CN116041336B - New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound - Google Patents
New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound Download PDFInfo
- Publication number
- CN116041336B CN116041336B CN202310017273.6A CN202310017273A CN116041336B CN 116041336 B CN116041336 B CN 116041336B CN 202310017273 A CN202310017273 A CN 202310017273A CN 116041336 B CN116041336 B CN 116041336B
- Authority
- CN
- China
- Prior art keywords
- oxaspiro
- preparation
- ray powder
- powder diffraction
- fluorophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- -1 6-oxaspiro [4,5] decane compound Chemical class 0.000 title claims abstract description 19
- 239000013078 crystal Substances 0.000 title abstract description 53
- 239000003814 drug Substances 0.000 claims abstract description 13
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 29
- 238000002411 thermogravimetry Methods 0.000 claims description 27
- 229940079593 drug Drugs 0.000 claims description 7
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 3
- 229940035676 analgesics Drugs 0.000 claims 1
- 239000000730 antalgic agent Substances 0.000 claims 1
- 239000002756 mu opiate receptor agonist Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 238000000034 method Methods 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000012360 testing method Methods 0.000 description 17
- 239000000843 powder Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- UTYPARUARYGOQR-MUUNZHRXSA-N 2-[(9R)-9-(4-fluorophenyl)-6-oxaspiro[4.5]decan-9-yl]-N-[(2-pyridin-4-ylphenyl)methyl]ethanamine Chemical compound FC1=CC=C([C@@]2(CCNCC(C=CC=C3)=C3C3=CC=NC=C3)CC3(CCCC3)OCC2)C=C1 UTYPARUARYGOQR-MUUNZHRXSA-N 0.000 description 8
- 238000002441 X-ray diffraction Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 230000004580 weight loss Effects 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- DMNOVGJWPASQDL-OAQYLSRUSA-N n-[(3-methoxythiophen-2-yl)methyl]-2-[(9r)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine Chemical compound C1=CSC(CNCC[C@@]2(CC3(CCCC3)OCC2)C=2N=CC=CC=2)=C1OC DMNOVGJWPASQDL-OAQYLSRUSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000004448 titration Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910002483 Cu Ka Inorganic materials 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 230000000202 analgesic effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 102000051367 mu Opioid Receptors Human genes 0.000 description 3
- 108020001612 μ-opioid receptors Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LEJBBGNFPAFPKQ-UHFFFAOYSA-N 2-(2-prop-2-enoyloxyethoxy)ethyl prop-2-enoate Chemical compound C=CC(=O)OCCOCCOC(=O)C=C LEJBBGNFPAFPKQ-UHFFFAOYSA-N 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229950005956 oliceridine Drugs 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application relates to the field of medicine crystal forms, in particular to a crystal form of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine monohydrochloride and a preparation method thereof. The crystal form of the compound of the formula (I) obtained by the application is not easy to absorb moisture, has good solubility, excellent physical stability and chemical stability, and the preparation method has mild conditions, simple operation and good process reproducibility, and the obtained product has high purity, so that the condition of realizing industrial production is controllable, and the application is beneficial to large-scale industrialization.
Description
Technical Field
The invention belongs to the field of drug crystal forms, and particularly relates to a (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine monohydrochloride crystal form and a preparation method thereof.
Background
There have been studies showing that there are three different types of molecules and pharmacologies of Opioid Receptors (ORs): delta, kappa and mu. Opioid drugs are primarily conducted through the opioid μ receptor. Mu receptor is classical GPCR, and a great deal of research shows that the mu receptor biased agonist has better analgesic effect and can reduce related side effects. This provides the possibility to develop ideal opioids. Currently, trevena's TRV130 (oliceridine) is marketed under FDA approval at month 8 of 2020 for postoperative analgesia. The TRV130 three-phase clinical results showed: under the dosage of the same analgesic effect, the toxic and side effects of the TRV130 are lower than those of morphine, but no obvious difference exists, the toxic and side effects are large, the daily accumulated dosage of the TRV130 is not more than 27mg, and the safety window is narrow.
The invention provides (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine monohydrochloride on the basis of the existing domestic and foreign researches, the free state of the compound is oily liquid, and the hydrochloride is solid at normal temperature, so that the compound has good pharmacokinetic property, long half-life, good analgesic effect and good drug forming property.
The structural formula of the (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine monohydrochloride is shown as the formula (I):
The relevant crystalline forms of compound I have not been reported in the literature. As is well known, the crystal forms of the medicines have influence on the quality of the preparation and the production process, and research on the crystal forms of the medicines can provide references for preparation workers in the aspects of prescription development, new medicament design, production process optimization, medicine quality control and clinical efficacy. Different crystal forms of the same medicine may be significantly different in appearance, solubility, melting point, dissolution rate, bioequivalence and the like, thereby affecting the stability, bioavailability and curative effect of the medicine. Therefore, research on the crystal forms of the compound I is necessary, and one or more crystal forms which are simple in preparation method, good in solubility, high in stability, high in purity, not easy to absorb moisture and suitable for industrial production are developed.
Disclosure of Invention
The invention aims to provide a plurality of crystal forms of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine monohydrochloride, and part of the crystal forms have good crystal form stability and chemical stability and can be better applied to clinic.
The invention provides a crystal form A of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form A has characteristic peaks at angles of 2 theta of 5.36+/-0.2 degrees, 10.72+/-0.2 degrees, 14.50+/-0.2 degrees, 16.12+/-0.2 degrees, 17.10+/-0.2 degrees, 23.86+/-0.2 degrees, 26.38 +/-0.2 degrees and 27.00+/-0.2 degrees.
The invention provides a crystal form A of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at angles of 5.36±0.2°、10.72±0.2°、12.14±0.2°、14.50±0.2°、16.12±0.2°、17.10±0.2°、19.38±0.2°、23.86±0.2°、26.38±0.2°、27.00±0.2° and 29.44+/-0.2 degrees of 2 theta.
Form a of the present application uses Cu-Ka radiation, X-ray powder diffraction patterns expressed in terms of 2θ, with characteristic diffraction peaks near 5.36±0.2°、10.72±0.2°、12.14±0.2°、14.50±0.2°、16.12±0.2°、17.10±0.2°、19.38±0.2°、23.86±0.2°、26.38±0.2°、27.00±0.2° and 29.44±0.2°.
Preferably, the X-ray powder diffraction pattern of form a is substantially as shown in figure 1.
The differential scanning calorimetric profile (DSC) of form A is shown in FIG. 2, which has a maximum endothermic peak at 176.24 + -3deg.C.
The thermogravimetric analysis (TGA) of form a is shown in figure 3, with no significant weight loss in the range of 30-150 ℃.
The invention also relates to a method for preparing the crystal form A, which comprises the following two steps:
(1) Adding an organic solvent into (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine until the organic solvent is dissolved, slowly dropwise adding concentrated hydrochloric acid into the solution at the temperature of 0-20 ℃, and fully stirring for 3-24 hours to obtain a crystal form A.
(2) Adding an organic solvent into (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decane-9-yl) -N- (2- (pyridine-4-yl) benzyl) ethylamine until the organic solvent is dissolved, slowly dropwise adding an organic solution of hydrogen chloride into the solution at the temperature of 0-20 ℃, and fully stirring for 3-24 hours to obtain a crystal form A.
The organic solvent in the method (1) or the method (2) in the scheme is a single solvent, and the solvent is selected from one of ethyl acetate, acetone, acetonitrile or tetrahydrofuran.
The invention provides a crystal form B of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form B has characteristic peaks at angles of 2 theta of 5.14+/-0.2 degrees, 11.74+/-0.2 degrees, 14.96+/-0.2 degrees, 18.54+/-0.2 degrees, 19.06+/-0.2 degrees, 23.12+/-0.2 degrees, 25.52+/-0.2 degrees and 28.42+/-0.2 degrees.
The invention provides a crystal form B of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form B has characteristic diffraction peaks at angles of 5.14±0.2°、11.74±0.2°、14.24±0.2°、14.96±0.2°、15.26±0.2°、15.52±0.2°、16.06±0.2°、16.48±0.2°、17.06±0.2°、18.54±0.2°、19.06±0.2°、20.94±0.2°、23.12±0.2°、25.52±0.2° and 28.42+/-0.2 degrees of 2 theta.
Form B of the present application uses Cu-Ka radiation, X-ray powder diffraction patterns expressed in terms of 2θ, with characteristic diffraction peaks around 5.14±0.2°、11.74±0.2°、14.24±0.2°、14.96±0.2°、15.26±0.2°、15.52±0.2°、16.06±0.2°、16.48±0.2°、17.06±0.2°、18.54±0.2°、19.06±0.2°、20.94±0.2°、23.12±0.2°、25.52±0.2° and 28.42±0.2°.
Preferably, the X-ray powder diffraction pattern of form B is substantially as shown in figure 4.
The differential scanning calorimetric profile (DSC) of form B is shown in FIG. 5, which has a maximum endothermic peak at 178.59.+ -. 3 ℃.
The thermogravimetric analysis (TGA) of form B is shown as 6, which has no significant weight loss in the range of 30-130 ℃.
The invention provides a crystal form C of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern has characteristic peaks at angles of 2 theta of 5.28+/-0.2 degrees, 12.12+/-0.2 degrees, 14.78+/-0.2 degrees, 17.02+/-0.2 degrees, 18.00+/-0.2 degrees, 19.14+/-0.2 degrees, 24.92+/-0.2 degrees and 29.36+/-0.2 degrees.
The invention provides a crystal form C of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at angles of 5.28±0.2°、10.64±0.2°、12.12±0.2°、14.78±0.2°、15.60±0.2°、16.04±0.2°、17.02±0.2°、18.00±0.2°、19.14±0.2°、19.52±0.2°、24.92±0.2° and 29.36+/-0.2 degrees of 2 theta.
Form C of the present application uses Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of 2θ, with characteristic diffraction peaks around 5.28±0.2°、10.64±0.2°、12.12±0.2°、14.78±0.2°、15.60±0.2°、16.04±0.2°、17.02±0.2°、18.00±0.2°、19.14±0.2°、19.52±0.2°、24.92±0.2° and 29.36±0.2°.
Preferably, the X-ray powder diffraction pattern of form C is substantially as shown in fig. 7.
The differential scanning calorimetric profile (DSC) of form C is shown in FIG. 8, which has a maximum endothermic peak at 182.73.+ -. 3 ℃.
The thermogravimetric analysis (TGA) of form C is shown in figure 9, with no significant weight loss in the range of 30-160 ℃.
The invention provides a crystal form E of a compound shown in a formula (I), wherein an X-ray powder diffraction pattern of the crystal form E has characteristic diffraction peaks at angles of 9.28±0.2°、10.98±0.2°、11.94±0.2°、12.44±0.2°、14.52±0.2°、16.54±0.2°、17.20±0.2°、18.06±0.2°、18.66±0.2°、19.10±0.2°、20.44±0.2°、20.88±0.2°、21.90±0.2°、22.40±0.2°、23.38±0.2°、24.62±0.2°、26.04±0.2°、27.40±0.2° and 30.44+/-0.2 degrees of 2 theta.
Form E of the present application uses Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of 2θ, with a characteristic diffraction peak near 9.28±0.2°、10.98±0.2°、11.94±0.2°、12.44±0.2°、14.52±0.2°、16.54±0.2°、17.20±0.2°、18.06±0.2°、18.66±0.2°、19.10±0.2°、20.44±0.2°、20.88±0.2°、21.90±0.2°、22.40±0.2°、23.38±0.2°、24.62±0.2°、26.04±0.2°、27.40±0.2°、30.44±0.2°.
Preferably, the X-ray powder diffraction pattern of form E is substantially as shown in figure 10.
The differential scanning calorimetric profile (DSC) of form E is shown in FIG. 11.
The thermogravimetric analysis (TGA) of form E is shown in figure 12, with no significant weight loss in the range of 30-130 ℃.
The beneficial effects brought by the invention are as follows:
1. the crystal form A, B, C prepared by the application has low hygroscopicity, high solubility and excellent physical stability and chemical stability.
2. The preparation condition of the crystal form A, B, C is mild, and the operation is simple. By controlling each key parameter in the preparation process of the crystal form A, B, C, the preparation method can obtain a single crystal form, has good process reproducibility, shows unexpected purification effect and is beneficial to large-scale industrialization.
Drawings
Figure 1 is an XRD pattern of form a obtained in example 1.
FIG. 2 is a DSC chart of form A obtained in example 1.
FIG. 3 is a TGA spectrum of form A obtained in example 1.
Fig. 4 is an XRD pattern of form B obtained in example 6.
FIG. 5 is a DSC chart of form B obtained in example 6.
FIG. 6 is a TGA spectrum of form B obtained in example 6.
Fig. 7 is an XRD pattern of form C obtained in example 7.
FIG. 8 is a DSC chart of form C obtained in example 7.
FIG. 9 is a TGA spectrum of form C obtained in example 7.
Figure 10 is an XRD pattern of form E obtained in example 8.
FIG. 11 is a DSC chart of form E obtained in example 8.
FIG. 12 is a TGA spectrum of form E obtained in example 8.
Fig. 13 is an XRD comparison pattern before and after form a is placed for influencing factors.
FIG. 14 is a DSC contrast chart of form A before and after placement of influencing factors.
Fig. 15 is a TGA comparison plot of form a before and after placement of the influencing factors.
Figure 16 is an XRD contrast pattern of form B before and after placement of the influencing factors.
FIG. 17 is a DSC contrast chart of form B before and after placement of influencing factors.
Figure 18 is an XRD contrast pattern of form C before and after placement of the influencing factors.
Fig. 19 is a DSC profile before and after form C placement of influencing factors.
Figure 20 is an XRD contrast pattern of form E before and after placement of the influencing factors.
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.
The abbreviations used in the present application are explained as follows:
XRD: powder diffraction by X-rays
The X-ray powder diffraction (XRD) test of the application is carried out by adopting a Liaoning Dandong DX-2700B powder diffractometer, and specific parameters are as follows:
DSC: differential scanning calorimeter
The Differential Scanning Calorimeter (DSC) is measured by adopting METTLER TOLEDO model DSC-1, the heating rate is 10 ℃/min, the temperature range is 25-200 ℃, and the nitrogen purging rate in the test process is 50mL/min.
TGA: thermogravimetric analyzer
The thermogravimetric analysis (TGA) is measured by adopting METTLER TOLEDO model TGA-2, the heating rate is 10 ℃/min, the temperature range is 30-300 ℃, and the nitrogen purging rate in the test process is 20mL/min. Example 1: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride form A
To 36.100g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (purity: 99.23%) was added 650mL of acetone, which was dissolved by stirring, 6.950mL of concentrated hydrochloric acid (36% strength) was slowly added at 5℃and stirred at 5℃for 15 hours after the dropwise addition, and the mixture was filtered and dried under vacuum at 60℃to give 29.730g of a white solid with a yield of 76.11% and a purity of 99.92%. The hydrochloric acid content was found to be 7.87% (theoretical 7.58%) by titration.
The resulting samples were subjected to differential scanning calorimetric (FIG. 2) and thermogravimetric analysis (FIG. 3) with melting endotherm peaks in the range of 173.84-178.12 ℃ and no significant weight loss in the range of 30-150 ℃. This form was designated form a.
The X-ray powder measurement was performed using Cu-ka rays, whose spectra have diffraction angles, interplanar spacings, and relative intensities as shown in table 1:
TABLE 1 diffraction angle, interplanar spacing and relative intensity for form A
The error of the 2 theta diffraction angle is + -0.20 deg..
Still further, form a prepared in example 1 has an XRD pattern substantially as shown in figure 1.
Example 2: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride form A
To 1.576g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (purity: 96.64%) was added 60mL of ethyl acetate, and the mixture was dissolved by stirring, 303. Mu.L of concentrated hydrochloric acid (36% strength) was slowly added at 5℃and stirred at 0℃for 3 hours after the addition, and the mixture was filtered and dried under vacuum at 60℃to give 1.047g of a white solid with a yield of 61.41% and a purity of 99.46%. The hydrochloric acid content was found to be 8.20% (theoretical 7.58%) by titration. The powder diffraction pattern, differential scanning calorimetric pattern and thermogravimetric analysis pattern thereof were substantially identical to those of example 1.
Example 3: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride form A
To 1.392g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (purity: 96.64%) was added 56mL of ethyl acetate, which was dissolved by stirring, 1.565mL of ethyl hydrogen chloride solution (concentration: 2 mol/L) was slowly added at 5℃and stirred at 5℃for 24 hours after the completion of the dropwise addition, and the mixture was filtered and dried under vacuum at 60℃to give 1.109g of a white solid with a yield of 73.64% and a purity of 99.39%. The powder diffraction pattern, differential scanning calorimetric pattern and thermogravimetric analysis pattern thereof were substantially identical to those of example 1.
Example 4: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride form A
To 0.287g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (purity: 92.68%) was added 6mL of acetonitrile, and the mixture was dissolved by stirring, 55. Mu.L of concentrated hydrochloric acid (36% strength) was slowly added at 5℃and stirred at 5℃for 3 hours after the completion of the dropwise addition, then 3mL of methyl t-butyl ether was added and stirring was continued for 3 hours, filtered and dried under vacuum at 60℃to give 0.242g of a white solid with a yield of 77.93% and a purity of 98.79%. The powder diffraction pattern, differential scanning calorimetric pattern and thermogravimetric analysis pattern thereof were substantially identical to those of example 1.
Example 5: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride form A
To 0.289g of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine (purity: 92.68%) was added 6mL of tetrahydrofuran, and the mixture was dissolved by stirring, 56. Mu.L of concentrated hydrochloric acid (36% strength) was slowly added at 5℃and stirred at 5℃for 3 hours after the completion of the dropwise addition, then 3mL of N-heptane was added and stirring was continued for 3 hours, filtered and dried under vacuum at 60℃to give 0.238g of a white solid with a yield of 76.11% and a purity of 93.53%. The powder diffraction pattern, differential scanning calorimetric pattern and thermogravimetric analysis pattern thereof were substantially identical to those of example 1.
Example 6: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride form B
To 1.700g of form A (purity: 99.92%) was added 17mL of isopropanol, stirred at 60℃for 6h, filtered and dried under vacuum at 60℃to give 1.203g of a white solid in a yield of 70.76% and a purity of 100.00%. The hydrochloric acid content was found to be 7.68% (theoretical 7.58%) by titration.
The resulting samples were subjected to differential scanning calorimetric (FIG. 5) and thermogravimetric analysis (FIG. 6) with melting endotherm peaks in the 175.41-180.81 ℃range and no significant weight loss in the 30-130 ℃. This form was designated form B.
The X-ray powder measurement was performed using Cu-ka rays, whose spectra have diffraction angles, interplanar spacings, and relative intensities as shown in table 2:
TABLE 2 diffraction angle, interplanar spacing and relative intensity for form B
The error of the 2 theta diffraction angle is + -0.20 deg..
Still further, form B prepared in example 6 has an XRD pattern substantially as shown in figure 4.
Example 7: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride form C
To 2.000g of form A (purity: 99.92%) was added 30mL of isopropyl acetate, stirred at 60℃for 16 hours, filtered, and dried under vacuum at 60℃to give 1.894g of a white solid in 94.70% yield and 100.0% purity. The hydrochloric acid content was found to be 7.75% (theoretical 7.58%) by titration.
The resulting samples were subjected to differential scanning calorimetric (FIG. 8) and thermogravimetric analysis (FIG. 9) with melting endotherm peaks in the 180.15-184.79℃range and no significant weight loss in the 30-160 ℃. This form was designated form C.
The X-ray powder measurement was performed using Cu-ka rays, whose spectra have diffraction angles, interplanar spacings, and relative intensities as shown in table 3:
TABLE 3 diffraction angle, interplanar spacing and relative intensity for form C
The error of the 2 theta diffraction angle is + -0.20 deg..
Still further, form C prepared in example 7 has an XRD pattern substantially as shown in figure 7.
Example 8: preparation of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride form E
To 2.000g of form A (purity: 99.92%) was added 20mL of butyl formate, stirred at 60℃for 18h, filtered and dried under vacuum at 60℃to give 1.058g of a white solid in a yield of 52.90% and a purity of 98.82%. The hydrochloric acid content was found to be 7.68% (theoretical 7.58%) by titration.
The resulting samples were subjected to differential scanning calorimetric analysis (FIG. 11) and thermogravimetric analysis (FIG. 12) which showed no melting endotherm in the range of 25-200℃and no significant weight loss in the range of 30-130 ℃. This form was designated form E.
The X-ray powder measurement was performed using Cu-ka rays, whose spectra have diffraction angles, interplanar spacings, and relative intensities as shown in table 4:
TABLE 4 diffraction angle, interplanar spacing and relative intensity for form E
The error of the 2 theta diffraction angle is + -0.20 deg..
Still further, form E prepared in example 8 has an XRD pattern substantially as shown in figure 10.
Test example 1: stability investigation experiment
To examine the physical and chemical stability of the various crystalline forms prepared in the present invention, form a prepared in example 3, form B prepared in example 6, form C prepared in example 7 and form E samples prepared in example 8 were left open for 30 days under three conditions of high temperature (60 ℃), high humidity (92.5% rh) and light (4500 lx±500 lx), respectively, sampled for 5 days, 15 days, 30 days, tested XRD, DSC, TGA and HPLC, and compared with the results for 0 days, the results were as follows:
TABLE 5 factor influence stability test data for form A
TABLE 6 influence factor stability test data for form B
TABLE 7 stability test data on influencing factors for form C
TABLE 8 factor influence stability test data for form E
As can be seen from Table 5 and FIGS. 13 to 15, form A was stable in crystal morphology when left under three conditions of high temperature (60 ℃), high humidity (92.5% RH) and light irradiation for 30 days, and showed no significant moisture absorption and no significant decrease in purity.
From Table 6 and FIGS. 16 to 17, it is understood that form B was stable in crystal morphology without significant decrease in purity when left under three conditions of high temperature (60 ℃), high humidity (92.5% RH) and light irradiation for 30 days.
As can be seen from Table 7 and FIGS. 18 to 19, form C was stable in crystal morphology without significant decrease in purity when left under three conditions of high temperature (60 ℃), high humidity (92.5% RH) and light irradiation for 30 days.
As can be seen from table 8 and fig. 20, form E remained stable in crystal morphology when left under high temperature (60 ℃) and light conditions for 30 days, but had significantly reduced purity and completely deliquesced under high humidity (92.5% rh) conditions.
Test example 2: moisture permeability investigation experiment
The hygroscopicity of form a, form B and form C was examined according to the chinese pharmacopoeia of the 2020 edition, guidelines for drug hygroscopicity test, and the results are shown in table 9:
TABLE 9 results of hygroscopicity tests for different crystal forms
The results of the hygroscopicity test show that the crystal form A, the crystal form B and the crystal form C have slightly hygroscopicity.
Test example 3: solubility test
To examine the solubility of form a prepared in accordance with the present invention in water, excess form a was dissolved in aqueous solutions of different pH, and supernatants were taken at 0.5h, 1h and 24h, respectively, and tested for solubility, as follows:
table 10 solubility results for form a
The solubility test result shows that the solubility of the crystal form A in pure water and media with different pH values is more than 3mg/mL.
Test example 4: in vivo pharmacokinetic testing in rats
(1) Purpose of test
The concentration level of the drug in plasma and its pharmacokinetic profile were examined after single oral administration of different crystal forms to rats at the same dose. Test animals: SD rats, female 3, 200-220g each, were supplied by Chengdu Ai Siwei mol Biotech Co.
(3) Test method
The test sample was prepared into a solution of 0.25mg/mL with physiological saline, administered to the tail vein in a volume of 4mL/kg (administration dose of 1 mg/kg), blood was taken from the jugular vein 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 6h, 8h before and after administration, placed in an anticoagulant tube containing EDTA-K2, centrifuged at low temperature of 2000g at 4℃and plasma was transferred to a microcentrifuge tube for LCMS/MS detection.
(4) Test results
The main pharmacokinetic parameters of female and male rats after single oral administration of the different crystal forms are shown in the following tables 11 and 12:
TABLE 11 Primary pharmacokinetic parameters after Single oral administration in female mice
| Parameters (parameters) | Crystal form A | Crystal form B | Crystal form C | Crystal form E |
| T1/2(h) | 1.89±0.42 | 1.43±0.06 | 1.45±0.12 | 1.71±0.33 |
| Cmax(ng·mL-1) | 159.1±59.19 | 137.5±3.54 | 148.7±17.01 | 149.0±39.89 |
| AUClast(h·ng·mL-1) | 233.4±63.58 | 175.2±27.57 | 196.7±30.31 | 231.9±30.59 |
| Cl_F_obs(mL/hr/kg) | 4.17±0.92 | 5.64±0.85 | 5.05±0.72 | 4.16±0.52 |
| MRT(h) | 2.01±0.33 | 1.56±0.01 | 1.68±0.15 | 1.85±0.37 |
Table 12 main pharmacokinetic parameters of male mice after single oral administration
Animal experiments show that the maximum blood concentration of the crystal forms A, B, C and E in female mice and male mice can reach 120 ng.mL -1, which proves that the four crystal forms have better bioavailability.
In summary, crystalline form A, B, C has good crystalline form stability, chemical stability and bioavailability.
Meanwhile, the preparation condition of the crystal form A, B, C is mild, and the operation is simple; by controlling each key parameter in the preparation process, a single crystal form is obtained, and the process reproducibility is good; the crude product of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine with the purity of more than 90% and less than 98% is utilized to obtain the crystal form of the compound (I) with the purity of more than 99%, and the unexpected purification effect is shown.
It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds of the present application and the process for preparing them without departing from the spirit or scope of the application, and thus the scope of the application encompasses numerous modifications and variations as come within the scope of the claims and their equivalents.
Claims (15)
1. Crystalline form B of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride having an X-ray powder diffraction pattern with characteristic peaks at 2θ angles of 5.14±0.2°, 11.74±0.2°, 14.96±0.2°, 18.54±0.2°, 19.06±0.2°, 23.12±0.2°, 25.52±0.2° and 28.42±0.2°.
2. Form B of claim 1, wherein the X-ray powder diffraction pattern of form B has characteristic peaks at angles of 2Θ of 5.14±0.2°、11.74±0.2°、14.24±0.2°、14.96±0.2°、15.26±0.2°、15.52±0.2°、16.06±0.2°、16.48±0.2°、17.06±0.2°、18.54±0.2°、19.06±0.2°、20.94±0.2°、23.12±0.2°、25.52±0.2° and 28.42 ± 0.2 °.
3. Form B of claim 2, wherein the X-ray powder diffraction pattern of form B is substantially as shown in figure 4.
4. Form B of any one of claims 1-3, wherein the differential scanning calorimetry pattern of form B has a maximum endothermic peak in the range of 178.59 ± 3 ℃.
5. Form B of claim 4, wherein the differential scanning calorimeter profile of form B is substantially as shown in figure 5.
6. Form B of any one of claims 1-3, wherein the thermogravimetric analysis profile of form B is as shown in figure 6.
7. Crystalline form C of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride having an X-ray powder diffraction pattern with characteristic peaks at 2θ angles of 5.28±0.2°, 12.12±0.2°, 14.78±0.2°, 17.02±0.2°, 18.00±0.2°, 19.14±0.2°, 24.92±0.2° and 29.36±0.2°.
8. Form C of claim 7, wherein the X-ray powder diffraction pattern of form C has characteristic peaks at angles of 2Θ of 5.28±0.2°、10.64±0.2°、12.12±0.2°、14.78±0.2°、15.60±0.2°、16.04±0.2°、17.02±0.2°、18.00±0.2°、19.14±0.2°、19.52±0.2°、24.92±0.2° and 29.36 ± 0.2 °.
9. Form C of claim 8, wherein the X-ray powder diffraction pattern of form C is substantially as shown in figure 7.
10. Form C of any one of claims 7-9, wherein the differential scanning calorimetry pattern of form C has a maximum endothermic peak in the range of 182.73 ± 3 ℃.
11. Form C of claim 10, wherein the differential scanning calorimeter profile of form C is substantially as shown in figure 8
12. Form C of any one of claims 7-9, wherein the thermogravimetric analysis profile of form C is as shown in figure 9.
13. Use of a crystalline form of (R) -2- (9- (4-fluorophenyl) -6-oxaspiro [4,5] decan-9-yl) -N- (2- (pyridin-4-yl) benzyl) ethylamine monohydrochloride according to any one of claims 1-3, 7-9 for the preparation of a mu receptor agonist drug.
14. Use according to claim 13, for the preparation of analgesic drugs.
15. The use according to claim 14, for the preparation of a medicament for moderate to severe pain.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210072807 | 2022-01-21 | ||
| CN2022100728070 | 2022-01-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116041336A CN116041336A (en) | 2023-05-02 |
| CN116041336B true CN116041336B (en) | 2024-07-09 |
Family
ID=86123374
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310017273.6A Active CN116041336B (en) | 2022-01-21 | 2023-01-06 | New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116041336B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115677675A (en) * | 2021-07-21 | 2023-02-03 | 成都苑东生物制药股份有限公司 | Salt of 6-oxaspiro [4,5] decane compound, preparation method and application |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI2688403T1 (en) * | 2011-03-23 | 2017-08-31 | Trevena, Inc. | Opioid receptor ligands and methods of using and making same |
| CA3008637A1 (en) * | 2015-12-17 | 2017-06-22 | Trevena, Inc. | Combinations of opioid receptor ligands and cytochrome p450 inhibitors |
| CN115124520A (en) * | 2017-07-04 | 2022-09-30 | 四川海思科制药有限公司 | Opioid receptor agonists and uses thereof |
| CN109516982B (en) * | 2017-09-18 | 2022-08-23 | 上海华汇拓医药科技有限公司 | Mu-opioid receptor agonist, preparation method thereof and application thereof in medicine field |
-
2023
- 2023-01-06 CN CN202310017273.6A patent/CN116041336B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115677675A (en) * | 2021-07-21 | 2023-02-03 | 成都苑东生物制药股份有限公司 | Salt of 6-oxaspiro [4,5] decane compound, preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116041336A (en) | 2023-05-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107428727B (en) | New crystal form of neratinib maleate and preparation method thereof | |
| CN111187253A (en) | Novel crystalline form of axitinib | |
| CN112142679A (en) | Gefitinib and vanillic acid eutectic methanol solvate and preparation method thereof | |
| CN108689991B (en) | New crystal salt of Vonoprazan and preparation method thereof | |
| CN110483486A (en) | A kind of western Tenylidone of Austria coughs up hydrochlorate crystal form and preparation method thereof | |
| CN103755687B (en) | Hydrochloric acid Tandospirone crystalline form I and preparation method thereof | |
| CN116041336B (en) | New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound | |
| EP2710009B1 (en) | Novel crystalline asenapine hydrochloride salt forms | |
| CN111233878B (en) | Galanthamine pamoate and preparation method thereof | |
| CN110540542A (en) | Sodium salt and crystal form of phenylacetic acid compound and preparation method thereof | |
| EP2851363B1 (en) | Agomelatine acid radical composite, and preparation method and application thereof | |
| CN116589451B (en) | New crystal form, application and preparation method of 6-oxaspiro [4,5] decane compound | |
| CN113024557B (en) | Penamine A alkaloid structure simplified substance and application thereof | |
| CN111670191B (en) | Crystal form of pyridone derivative, preparation method and application | |
| JP2024500632A (en) | Preparation process of arimoclomol citrate and its intermediates | |
| CN112125910A (en) | Alvatinib crystal form and preparation method thereof | |
| KR20230008047A (en) | Crystal form of nitrosol soline prodrug, pharmaceutical composition containing it, method for its preparation and use thereof | |
| CN110845492B (en) | Ipratropium bromide monohydrate | |
| CN110845491B (en) | Ipratropium bromide crystal | |
| CN113929630B (en) | Gefitinib drug co-crystal | |
| CN113372332B (en) | Novel crystal form of octreotide | |
| CN113943270B (en) | Acetinib crystal form | |
| US11136314B2 (en) | Forms of afatinib dimaleate | |
| CN113929629A (en) | Acid addition salt of gefitinib | |
| CN106749048B (en) | Erlotinib hydrochloride crystal form compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20240313 Address after: 610200 Chengdu Tianfu International Biological City, Chengdu, Sichuan Province (No. 9 Lekang Road, Shuangliu District) Applicant after: Chengdu shuoder Pharmaceutical Co.,Ltd. Country or region after: China Address before: 611731 No. 8 Xiyuan Avenue, Chengdu High-tech Zone, Sichuan Province Applicant before: Chengdu Easton Biopharmaceuticals Co.,Ltd. Country or region before: China |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |