WO2014036865A1 - 芬戈莫德粘酸盐及其晶体的制备方法和用途 - Google Patents
芬戈莫德粘酸盐及其晶体的制备方法和用途 Download PDFInfo
- Publication number
- WO2014036865A1 WO2014036865A1 PCT/CN2013/080393 CN2013080393W WO2014036865A1 WO 2014036865 A1 WO2014036865 A1 WO 2014036865A1 CN 2013080393 W CN2013080393 W CN 2013080393W WO 2014036865 A1 WO2014036865 A1 WO 2014036865A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fingolimod
- crystal form
- mucate
- solution
- crystal
- Prior art date
Links
- 229960000556 fingolimod Drugs 0.000 title claims abstract description 60
- 239000013078 crystal Substances 0.000 title claims abstract description 51
- KKGQTZUTZRNORY-UHFFFAOYSA-N fingolimod Chemical compound CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 KKGQTZUTZRNORY-UHFFFAOYSA-N 0.000 title claims abstract 16
- 238000000034 method Methods 0.000 title claims description 18
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 14
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 claims abstract description 7
- 239000003937 drug carrier Substances 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 229940075993 receptor modulator Drugs 0.000 claims abstract description 4
- 239000002955 immunomodulating agent Substances 0.000 claims abstract 2
- 229940121354 immunomodulator Drugs 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 claims description 15
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 230000002584 immunomodulator Effects 0.000 abstract 1
- SWZTYAVBMYWFGS-UHFFFAOYSA-N fingolimod hydrochloride Chemical compound Cl.CCCCCCCCC1=CC=C(CCC(N)(CO)CO)C=C1 SWZTYAVBMYWFGS-UHFFFAOYSA-N 0.000 description 52
- 239000002253 acid Substances 0.000 description 13
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 7
- 229960004967 fingolimod hydrochloride Drugs 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000002411 thermogravimetry Methods 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 238000001069 Raman spectroscopy Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000000835 fiber Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229960000074 biopharmaceutical Drugs 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 210000003563 lymphoid tissue Anatomy 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011833 salt mixture Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000011345 viscous material Substances 0.000 description 2
- KCLRDQBTTJFLLU-UHFFFAOYSA-N 2-amino-2-methyl-4-(4-octylphenyl)butane-1,1-diol Chemical compound CCCCCCCCC1=CC=C(CCC(C)(N)C(O)O)C=C1 KCLRDQBTTJFLLU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 1
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000012863 analytical testing Methods 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000012362 drug development process Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 230000008863 intramolecular interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003836 solid-state method Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- 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
Definitions
- the present invention relates to the field of medicinal chemistry, and in particular to fingolimodic acid salts, crystalline forms A thereof, and processes for their preparation.
- Fingolimodidate is a pharmaceutically acceptable salt for the treatment or prevention of various autoimmune disorders. Background technique
- a salt form may have a polymorphic form.
- Polymorphism is not only controlled by the internal structure of the molecule itself, functional group properties, intramolecular and intermolecular interactions, but also by drug synthesis process design, crystallization and purification conditions, formulation excipient selection, formulation process Route and granulation methods, as well as storage conditions, packaging materials and other factors. Different crystal forms have different colors, melting points, dissolution, dissolution properties, chemical stability, reactivity, mechanical stability, etc. These physicochemical properties or processability sometimes directly affect the safe and effective performance of the drug. Therefore, crystal form research and control has become an important research content in the drug development process.
- Crystallization studies include two stages of crystal discovery and crystal form optimization.
- the crystal discovery stage a variety of crystallization methods are used, such as melt crystallization, solution evaporation, rapid cooling and suspension crystallization, by changing the crystallization conditions, solvent , external factors affecting the crystallization of the drug, such as temperature, speed and ratio of suspended solvent.
- High-throughput sample preparation platform is used, and hundreds of crystallization tests are performed at the same time, using micro sample preparation techniques and analytical testing methods. New crystal forms were prepared and discovered.
- the new crystal form is subjected to process amplification and preparation conditions, and various solid characterization methods such as X-ray diffraction, solid state nuclear magnetic resonance, Raman spectroscopy, infrared spectroscopy and the like are used to characterize the crystal.
- various solid characterization methods such as X-ray diffraction, solid state nuclear magnetic resonance, Raman spectroscopy, infrared spectroscopy and the like are used to characterize the crystal.
- DSC and TGA are used.
- the physicochemical properties of the crystal forms were studied by DVS, HPLC, etc., and the hygroscopicity, chemical stability, physical state stability, and processability of different crystal forms were compared.
- the most preferred solid form is selected for development.
- the chemical name of Fingolimod is 2-(4-n-octylphenethyl)-2-aminopropanediol, which has the following chemical formula:
- Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator that binds to the S1P receptor on the surface of lymphocytes after phosphorylation in vivo, alters lymphocyte migration, and forces cells into lymphoid tissues, preventing them from Leave the lymphoid tissue to enter the graft to achieve immunosuppressive effects.
- S1P sphingosine-1-phosphate
- hydrochloride is mainly used to treat multiple sclerosis.
- Fingolimod has been reported in various salt forms. Fingolimod hydrochloride is reported in the patent WO9408943; four crystal forms of I-IV of fingolimod hydrochloride are reported in the patent WO2010055028 and a preparation method thereof; fingolimod is reported in the patent WO2010055027 Tartrate, lactate, benzoate, succinate, malonate, acetate and propionate and corresponding crystalline forms; fingolimod's ascorbate, amber is reported in patent WO2011009634 Acid salts, oxalates, phosphates, mandelates and adipates, and the corresponding crystalline forms.
- the present invention reports a new fingolimod salt type, fingolimod's mucate, and its crystalline form A crystal form.
- the present invention aims to provide a stable fingolimod acid salt and its crystal form A.
- the invention provides
- fingolimodic acid salt exists in the form of crystal, has high crystallinity, low hygroscopicity, and forms a regular crystal form, which is beneficial to the process of the drug and improves the performance of the drug.
- the fingolimod acid salt provided by the present invention is a crystal form A.
- Form A of fingolimod's mulate characterized by an X-ray powder diffraction pattern obtained with Cu Ko rays at about 6.1, 9.1, 12.2, 14.9, 15.7, 17.8, 18.5, 19.6, 20.6, 21.4 , 21.8, 22.5, 24.5° have characteristic peaks. Its differential scanning calorimetry (DSC) has a characteristic endothermic peak at about 226 °C.
- the present invention also provides a method for preparing a crystal form of fingomod's mulate, comprising the following steps:
- Viscous acid solution Dissolve the viscous acid in water to form an aqueous solution of 0.001 M-0.01 M;
- Fingolimod solution Dissolve fingolimod in organic solvent or water to form 0.005 M-0.02
- the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone and methyl isobutyl ketone.
- the organic solvent is selected from the group consisting of a mixture of one or more of methanol, ethanol, tetrahydrofuran, acetone, methyl ethyl ketone and methyl isobutyl ketone.
- the present invention also provides the use of said fingolimodide and its crystalline form A in the preparation of a medicament as a sphingosine-1-phosphate (S1P) receptor modulator, more specifically for preparation as an immunization
- S1P sphingosine-1-phosphate
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising fingolimodic acid salt as described above or said crystalline form A and a pharmaceutically acceptable carrier.
- the present invention relates to a new fingolimod salt type, fingolimodide, and its crystalline form A crystal form, by X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential Characterization by solid state methods such as scanning calorimetry (DSC), infrared (IR), Raman, and hygroscopicity analysis (DVS).
- XRPD X-ray powder diffraction
- TG thermogravimetric analysis
- DSC scanning calorimetry
- IR infrared
- Raman Raman
- the preparation method of the invention is simple in operation, good in reproducibility, and stable in obtaining the target crystal form.
- the fingolimodide salt of the present invention has good stability. Under the conditions of 80 ° C / 75% relative humidity, commercially available fingolimod hydrochloride (FTY720) began to decompose two weeks and turned into a brown viscous material. The fingolimod acid salt still maintains a good solid state and is more chemically stable.
- the present invention also provides a pharmaceutical preparation of the fingolimodic acid salt A crystal form of the present invention.
- the pharmaceutical preparation of the present invention contains 0.01 to 20% by weight, preferably 0.1 to 10% by weight, based on the total weight of the preparation, of the salt.
- the pharmaceutical preparation may be a solid pharmaceutical composition in a form suitable for oral administration such as a tablet or a capsule.
- the composition can be prepared by conventional methods, for example, by mixing a salt of the present invention with a pharmaceutically acceptable carrier or diluent.
- the composition provides a convenient means of oral administration of the compound, has no disadvantages of injectable or oral liquid preparations, and has good physicochemical and storage properties.
- Example 1 X-ray powder diffraction pattern of fingolimod new mulate A crystal form.
- Figure 2. Example 1 Thermogravimetric analysis (TG) plot of fingolimod new mulate A crystal form.
- Example 1 Differential scanning calorimetry (DSC) plot of fingolimod new mulate A crystal form.
- Figure 4. Example 1 Infrared spectroscopy (IR) image of fingolimod new mulate A crystal form.
- the X-ray powder diffraction pattern of the product obtained by Cu ⁇ ray diffraction is about 2: having a significant peak as given below: .
- the fingolimodide 500 mg obtained in Example 1 was placed in an Erlenmeyer flask and 25 mL of ethanol was added. Stir by adding a magnetic stirrer to form a suspension. The rotation speed was 200 rpm and the mixture was stirred at room temperature for 3 days. The suspension was filtered, washed with a small amount of ethanol solvent and dried at room temperature under reduced pressure. A white crystalline powder (type A) of 455 mg was obtained in a yield of 91%.
- the X-ray powder diffraction pattern of this product obtained by Cu ⁇ ray diffraction is about 2: having a significant peak as given below:
- the fingolimodic acid salt 500 mg obtained in Example 2 was dissolved in methanol, slowly evaporated, filtered, and dried under reduced pressure at room temperature.
- a white crystalline powder (type A) of 400 mg was obtained in a yield of 80%.
- the X-ray powder diffraction pattern of this product obtained by Cu ⁇ ray diffraction is about 2: having a significant peak as given below:
- the X-ray powder diffraction pattern of this product obtained by Cu ⁇ ray diffraction is about 2: having a significant peak as given below:
- the X-ray powder diffraction pattern of this product obtained by Cu ⁇ ray diffraction is about 2: having a significant peak as given below:
- micronized fingolimod slime salt 116.7 g was sieved, mixed with 9623.8 g of microcrystalline fiber, and passed through a 30 mesh sieve.
- a product composition was prepared by mixing 200 g of magnesium stearate with a fingolimodide salt mixture using a 20 mesh sieve. The product composition was then compressed on a tablet machine using a 7 mm die to form 120 mg tablets, each containing:
- Example 7 the method of Example 7 was repeated except that hydrogenated castor oil was used in place of magnesium stearate.
- Example 2 5.8 g of the fingolimod's crystal form A obtained in Example 1 was mixed with 376 g of microcrystalline fibers, and the mixture was sieved through a 35 mesh sieve.
- each capsule contains:
- Example 9 the method of Example 9 was repeated except that hydrogenated castor oil was used in place of magnesium stearate.
- Example 9 the procedure of Example 9 was repeated except that hydroxypropylmethylcellulose was used in place of hydroxypropylcellulose.
- the high-performance liquid phase was used to detect changes in fingolimod content under the same conditions for 2, 4, and 6 weeks.
- fingolimod hydrochloride At 80 ° C / 75% relative humidity, commercially available fingolimod hydrochloride (FTY720) began to decompose two weeks and turned into a brown viscous material. The fingolimod acid salt still maintains a good solid state and the chemical is more stable.
Abstract
本发明涉及一种芬戈莫德粘酸盐、其A晶型及其制备方法,所述晶型A用Cu Kα射线衍射得到的X-射线粉末衍射图谱在2θ约:6.1,9.1,12.2,14.9,15.7,17.8,18.5,19.6,20.6,21.4,21.8,22.5,24.5°具有特征峰。本发明还涉及所述A晶型在制备作为鞘氨醇-l-磷酸(S1P)受体调节剂的药物中的用途,更具体而言,涉及在制备作为免疫调节剂的药物中用途。此外,本发明还提供了药物组合物,其包含所述的芬戈莫德粘酸盐或所述的A晶型以及药学上可接受的载体。
Description
芬戈莫德粘酸盐及其晶体的制备方法和用途
技术领域 本发明属药物化学技术领域, 具体涉及芬戈莫德粘酸盐、 其晶型 A以及 它们的制备方法。 芬戈莫德粘酸盐是治疗或预防各种自身免疫性病症的可药 用的盐。 背景技术
近一半的药物分子都是以盐的形式存在和给药的。 用一种与药物带相反 电荷的分子或离子与药物结合成盐, 可改善药物某些不理想的物理化学或生 物药学性质, 如改变药物的溶解度或溶出度、 降低吸湿性、 提高稳定性、 改 变熔点、 改善研磨性能、 便于制备纯化、 提高渗透性等。 药物的每一种盐型 都具有独特的性质, 盐型的最终确定其实就是在物理化学性质和生物药学性 质之间寻找平衡。 一种盐型可能存在多晶型。 多晶型现象不光受到分子本身 的空间结构和官能基团性能,分子内和分子间的相互作用等内在因素的控制, 它还受药物合成工艺设计、 结晶和纯化条件、 制剂辅料选择、 制剂工艺路线 和制粒方法、 以及储存条件、 包装材料等诸方面因素的影响。 不同晶型具有 不同的颜色、 熔点、 溶解、 溶出性能、 化学稳定性、 反应性、 机械稳定性等, 这些物理化学性能或可加工性能有时直接影响到药物的安全、 有效性能。 因 此, 晶型研究和控制成为药物研发过程中的重要研究内容。
晶型研究包括晶体发现和晶型优选的两个阶段, 在晶体发现阶段, 主要 采用多种结晶手段, 如熔融结晶, 溶液挥发, 快速冷却和混悬法的结晶方法, 通过改变结晶条件, 溶剂, 温度, 速度和混悬溶剂比例等影响药物结晶的外 部因素。 采用高通量样品制备平台, 同时经过数百次结晶试验, 运用微量样 品制备技术和分析测试手段。 制备和发现新的晶型。 在晶型优选阶段, 要对
于新的晶型进行工艺放大和制备条件摸索, 采用多种固体表征手段, 如 X-射 线衍射, 固体核磁共振, 拉曼光谱, 红外光谱等手段对晶体进行表征, 另外, 要采用 DSC、 TGA、 DVS、 HPLC等对晶型进行物化性能研究, 比较不同晶 型的吸湿性、 化学稳定、 物理状态稳定性、 可加工性等进行研究。 最后选择 最为优选的固体形态进行开发。 芬戈莫德(Fingolimod)的化学名为: 2-(4-正辛基苯乙基 )-2-氨基丙二醇, 其化学结构式如下:
芬戈莫德是鞘氨醇 -1-磷酸 (S1P)受体调节剂,在体内经磷酸化后与淋巴细 胞表面的 S1P受体结合, 改变淋巴细胞的迁移, 促使细胞进入淋巴组织, 阻 止其离开淋巴组织进入移植物, 从而达到免疫抑制的效果。 目前临床上主要 将其盐酸盐用于治疗多发性硬化症。
芬戈莫德有多种盐型的报道。 在专利 WO9408943 中报道了芬戈莫德盐 酸盐;在专利 WO2010055028中报道了芬戈莫德盐酸盐的 I-IV四种晶型及其 制备方法; 在专利 WO2010055027中报道了芬戈莫德的酒石酸盐、 乳酸盐、 苯甲酸盐、 琥珀酸盐、 丙二酸盐、 乙酸盐和丙酸盐以及相应的结晶形式; 在 专利 WO2011009634中报道了芬戈莫德的抗坏血酸盐、 琥珀酸盐、 草酸盐、 磷酸盐、 扁桃酸盐和己二酸盐以及相应的结晶形式。
发明内容
本发明在综合盐型筛选和晶型筛选的基础上, 报道一种芬戈莫德新的盐 型即芬戈莫德粘酸盐, 以及其结晶形式 A晶型。
研究发现, 芬戈莫德粘酸盐以晶体形式存在, 且结晶度高、 吸湿性小, 并形成规整的晶体型态, 因而有利于药物的工艺处理, 提高成药性能。
本发明提供的芬戈莫德粘酸盐为 A晶型。
芬戈莫德粘酸盐的 A晶型,其特征在于用 Cu Ko射线得到的 X-射线粉末 衍射图谱在 2Θ约: 6.1, 9.1, 12.2, 14.9, 15.7, 17.8, 18.5, 19.6, 20.6, 21.4, 21.8, 22.5, 24.5°具有特征峰。其差示扫描量热分析 (DSC)在约 226°C有特征吸热峰。
芬戈莫德粘酸盐的 A晶型 XRPD图如图 1所示,具有如下给出的显著峰:
度 (2Θ) 相对强度 (%)
6.1 91
9.1 100
12.2 16
14.9 3
15.3 3
17.8 12
18.6 6
19.6 8
20.6 7
21.4 90
21.8 27
22.5 9
24.6 30 本发明还提供了一种芬戈莫德粘酸盐的 A晶型的制备方法,包括如下歩 骤:
(1) 粘酸溶液: 将粘酸溶解在水中配成 0.001 M-0.01 M的水溶液;
(2) 芬戈莫德溶液:将芬戈莫德溶解在有机溶剂或水中配成 0.005 M-0.02
M的芬戈莫德溶液;
(3) 成盐: 将粘酸溶液和芬戈莫德溶液按照粘酸与芬戈莫德的摩尔比为 1 :2混合, 在 40°C条件下加热 1小时;
(4) 干燥: 反应后的溶液, 用溶剂洗涤后, 于室温至 100°C常压或减压烘 干即得 A型芬戈莫德粘酸盐结晶。
其中, 在歩骤 (2 ) 中, 所述有机溶剂选自甲醇、 乙醇、 异丙醇、 乙腈、 四氢呋喃、丙酮、丁酮和甲基异丁基酮中的一种或多种的混合物。在歩骤(4) 中, 所述有机溶剂选自甲醇、 乙醇、 四氢呋喃、 丙酮、 丁酮和甲基异丁基酮 中的一种或多种的混合物。
本发明也提供了所述的芬戈莫德粘酸盐及其 A晶型在制备作为鞘氨醇 -1- 磷酸 (S1P)受体调节剂的药物中的用途,更具体地为制备作为免疫调节剂的药 物中用途。
本发明还提供了药物组合物, 其包含如上所述的芬戈莫德粘酸盐或所述 的 A晶型以及药学上可接受的载体。
本发明涉及的一种芬戈莫德新的盐型即芬戈莫德粘酸盐, 以及其结晶形 式 A晶型, 经 X-射线粉末衍射 (XRPD)、 热失重分析 (TG)、 差示扫描量热分 析 (DSC )、 红外 (IR)、 拉曼 (Raman)以及吸湿性分析 (DVS)等固态方法表征。
本发明涉及的制备方法操作简单, 重现性好, 可以稳定获得目标晶型。
本发明涉及的芬戈莫德粘酸盐稳定性好。 在 80°C/75%相对湿度条件下, 市售的芬戈莫德盐酸盐 (FTY720)两周开始发生分解, 变成棕色粘稠物。 而芬 戈莫德粘酸盐仍保持良好的固体状态, 化学更稳定。
本发明还提供了本发明的芬戈莫德粘酸盐 A晶型的药物制剂。本发明的 药物制剂基于制剂的总重量含有 0.01至 20重量%、 优选 0.1至 10重量%的 所述盐。
该药物制剂可以使用适用于口服施用、 例如片剂或胶囊的形式的固体药 物组合物。 该组合物可以用常规方法制备, 例如通过将本发明的盐与可药用 载体或稀释剂混合。 该组合物提供了口服使用该化合物的便利方式, 没有注 射用或口服液体制剂的缺点并且具有良好的物理化学和贮存性质。
附图说明
图 1. 实施例 1芬戈莫德新粘酸盐 A晶型的 X-射线粉末衍射 图。 图 2. 实施例 1芬戈莫德新粘酸盐 A晶型的热失重分析 (TG)图。
图 3. 实施例 1芬戈莫德新粘酸盐 A晶型的差示扫描量热分析 (DSC)图。 图 4. 实施例 1芬戈莫德新粘酸盐 A晶型的红外光谱 (IR)图。
图 5. 实施例 1芬戈莫德新粘酸盐 A晶型的拉曼光谱 (Raman)图。
图 6. 实施例 1芬戈莫德新粘酸盐 A晶型的吸湿性分析 (DVS)图
具体实施方式
实施例 1
取 1.05 g粘酸溶解在 1000 mL水中配成 0.005 M的水溶液; 取 3.07 g芬 戈莫德溶解在 500 mL四氢呋喃溶剂中配成 0.02 M的芬戈莫德溶液。 将粘酸 溶液和芬戈莫德溶液混合, 在 40°C条件下加热 1小时。 反应后的溶液, 用四 氢呋喃溶剂洗涤后, 于室温至 100°C常压或减压烘干即得 A型芬戈莫德粘酸 盐结晶。
该产物用 Cu Κα射线衍射得到的 X-射线粉末衍射图谱在 2Θ约: 具有如 下给出的显著峰:
。度 (2Θ) 相对强度 (%)
6.1 91
9.1 100
12.2 16
14.9 3
15.3 3
17.8 12
18.6 6
19.6 8
20.6 7
21.4 90
21.8 27
22.5 9
24.6 30 实施例 2
取 1.05 g粘酸溶解在 1000 mL水中配成 0.005 M的水溶液; 取 3.07 g芬 戈莫德溶解在 500 mL甲醇溶剂中配成 0.02 M的芬戈莫德溶液。 将粘酸溶液 和芬戈莫德溶液混合, 在 40°C条件下加热 1小时。 反应后的溶液, 用甲醇溶 剂洗涤后, 于室温至 100°C常压或减压烘干即得 A型芬戈莫德粘酸盐结晶。
该产物用 Cu Κα射线衍射得到的 X-射线粉末衍射图谱在 2Θ约: 具有如 下给出的显著峰:
。度 (2Θ) 相对强度 (%)
6.1 91
9.1 100
12.2 16
14.9 3
15.3 3
17.8 12
18.6 6
19.6 8
20.6 7
21.4 90
21.8 27
22.5 9
24.6 30 实施例 3
取实施例 1 中得到的芬戈莫德粘酸盐 500 mg置于锥形瓶中, 加入乙醇 25 mL。 加入磁力搅拌子搅拌, 形成混悬液。 转速为 200 rpm, 保持在室温条 件下搅拌 3天。 混悬液过滤, 用少量乙醇溶剂洗涤后, 于室温减压干燥。 得 到白色结晶性粉末 (A型) 455 mg, 产率为 91%。
该产物用 Cu Κα射线衍射得到的 X-射线粉末衍射图谱在 2Θ约: 具有如 下给出的显著峰:
。度 (2Θ) 相对强度(%)
12.2 16
14.8 5
15.3 3
17.8 12
18.7 6
19.6 9
20.6 7
21.4 90
21.8 29
22.5 9
24.7 32 实施例 4
取实施例 2中得到的芬戈莫德粘酸盐 500 mg溶解在甲醇中, 缓慢挥发, 过滤, 于室温减压干燥。 得到白色结晶性粉末 (A型) 400 mg, 产率为 80%。
该产物用 Cu Κα射线衍射得到的 X-射线粉末衍射图谱在 2Θ约: 具有如 下给出的显著峰:
。度 (2Θ) 相对强度(%)
6.1 91
9.1 100
12.2 16
14.9 5
15. 2
17.8 12
18.6 8
19.7 8
20.6 7
21.4 90
21.8 26
22.5 9
24.6 30 实施例 5
取 1.05 g粘酸溶解在 1000 mL水中配成 0.005 M的水溶液; 取 3.07 g芬 戈莫德溶解在 500 mL乙醇溶剂中配成 0.02 M的芬戈莫德溶液。 将粘酸溶液 和芬戈莫德溶液混合, 在 40°C条件下加热 1小时。 反应后的溶液, 用乙醇溶 剂洗涤后, 于室温至 100°C常压或减压烘干即得 A型芬戈莫德粘酸盐结晶。
该产物用 Cu Κα射线衍射得到的 X-射线粉末衍射图谱在 2Θ约: 具有如 下给出的显著峰:
。度 (2Θ) 相对强度(%)
6.1 89
9.1 100
12.2 16
14.9 3
15.2 5
17.9 14
18.6 6
19.6 8
20.7 7
21.4 90
21.8 27
22.5 10
24.6 30 实施例 6
取 1.05 g粘酸溶解在 1000 mL水中配成 0.005 M的水溶液; 取 3.07 g芬 戈莫德溶解在 500 mL丙酮溶剂中配成 0.02 M的芬戈莫德溶液。 将粘酸溶液 和芬戈莫德溶液混合, 在 30°C条件下加热 1小时。 反应后的溶液, 用丙酮溶 剂洗涤后, 于室温至 100°C常压或减压烘干即得 A型芬戈莫德粘酸盐结晶。
该产物用 Cu Κα射线衍射得到的 X-射线粉末衍射图谱在 2Θ约: 具有如 下给出的显著峰:
度 (2Θ) 相对强度 (%)
6.1 90
9.1 100
12.2 16
14.9 3
15.3 7
17.8 12
18.6 6
19.6 8
20.6 7
21.4 90
21.8 27
22.5 8
24.7 30
实施例 7
将 116.7 g微粉化的芬戈莫德粘酸盐过筛,与 9623.8 g微晶纤维混合,并 过 30目筛。 使用 20目筛将 200 g硬脂酸镁与芬戈莫德粘酸盐混合物混合以 制备产物组合物。 然后将该产物组合物在压片机上用 7 mm的模具压制, 以 形成 120 mg片剂, 每片含有:
实施例 8
在另一实施例中, 重复实施例 7的方法, 不同的是用氢化蓖麻油替代硬 脂酸镁。
实施例 9
将 5.8 g实施例 1所得芬戈莫德粘酸盐 A晶型与 376 g微晶纤维混匀,然 后将该混合物通过 35目筛过筛。
将芬戈莫德粘酸盐混合物与 12 g羟丙基纤维素和 6 g硬脂酸镁一起加入 制粒机中。将混合物混匀后,在包封装置上将组合物填充到 3号硬明胶壳内。 向每粒胶囊加入 120 mg产物组合物。 因此, 每粒胶囊含有:
:戈莫德粘酸盐 1.7 mg
微晶纤维 113.9 mg
羟丙基纤维素 3.6 mg
硬脂酸镁 1.8 mg
心 H 120 mg
实施例 10
在另一实施例中, 重复实施例 9的方法, 不同的是用氢化蓖麻油替代硬 脂酸镁。
实施例 11
在另一实施例中, 重复实施例 9的方法, 不同的是用羟丙基甲基纤维素 替代羟丙基纤维素。
实验例 12
实施例 1所得的芬戈莫德粘酸盐 A晶型与购买的芬戈莫德盐酸盐原料药 之间的稳定性差异进行的加速实验: 取 FTY720与芬戈莫德粘酸盐各六份 10 mg于 1.5 mL玻璃瓶中。 三份放置在盛有 NaCl饱和溶液的密封干燥器, 并 放置在 80°C烘箱中;另三分直接放置在 80°C烘箱中;两种条件下分别在第二、 四、 六周取出一份, 观察样品颜色及 XRPD等变化情况, 并采用 HPLC检测 其相应的纯度。 纯度的计算方法为面积归一法。
表 1. 芬戈莫德粘酸盐与药用的芬戈莫德盐酸盐 (FTY720; 市售原料药, 上海华升生物科技有限公司提供:)的稳定性比较
在 80°C/75%相对湿度条件下,市售的芬戈莫德盐酸盐 (FTY720)两周开始 发生分解, 变成棕色粘稠物。 而芬戈莫德粘酸盐仍保持良好的固体状态, 化 学更稳定。
Claims
1、 一种芬戈莫德粘酸盐的 A晶型, 其特征在于, 该晶型用 Cu Ko射线 衍射得到的 X-射线粉末衍射图谱在 2Θ约: 6.1, 9.1, 12.2, 14.9, 15.7, 17.8, 18.5, 19.6, 20.6, 21.4, 21.8, 22.5, 24.5°具有特征峰。
2、 根据权利要求 1 所述的 A晶型, 该晶型其差示扫描量热分析 (DSC) 在约 226°C有特征吸热峰。
3、 一种芬戈莫德粘酸盐的 A晶型的制备方法, 该方法包括如下歩骤:
(1) 粘酸溶液: 将粘酸溶解在水中配成 0.001 M-0.01 M的水溶液;
(2) 芬戈莫德溶液:将芬戈莫德溶解在有机溶剂或水中配成 0.005 M-0.02 M的芬戈莫德溶液;
(3) 成盐: 将粘酸溶液和芬戈莫德溶液按照粘酸与芬戈莫德的摩尔比为 1 :2混合, 在 40°C条件下加热 1小时;
(4) 干燥: 反应后的溶液, 用溶剂洗涤后, 于室温至 100°C常压或减压烘 干即得 A型芬戈莫德粘酸盐结晶。
4、 根据权利要求 3所述的方法, 其中, 在歩骤 (2 ) 中, 所述有机溶剂 选自甲醇、 乙醇、 异丙醇、 乙腈、 四氢呋喃、 丙酮、 丁酮和甲基异丁基酮中 的一种或多种的混合物; 在歩骤(4) 中, 所述有机溶剂选自甲醇、 乙醇、 四 氢呋喃、 丙酮、 丁酮和甲基异丁基酮中的一种或多种的混合物。
5、 根据权利要求 1所述的芬戈莫德粘酸盐的 A晶型在制备作为鞘氨醇 -1-磷酸 (S IP)受体调节剂的药物中的用途。
6、 根据权利要求 1所述的芬戈莫德粘酸盐的 A晶型在制备作为免疫调 节剂的药物中用途。
7、 药物组合物, 其包含权利要求 1所述的芬戈莫德粘酸盐的 A晶型以 及药学上可接受的载体。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210326164.4 | 2012-09-05 | ||
CN201210326164.4A CN102887829B (zh) | 2012-09-05 | 2012-09-05 | 芬戈莫德粘酸盐及其晶体的制备方法和用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014036865A1 true WO2014036865A1 (zh) | 2014-03-13 |
Family
ID=47531530
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2013/080393 WO2014036865A1 (zh) | 2012-09-05 | 2013-07-30 | 芬戈莫德粘酸盐及其晶体的制备方法和用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN102887829B (zh) |
WO (1) | WO2014036865A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102887829B (zh) * | 2012-09-05 | 2014-07-02 | 中国科学院上海药物研究所 | 芬戈莫德粘酸盐及其晶体的制备方法和用途 |
CN107260714A (zh) * | 2014-04-04 | 2017-10-20 | 施福东 | 芬戈莫德及其结构类似物用于制备治疗脑梗死药物的应用 |
WO2018184185A1 (zh) * | 2017-04-07 | 2018-10-11 | 杭州领业医药科技有限公司 | 奥扎莫德加成盐晶型、制备方法及药物组合物和用途 |
EP4353709A1 (en) * | 2021-05-31 | 2024-04-17 | Shanghai Yonsun Biotechnology Co., Ltd. | Pharmaceutical salt of fingolimod, preparation method therefor, pharmaceutical composition containing same and use thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007143081A2 (en) * | 2006-06-02 | 2007-12-13 | The Ohio State University Research Foundation | Therapeutic agents for the treatment of lymphoid malignancies |
CN102209705A (zh) * | 2008-11-11 | 2011-10-05 | 诺瓦提斯公司 | 芬戈莫德盐酸盐的结晶形式 |
WO2012041358A1 (en) * | 2010-10-01 | 2012-04-05 | Synthon B.V. | Process for making fingolimod hydrochloride crystals |
CN102887829A (zh) * | 2012-09-05 | 2013-01-23 | 中国科学院上海药物研究所 | 芬戈莫德粘酸盐及其晶体的制备方法和用途 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008521827A (ja) * | 2004-11-29 | 2008-06-26 | ノバルティス アクチエンゲゼルシャフト | S1p受容体アゴニストの投与レジメン |
GB0612721D0 (en) * | 2006-06-27 | 2006-08-09 | Novartis Ag | Organic compounds |
BRPI0921533A2 (pt) * | 2008-11-11 | 2016-01-12 | Novartis Ag | composto orgânicos |
WO2012071524A1 (en) * | 2010-11-24 | 2012-05-31 | Ratiopharm Gmbh | Arylsulfonate salts of fingolimod and processes for preparation thereof |
WO2012070059A1 (en) * | 2010-11-25 | 2012-05-31 | Shilpa Medicare Limited | Fingolimod polymorphs and their processes |
CN102120720B (zh) * | 2011-01-25 | 2013-05-22 | 上海华升生物科技有限公司 | 盐酸芬戈莫德的合成新方法 |
-
2012
- 2012-09-05 CN CN201210326164.4A patent/CN102887829B/zh active Active
-
2013
- 2013-07-30 WO PCT/CN2013/080393 patent/WO2014036865A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007143081A2 (en) * | 2006-06-02 | 2007-12-13 | The Ohio State University Research Foundation | Therapeutic agents for the treatment of lymphoid malignancies |
CN102209705A (zh) * | 2008-11-11 | 2011-10-05 | 诺瓦提斯公司 | 芬戈莫德盐酸盐的结晶形式 |
WO2012041358A1 (en) * | 2010-10-01 | 2012-04-05 | Synthon B.V. | Process for making fingolimod hydrochloride crystals |
CN102887829A (zh) * | 2012-09-05 | 2013-01-23 | 中国科学院上海药物研究所 | 芬戈莫德粘酸盐及其晶体的制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
CN102887829B (zh) | 2014-07-02 |
CN102887829A (zh) | 2013-01-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10954223B2 (en) | Canagliflozin monohydrate and its crystalline forms, preparation methods and uses thereof | |
US9309201B2 (en) | Process for preparating ivabradine hydrochloride form IV and methods of treatment of disease using ivabradine hydrochloride form IV | |
WO2011095059A1 (zh) | 达沙替尼多晶型物及其制备方法和药物组合物 | |
TW201313703A (zh) | 阿齊沙坦的新晶型及其製備方法 | |
CN112142679B (zh) | 一种吉非替尼与香草酸共晶甲醇溶剂合物及其制备方法 | |
US11117875B2 (en) | Crystalline forms, preparation methods and pharmaceutical compositions of ozanimod | |
WO2018184185A1 (zh) | 奥扎莫德加成盐晶型、制备方法及药物组合物和用途 | |
JP2022531969A (ja) | 癌を治療するためのRaf阻害剤としてのN-(3-(2-(2-ヒドロキシエトキシ)-6-モルホリノピリジン-4-イル)-4-メチルフェニル)-2-(トリフルオロメチル)イソニコチンアミドの新規な結晶形態 | |
WO2014082354A1 (zh) | 西达本胺的晶型及其制备方法与应用 | |
WO2014036865A1 (zh) | 芬戈莫德粘酸盐及其晶体的制备方法和用途 | |
US20090093652A1 (en) | Crystalline forms cinacalcet fumarate and cinacalcet succinate and processes for preparation thereof | |
CN116350618A (zh) | 一种稳定的含有非甾体抗炎药衍生物的药物组合物 | |
WO2023193563A1 (zh) | 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物 | |
CN103421011B (zh) | 一种制备磷酸西他列汀无水晶型i的方法 | |
WO2007059325A2 (en) | Drying methods of montelukast sodium by azeotropic removal of the solvent | |
TWI662031B (zh) | 1-{2-氟-4-[5-(4-異丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸的晶型 | |
WO2021000687A1 (zh) | Pac-1晶型的制备方法 | |
US20080255231A1 (en) | Polymorphs of rivastigmine hydrogentartrate | |
CN104936947A (zh) | 氯卡色林盐及其晶体、其制备方法和用途 | |
CN112110865A (zh) | 一种异烟酰胺阿西莫司共晶体ⅱ及其制备方法 | |
EP3004104A1 (en) | Crystalline form of n,n-dicyclopropyl-4-(1,5-dimethyl-1 h-pyrazol-3-ylamino)-6-ethyl-1 -methyl-1,6-dihyrdroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
CN109438372A (zh) | 一种甲基吡嗪衍生物甲醇合物 | |
CN108299412A (zh) | 一种s1p1受体激动剂的加成盐及其晶型和药物组合物 | |
CN117886783A (zh) | 一种紫杉烷化合物的水合物晶型c及其制备方法、用途 | |
CN104812752B (zh) | 阿齐沙坦酯的晶型及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13836012 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 13836012 Country of ref document: EP Kind code of ref document: A1 |