 99.5%.
Comparative example 1: preparation of Lei Fen Naxin form I
2.3g of Lei Fen narsin was added to 2mL of a water/acetonitrile (1/1) mixed solvent, mixed in a water bath at 70℃for 2 hours, cooled to room temperature, left at 4℃for 1 hour, added with 0.5mL of water and 0.4mL of acetonitrile, slowly cooled overnight, the reaction solution was heated and cooled to circulate (60℃for 1 hour, 70℃solid was dissolved, 3 times were repeated and then warmed to 60℃for 1 hour), the mixture was cooled overnight with slow stirring turned off, solid was precipitated, sticky walls, and the mixture was cooled by heating and cooling circulation (60℃for 3 hours, slowly cooled, and then 60℃for 3 hours) on the third day. After cooling overnight with slow stirring, 3 days, the mixture was filtered and dried in a vacuum oven (40-50 ℃ C.) to give 1.5g Lei Fen of the crystalline form I with an HPLC purity of 98.9%.
Comparative example 2: preparation of Lei Fen Naxin form II
Lei Fen of the nacin prepared according to comparative example I was taken and 0.7g of the nacin was dissolved in 1mL of acetonitrile, 3mL of methyl tert-butyl ether was added, the solution was cloudy, and 0.5mL of acetonitrile was additionally added to clarify the reaction solution, the reaction solution was allowed to stand and crystallize overnight, filtration was carried out, the solid was severely hygroscopic and thickened during the filtration, and the solid was dried in a vacuum oven (40 to 50 ℃) to obtain 0.5g of Lei Fen nacin form II with an HPLC purity of 99.2%.
Example 8: chemical stability at 40 DEG C
The chemical stability of Lei Fen nacin form VI of the present invention and forms I and II of patent CN101163677B were compared and shown in table 1 when placed at 40±2 ℃ with a relative humidity of 75±5%.
TABLE 1 investigation of chemical stability of Lei Fen Naxin at 40.+ -. 2 °C
At 40 ℃, form VI is lower than form I and form II impurities X and total impurities, showing better chemical stability.
Example 9: chemical stability of 90.+ -. 5% relative humidity
The chemical stability of Lei Fen nacin form VI of the present invention and form I of patent CN101163677B were compared at high humidity. As shown in table 2.
Table 2 Lei Fen study of 90±5% relative humidity chemical stability
Under the high humidity condition of 90+/-5%, lei Fen octyl crystal form VI has better chemical stability than crystal form I.
Example 10: lei Fen investigation of hygroscopicity of Naxin
The Lei Fen narcissus prepared by the invention is compared with the crystal forms I and II in hygroscopicity at the relative humidity of 25+/-1 ℃/80+/-2%. Three dry glass weighing bottles with plugs are taken, placed at the temperature of 25+/-1 ℃ and the relative humidity of 80+/-2% in one day before test, respectively weighed a certain amount of crystal form I and crystal form VI, tiled in the weighing bottles, stored for 24 hours at the temperature of 25+/-1 ℃/80+/-2% RH, respectively weighed the solid weight and calculated the weight gain proportion. The results are shown in Table 3:
table 3 Lei Fen study of hygroscopicity of narafine
| Crystal form I (weight gain%) | Crystal form II (weight gain%) | Crystal form VI (weight gain%) |
| 5.4 | 3.6 | 0.2 |
Under the high humidity condition, lei Fen that the octyl crystal form VI has obviously smaller moisture absorption and weight gain than the crystal forms I and II, and the crystal form VI has weak moisture absorption.
Example 11: lei Fen Naxin inhalation solution (175. Mu.g/3 mL)
Inhalation was formulated with Lei Fen nataxin solution: adding appropriate amount of injectable water, stirring to dissolve sodium chloride, citric acid and sodium citrate, adding the crystal form VI of Lei Fen of example 8, adjusting pH to 5.0 with appropriate amount of hydrochloric acid or sodium hydroxide, dissolving for about 2 min, and supplementing water to full amount. The formulation recipe is shown in Table 4.
Table 4 formulation of Lei Fen Naxin solution for inhalation
Example 12: lei Fen Composition of dissolution rates of the inhalation solutions
Lei Fen and I forms of the invention were prepared as Lei Fen solutions for inhalation, respectively, according to the recipe of example 11, and compared to dissolution rates, lei Fen form VI was dissolved for about 2 minutes, form I was dissolved for about 8 minutes, and Lei Fen form VI was significantly faster than form I.
Example 13: stability of Lei Fen Naxin inhalation solution
Lei Fen nacin inhalation solution is prepared according to the prescription table of example 11 respectively by the Lei Fen nacin crystal form VI and the crystal form I, and the solution is hermetically stored at 20-30 ℃ in a dark place and has comparative stability. As shown in table 5.
TABLE 5 stability of Lei Fen Naxin inhalation solution
Under the same conditions, lei Fen that was formulated using form VI had significantly better chemical stability than form I.
Claims (7)
1. Form VI of raffinancin, characterized by an X-ray powder diffraction pattern, expressed in terms of 2Θ (°), having 4.95±0.2°, 7.46±0.2°, 10.00±0.2°, 12.93±0.2°, 14.81±0.2°, 17.63 ±0.2°, 18.66±0.2°, 19.74±0.2°, 20.44±0.2°, 21.34±0.2°, 22.69±0.2°, 25.34±0.2°.
2. The Lei Fen nacin form VI of claim 1, further characterized by a differential scanning calorimetry thermogram exhibiting an endothermic peak at about 100-115 ℃.
3. Lei Fen nacin form VI according to claim 1, characterized by a melting point of 106.8-110.5 ℃.
4. The preparation method of Lei Fen nacin crystal form VI according to claim 1, comprising the steps of dissolving Lei Fen nacin in an organic solvent (1), particularly acetonitrile, heating to 40-60 ℃ and stirring until the nacin is completely dissolved, cooling to 0-30 ℃ and crystallizing; or adding another organic solvent (2) for crystallization, cooling to 0-30 ℃, continuing crystallization, suction filtering, and vacuum drying at 40-50 ℃ to obtain Lei Fen octyl crystal form VI.
5. The process according to claim 4, wherein the organic solvent (1) is preferably acetonitrile, and the ratio of Lei Fen naproxen to acetonitrile is 1:5-50 g/mL.
6. The preparation method according to claim 4, wherein the organic solvent (2) is one or more mixed solvents selected from ethyl acetate, isopropyl acetate, methyl acetate, n-propyl acetate, butyl acetate, ethyl formate, propyl formate and isopropyl ether, and the organic solvents (1) and (2) can be mixed in any ratio, wherein the ratio of the organic solvent (1) to the organic solvent (2) is 1:0.1-20, g/mL; the ratio of Lei Fen naproxen to the mixed solvent of the organic solvent (1) and the organic solvent (2) is 1: 5-100 g/mL.
7. The process according to claim 6, wherein the organic solvent (2) is isopropyl ether.
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