CN114213322A - Eutectic crystal of methanesulfonic acid lunvatinib gallic acid and preparation method thereof - Google Patents
Eutectic crystal of methanesulfonic acid lunvatinib gallic acid and preparation method thereof Download PDFInfo
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- CN114213322A CN114213322A CN202210006354.1A CN202210006354A CN114213322A CN 114213322 A CN114213322 A CN 114213322A CN 202210006354 A CN202210006354 A CN 202210006354A CN 114213322 A CN114213322 A CN 114213322A
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- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 title claims abstract description 160
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 title claims abstract description 159
- 229940074391 gallic acid Drugs 0.000 title claims abstract description 80
- 235000004515 gallic acid Nutrition 0.000 title claims abstract description 80
- 230000005496 eutectics Effects 0.000 title claims abstract description 70
- 229940098779 methanesulfonic acid Drugs 0.000 title claims abstract description 46
- 239000013078 crystal Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000005303 weighing Methods 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 238000010521 absorption reaction Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000013557 residual solvent Substances 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000000862 absorption spectrum Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 abstract description 38
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 abstract description 38
- 229960002965 pravastatin Drugs 0.000 abstract description 38
- 238000001879 gelation Methods 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 7
- 239000000178 monomer Substances 0.000 abstract description 7
- 238000011161 development Methods 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 description 26
- UWXSAYUXVSFDBQ-CYBMUJFWSA-N 4-n-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-n-[(4r)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine Chemical compound C[C@@H]1COC(NC=2C=C3C(NC=4C=C(Cl)C(OCC=5SC=CN=5)=CC=4)=NC=NC3=CC=2)=N1 UWXSAYUXVSFDBQ-CYBMUJFWSA-N 0.000 description 25
- 229950006605 varlitinib Drugs 0.000 description 25
- 239000000843 powder Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 10
- 239000006069 physical mixture Substances 0.000 description 9
- 239000000523 sample Substances 0.000 description 7
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 6
- 238000007865 diluting Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000012738 dissolution medium Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000004677 Nylon Substances 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 3
- 229960001924 melphalan Drugs 0.000 description 3
- 229920001778 nylon Polymers 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000009210 therapy by ultrasound Methods 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001502 supplementing effect Effects 0.000 description 2
- IUTKPPDDLYYMBE-UHFFFAOYSA-N 3,4,5-trihydroxybenzoic acid;hydrate Chemical compound O.OC(=O)C1=CC(O)=C(O)C(O)=C1 IUTKPPDDLYYMBE-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101000851030 Homo sapiens Vascular endothelial growth factor receptor 3 Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960002588 cefradine Drugs 0.000 description 1
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940097942 gallic acid monohydrate Drugs 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001545 hydrotalcite Drugs 0.000 description 1
- 229910001701 hydrotalcite Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960001429 lenvatinib mesylate Drugs 0.000 description 1
- HWLFIUUAYLEFCT-UHFFFAOYSA-N lenvatinib mesylate Chemical compound CS(O)(=O)=O.C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 HWLFIUUAYLEFCT-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical class [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 1
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical class [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- 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
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a methanesulfonic acid lunvatinib gallic acid eutectic and a preparation method thereof, and belongs to the technical field of medicines. The eutectic is formed by combining the methanesulfonic acid lunvatinib and the gallic acid according to the molar ratio of 1: 2; the X-ray powder diffraction pattern of the eutectic crystal has characteristic peaks at 2 theta angles of 6.94 degrees, 10.37 degrees, 15.96 degrees, 20.88 degrees, 23.12 degrees, 25.08 degrees, 27.66 degrees and 30.04 degrees. According to the invention, the pravastatin mesylate and the gallic acid are prepared into the eutectic, so that the dissolving and dissolving capacity of the pravastatin mesylate monomer is improved, the hygroscopicity is greatly reduced, the gelation of the pravastatin mesylate is eliminated, and the eutectic has good stability and good application and development prospects.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a varlitinib mesylate gallic acid eutectic and a preparation method thereof.
Background
The Lenvatinib mesylate is a novel oral multi-target tyrosine kinase receptor inhibitor, can mainly inhibit the activity of vascular endothelial growth factor receptors VEGFR1, VEGFR2 and VEGFR3 so as to inhibit the growth of tumors, is mainly used for treating cancers such as liver cancer, thyroid cancer and the like in clinic, and has wide application prospect.
The methane sulfonic acid lunvatinib belongs to a BCS II type medicament of a biological pharmaceutical classification system, has poor solubility, and is condensed and crosslinked to generate gelation when contacting an aqueous medium, so that the dissolution rate and the bioavailability are influenced.
At present, calcium carbonate is added into a preparation for inhibiting the gelation of the melphalan mesylate, and in addition, the prior art also discloses that inorganic micromolecular auxiliary materials such as silicic acid or salt thereof, magnesium carbonate, calcium hydrophosphate and the like are added into the preparation for inhibiting the gelation, so that the bioavailability of the preparation is improved. Patent CN112190583A discloses a varlitinib mesylate pharmaceutical composition, wherein a gastric mucosa protective agent, namely hydrotalcite, is added to the pharmaceutical composition to achieve the purpose of inhibiting gelation of the varlitinib mesylate, but the above technologies all need to add auxiliary materials into the preparation and overcome the defect of slow dissolution of the varlitinib mesylate by combining a preparation process.
In addition, the problems of strong hygroscopicity and poor stability of the varlitinib mesylate also exist, and the defects of the physicochemical properties restrict the development of related preparation products. By developing a new crystal form of the novel pravastatin mesylate, the physicochemical property of the pravastatin mesylate is improved, the bioavailability of the pravastatin mesylate is improved, and the pravastatin mesylate crystal form has important research and development values.
Cocrystals refer to crystals formed by two or more molecules bound in a fixed stoichiometric ratio in the same crystal lattice by non-covalent interactions, and pharmaceutical cocrystals comprise one or more active pharmaceutical ingredients in their composition. After the drug forms a eutectic with a specific ligand, a series of changes may occur, such as increased solubility and dissolution rate, improved stability, and the like. In recent years, the eutectic technology is increasingly applied to the field of development of poorly soluble drugs and exhibits unique advantages.
Patent CN111574359A discloses a eutectic of ranvatinib and gallic acid, which is formed by combining ranvatinib with gallic acid monohydrate in a molar ratio of 1:1, and the eutectic has lower hygroscopicity than the marketed drug, ranvatinib mesylate, according to the description in the patent specification. However, the eutectic crystals mentioned in the patent do not improve the dissolution rate compared with the marketed drug of the varlitinib mesylate monomer, and the technical scheme still has the defect that the dissolution of the product cannot be improved.
Disclosure of Invention
In order to solve the problems of poor water solubility, strong hygroscopicity, easy gelation and the like of the pravastatin mesylate, the invention provides the pravastatin mesylate gallic acid eutectic and the preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
a eutectic crystal is formed by combining melphalan mesylate and gallic acid according to a molar ratio of 1: 2;
the X-ray powder diffraction pattern of the eutectic has characteristic peaks at 2 theta angles of 6.94 degrees, 10.37 degrees, 15.96 degrees, 20.88 degrees, 23.12 degrees, 25.08 degrees, 27.66 degrees and 30.04 degrees.
Further, the infrared absorption spectra of the co-crystals measured by KBr pellets were 3483.4 cm respectively-1、3440.2 cm-1、3389.3 cm-1、3359.8 cm-1、3270.6 cm-1、1688.3 cm-1、1659 cm-1、1602.9 cm-1、1543.1 cm-1、1523.8 cm-1、1458.2 cm-1、1419.6 cm-1、1400.3 cm-1、1338.6 cm-1、1242.2 cm-1、1207.5 cm-1、1188.2 cm-1、1045.1 cm-1、914.3 cm-1、868.0 cm-1、775.4 cm-1、702.1 cm-1Has an absorption peak.
Further, the co-crystal showed a single sharp endothermic melting peak at 187.0 ℃.
The preparation method of the eutectic crystal comprises the following steps:
and 3, drying the product obtained in the step 2 in vacuum to remove residual solvent, thus obtaining the eutectic.
Further, in the step 1, the organic solvent is one or a mixed solvent of methanol, acetonitrile and ethanol.
Further, in the step 2, the standing condition is 20-30 ℃.
Further, in the step 3, the temperature of vacuum drying is 20-30 ℃ and the time is 12-48 h.
The pravastatin gallic acid eutectic of the invention has different powder X-ray diffraction pattern, infrared spectrum and DSC pattern with the original pravastatin crystals and gallic acid crystals, so the solid form is completely different from the existing pravastatin crystals and gallic acid. Compared with the pravastatin mesylate, the eutectic can obviously improve the dissolution rate of the pravastatin mesylate, reduce the hygroscopicity, eliminate the gelation phenomenon of the pravastatin mesylate and has good stability.
Drawings
FIG. 1 is a powder X-ray diffraction pattern of crystals of varlitinib mesylate;
FIG. 2 is a powder X-ray diffraction pattern of gallic acid crystals;
FIG. 3 is a powder X-ray diffraction pattern of a co-crystal of pravastatin gallic acid mesylate;
FIG. 4 is an infrared spectrum of a crystalline form of pravastatin mesylate;
FIG. 5 is an infrared spectrum of gallic acid crystals;
FIG. 6 is an infrared spectrum of the eutectic of pravastatin gallic acid mesylate;
FIG. 7 is a DSC of crystals of varlitinib mesylate;
FIG. 8 is a DSC of gallic acid crystals;
FIG. 9 is a DSC of a physical mixture of pravastatin mesylate and crystals of gallic acid;
FIG. 10 is a DSC of eutectic of pravastatin gallic acid mesylate;
FIG. 11 is a graph comparing gelation of a eutectic of varlitinib mesylate and a eutectic of varlitinib mesylate on standing in water;
FIG. 12 is a graph comparing the characteristic dissolution results of varlitinib mesylate, a physical mixture of varlitinib mesylate and gallic acid crystals, and a eutectic of varlitinib mesylate in 0.1M HCl;
FIG. 13 is a graph comparing the powder dissolution profiles of varlitinib mesylate, a physical mixture of crystalline varlitinib mesylate and gallic acid, and a eutectic of varlitinib mesylate in 0.1M HCl;
FIG. 14 is a powder X-ray diffraction pattern of the eutectic of esvatinib gallic acid after being left under accelerated conditions (40 ℃ C., 75% RH) for 1 month, 2 months and 3 months;
FIG. 15 is a comparison of powder X-ray diffraction patterns of a screening of the ratio of varlitinib mesylate to gallic acid.
Detailed Description
The invention is described in further detail below with reference to the figures and the specific examples, which should not be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.
Example 1
Preparation of eutectic of methanesulfonic acid lunvatinib gallic acid
(1) Weighing powder of the methanesulfonic acid lunvatinib and the gallic acid with a molar ratio of 1:2, namely 523 mg of the methanesulfonic acid lunvatinib and 340 mg of the gallic acid, placing the powder in the same beaker (100 mL), adding 50mL of methanol, and performing ultrasonic treatment at 40 ℃ until the powder is completely dissolved to obtain a clear and transparent solution;
(2) filtering the solution with 0.22 μm nylon organic filter membrane into a crystallizing dish (diameter 60 mm), covering with preservative film, pricking holes, and slowly volatilizing to dry at 25 deg.C;
(3) and (3) placing the product in a vacuum drying oven with the temperature set at 25 ℃ for 24 h, removing residual solvent, and hermetically storing the finally obtained product under the low-temperature drying condition for later use.
Example 2
Preparation of eutectic of methanesulfonic acid lunvatinib gallic acid
(1) Weighing powder of the methanesulfonic acid lunvatinib and the gallic acid with a molar ratio of 1:2, namely 523 mg of the methanesulfonic acid lunvatinib and 340 mg of the gallic acid, placing the powder in the same beaker (100 mL), adding 50mL of acetonitrile, and carrying out ultrasonic treatment at 25 ℃ until the powder is completely dissolved to obtain a clear and transparent solution;
(2) filtering the solution with 0.22 μm nylon organic filter membrane into a crystallizing dish (diameter 60 mm), covering with preservative film, pricking holes, and slowly volatilizing to dry at 25 deg.C;
(3) and (3) placing the product in a vacuum drying oven with the temperature set at 30 ℃ for 24 h, removing residual solvent, and hermetically storing the finally obtained product under the low-temperature drying condition for later use.
Example 3
Preparation of eutectic of methanesulfonic acid lunvatinib gallic acid
(1) Weighing powder of the methanesulfonic acid lunvatinib and the gallic acid with a molar ratio of 1:2, namely 523 mg of the methanesulfonic acid lunvatinib and 340 mg of the gallic acid, placing the powder in the same beaker (100 mL), adding 50mL of ethanol, and performing ultrasonic treatment at 25 ℃ until the powder is completely dissolved to obtain a clear and transparent solution;
(2) filtering the solution with 0.22 μm nylon organic filter membrane into a crystallizing dish (diameter 60 mm), covering with preservative film, pricking holes, and slowly volatilizing to dry at 25 deg.C;
(3) and (3) placing the product in a vacuum drying oven with the temperature set at 30 ℃ for 12 h, removing residual solvent, and hermetically storing the finally obtained product under the low-temperature drying condition for later use.
The eutectic of the pravastatin mesylate and the gallic acid obtained in the example 1 is detected as follows:
1. powder X-ray diffraction
The instrument comprises the following steps: x-ray powder diffractometer (model: Mini Flex, Japan science)
Target: Cu-Kalpha target
Wavelength: 1.5406A
Tube voltage: 40 kV
Tube current: 15 mA
Step length: 0.02 degree
Scanning speed: 3 °/min
Scanning range: 3-40 degrees 2 theta
As a result: powder X-ray diffraction patterns of the eutectic of the pravastatin mesylate, the gallic acid and the pravastatin mesylate gallic acid are shown in figures 1-3. It is known that the powder X-ray diffraction spectrum of the eutectic of metavanilline mesylate and gallic acid expressed by 2 theta has characteristic diffraction peaks different from metavanilline mesylate crystals and gallic acid at 6.94 degrees, 10.37 degrees, 15.96 degrees, 20.88 degrees, 23.12 degrees, 25.08 degrees, 27.66 degrees and 30.04 degrees.
2. Fourier transform Infrared Spectroscopy (FTIR)
The instrument comprises the following steps: fourier transform infrared spectrometer (model: IRAffinity-1S, Shimadzu Japan)
Spectral range: 400 cm-1-4000 cm-1
And (3) measuring results: the eutectic crystal of the methanesulfonic acid lunvatinib gallic acid is 3483.4 cm-1、3440.2 cm-1、3389.3 cm-1、3359.8 cm-1、3270.6 cm-1、1688.3 cm-1、1659 cm-1、1602.9 cm-1、1543.1 cm-1、1523.8 cm-1、1458.2 cm-1、1419.6 cm-1、1400.3 cm-1、1338.6 cm-1、1242.2 cm-1、1207.5 cm-1、1188.2 cm-1、1045.1 cm-1、914.3 cm-1、868.0 cm-1、775.4 cm-1、702.1 cm-1Has an absorption peak.
The infrared spectra of the pravastatin mesylate, the gallic acid and the eutectic crystal of pravastatin mesylate gallic acid are respectively shown in figures 4-6.
3. Differential Scanning Calorimetry (DSC)
The instrument comprises the following steps: differential scanning calorimeter (type: DSC 2500, American TA instruments)
The range is as follows: 30-300 DEG C
The heating rate is as follows: 10 ℃ per min
And (3) measuring results: the DSC plot shows that there is a single sharp endothermic melting peak at 187.0 ℃ for the eutectic of melphalan mesylate gallic acid.
DSC graphs of the physical mixture of the methanesulfonic acid varlitinib, the gallic acid and the methanesulfonic acid varlitinib gallic acid with the molar ratio of 1:2 and the eutectic of the methanesulfonic acid varlitinib gallic acid are shown in figures 7-10 respectively.
4. Determination of binding ratio of pravastatin mesylate to gallic acid in pravastatin mesylate gallic acid eutectic
And (3) measuring the stoichiometric ratio of the two components in the eutectic of the methanesulfonic acid and the varlitinib gallic acid by adopting an HPLC method.
The instrument comprises the following steps: high performance liquid chromatograph (model: LC-2010AHT, Shimadzu instruments Japan)
Chromatographic conditions are as follows:
a chromatographic column: ultimate Lp-C18 (4.6 mm. times.250 mm, 5 μm)
Mobile phase: mobile phase A: 0.02 mol/L ammonium acetate buffer solution
Mobile phase B: acetonitrile-methanol (75: 25, v/v), mobile phase a: mobile phase B =55:45, v/v
Detection wavelength: 251 nm
Column temperature: 30 ℃ C
Flow rate: 1.2 mL/min
Sample introduction amount: 10 μ L
Operating time: 8 min
Control solution: taking about 12.5 mg of varenib mesylate, precisely weighing, placing in a 50mL measuring flask, adding about 20 mL of methanol, shaking to completely dissolve the medicine, diluting to a scale with 0.1% acetic acid water-acetonitrile (90: 10, v/v), and shaking uniformly. Precisely measuring 1 mL of the solution, placing the solution in a 50mL measuring flask, diluting the solution to a scale with 0.1% acetic acid water-acetonitrile (90: 10, v/v), and shaking the solution uniformly to obtain a reference solution of the pravastatin mesylate; weighing gallic acid about 20 mg, accurately weighing, placing in 50mL measuring flask, adding methanol about 20 mL, shaking to dissolve the medicine completely, diluting with 0.1% acetic acid water-acetonitrile (90: 10, v/v) to scale, and shaking. Precisely measuring 1 mL, placing in a 50mL measuring flask, diluting to scale with 0.1% acetic acid water-acetonitrile (90: 10, v/v), and shaking to obtain gallic acid control solution.
Test solution: taking about 20 mg of eutectic of the methanesulfonic acid and the ranvatinib gallic acid, precisely weighing, placing the eutectic into a 50mL measuring flask, adding about 20 mL of methanol, shaking to completely dissolve the medicine, diluting the eutectic to a scale with 0.1% acetic acid water-acetonitrile (90: 10, v/v), and shaking uniformly. Precisely measuring 1 mL, placing in a 50mL measuring flask, diluting to scale with 0.1% acetic acid water-acetonitrile (90: 10, v/v), and shaking to obtain a sample solution.
HPLC sample injection measurement is adopted, and results show that the mass percentages of the methanesulfonic acid lunatinib and the gallic acid in the methanesulfonic acid lunatinib gallic acid eutectic are 59.94% +/-0.42% and 40.02% +/-0.17%, respectively, and the binding molar ratio of the methanesulfonic acid lunatinib and the gallic acid in the methanesulfonic acid lunatinib gallic acid eutectic is about 1: 2.
5. Examination of gelation
Respectively sieving the isocrystals of the methanesulfonic acid lunvatinib and the methanesulfonic acid lunvatinib gallic acid through a 100-mesh sieve, weighing a proper amount of sieved samples, precisely weighing, placing the samples in beakers, adding a proper amount of purified water into the beakers, controlling the adding amount of the methanesulfonic acid lunvatinib in each beaker to be about 3g/100mL, uniformly stirring, standing, and observing the gelation phenomenon of the samples after standing for a period of time, wherein the result is shown in figure 11.
The result shows that the methanesulfonic acid lunvatinib can immediately generate gelation phenomenon in water, and stand after being uniformly stirred to quickly form inverted gel without flowing; the eutectic of the methanesulfonic acid lunatinib gallic acid does not have the gelation phenomenon in water, is in a suspension state during stirring, and does not form semisolid gel after standing for a period of time, which shows that the eutectic of the methanesulfonic acid lunatinib gallic acid can effectively eliminate the gelation phenomenon of the methanesulfonic acid lunatinib.
6. Intrinsic dissolution Rate determination
Respectively sieving physical mixture of the methanesulfonic acid lunvatinib and the methanesulfonic acid lunvatinib gallic acid with the molar ratio of 1:2 and eutectic of the methanesulfonic acid lunvatinib gallic acid through a 100-mesh sieve, weighing about 200 mg of each sample powder, and performing powder tabletting by using a hydraulic press under the pressure of 1 t to obtain compact regular circular tablets with the diameter of 13 mm. One bottom and side of the tablet was completely covered with a beeswax mold so that only one rounded surface was exposed to contact the dissolution medium. Dissolution test method the dissolution and release measurements were carried out according to the dissolution and release measurements (2020 edition, second method 0931 (Paddle method) of the general guidelines of the Chinese pharmacopoeia), with a dissolution medium of 900 mL of 0.1M HCl, at a speed of 50 rpm and at a temperature of 37 ℃. Putting the beeswax-coated tablet into a dissolution cup, immediately starting timing, taking 5 mL of dissolution liquid after 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min respectively, supplementing an equal amount of dissolution medium, filtering the taken dissolution liquid through a 0.22 mu m filter membrane, and discarding 3 mL of primary filtrate. The filtrate was taken, and the characteristic elution rate was calculated by measuring the filtrate by the HPLC method, and the result is shown in FIG. 12.
The results show that: the characteristic dissolution of the physical mixture of the eutectic of the methanesulfonic acid lunatinib gallic acid, the methanesulfonic acid lunatinib monomer and the methanesulfonic acid lunatinib gallic acid in a molar ratio of 1:2 in 0.1M HCl is obviously different. The characteristic dissolution rate of the varenib mesylate in the co-crystal is improved by about 4.1 times compared to the varenib mesylate monomer.
7. Determination of powder dissolution Rate
Separately, the physical mixture of the methanesulfonic acid lunvatinib and the methanesulfonic acid lunvatinib gallic acid with the molar ratio of 1:2 and the eutectic of the methanesulfonic acid lunvatinib gallic acid are sieved by a 100-mesh sieve, and the powder dissolution rate is measured according to a dissolution rate and release rate measuring method (2020 edition, Chinese pharmacopoeia, Tonghe 0931 second method (paddle method)). Respectively and precisely weighing 10 mg of powder, putting the powder into a dissolution cup, immediately starting timing, respectively taking 5 mL of dissolution liquid at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 90 min and 120 min, supplementing an equivalent amount of dissolution medium, filtering the taken dissolution liquid through a filter membrane of 0.22 mu m, and discarding 3 mL of primary filtrate. The dissolution rate was calculated by taking the filtrate and measuring by HPLC, and the result is shown in fig. 13.
The results show that: the dissolution of the physical mixture of the eutectic of the methanesulfonic acid lunatinib gallic acid, the methanesulfonic acid lunatinib monomer and the methanesulfonic acid lunatinib gallic acid in a molar ratio of 1:2 in 0.1M HCl is obviously different. Within 90 min, the dissolution rate of the eutectic of the pravastatin gallic acid mesylate in 0.1M HCl is higher than that of a physical mixture of the pravastatin mesylate monomer and the molar ratio of the monomer to the gallic acid mesylate is 1: 2.
8. Moisture absorption weight gain test
The eutectic crystal of the varlitinib mesylate and the gallic acid is respectively sieved by a 100-mesh sieve, and moisture absorption and weight increment experiments (a saturated sodium bromide solution (25 ℃ and 57 percent RH), a saturated sodium nitrite solution (25 ℃ and 65 percent RH) and a saturated ammonium chloride solution (25 ℃ and 80 percent RH)) are carried out on the eutectic crystal of the three under different humidity according to a dissolution rate and release rate measuring method (a second method (paddle method) of a general rule 9103 in the fourth part of China pharmacopoeia 2020), and the results are shown in table 1.
TABLE 1 hygroscopicity results of varlitinib mesylate and of eutectic of varlitinib mesylate and gallic acid at different relative humidities
The result shows that the eutectic of the pravastatin gallic acid mesylate can obviously reduce the hygroscopicity of the pravastatin mesylate.
9. Solid state stability
Sieving the eutectic of the Mesufornia acid with a 100-mesh sieve, respectively taking a proper amount of eutectic of the Mesufornia acid, placing the eutectic of the Mesufornia acid in penicillin bottles, sealing the penicillin bottles with plugs, and placing the penicillin bottles in a drug stability test box (the temperature is set to be 40 ℃ and the humidity is set to be 75% RH) for 1 month, 2 months and 3 months. And respectively sampling on time, observing the appearance change of the medicament, determining the content of the cefradine mesylate in the sample, performing X-ray powder diffraction (XRPD) characterization on the eutectic sample, and comprehensively inspecting the physical and chemical stability of the comparative sample under the acceleration condition.
The results of the content measurement of the sample are shown in Table 2.
TABLE 2 content determination of eutectic crystals of varlitinib mesylate
After the eutectic-free sodium sulfovinglycinate eutectic is placed for 1 month, 2 months and 3 months under the accelerated condition, the content of the eutectic-free sodium sulfovinglycinate eutectic is not obviously changed, XRPD superposition comparison graphs of samples and 0-day samples after the eutectic is placed for 1 month, 2 months and 3 months under the accelerated condition (40 ℃ and 75% RH) are shown in figure 14, and the results show that the eutectic-free sodium sulfovinglycinate eutectic has good solid stability under the accelerated condition.
Comparative example 1
Eutectic ligand ratio screening
The steps are the same as the preparation of the eutectic of the pravastatin gallic acid mesylate in the embodiment 1, and the difference is that the proportion of the pravastatin gallic acid mesylate to the gallic acid is different.
Weighing the powder of the pravastatin mesylate and the gallic acid in a molar ratio of 1:1, namely 523 mg of the pravastatin mesylate and 170 mg of the gallic acid, preparing the powder according to the method in the embodiment 1, judging whether eutectic is formed or not by powder X-ray diffraction of the product, wherein the experimental result is shown in figure 15, and the result shows that the eutectic of the pravastatin mesylate and the gallic acid cannot be prepared when the molar ratio of the pravastatin mesylate to the gallic acid is 1: 1.
Claims (8)
1. A co-crystal characterized by: is formed by combining the methanesulfonic acid lunvatinib and the gallic acid according to the molar ratio of 1: 2;
the X-ray powder diffraction pattern of the eutectic has characteristic peaks at 2 theta angles of 6.94 degrees, 10.37 degrees, 15.96 degrees, 20.88 degrees, 23.12 degrees, 25.08 degrees, 27.66 degrees and 30.04 degrees.
2. The co-crystal of claim 1, wherein: the infrared absorption spectra measured by KBr tablet are 3483.4 cm respectively-1、3440.2 cm-1、3389.3 cm-1、3359.8 cm-1、3270.6 cm-1、1688.3 cm-1、1659 cm-1、1602.9 cm-1、1543.1 cm-1、1523.8 cm-1、1458.2 cm-1、1419.6 cm-1、1400.3 cm-1、1338.6 cm-1、1242.2 cm-1、1207.5 cm-1、1188.2 cm-1、1045.1 cm-1、914.3 cm-1、868.0 cm-1、775.4 cm-1、702.1 cm-1Has an absorption peak.
3. The co-crystal of claim 1, wherein: the co-crystal shows a single sharp endothermic melting peak at 187.0 ℃.
4. A process for the preparation of the co-crystal according to claim 1, characterized in that: the method comprises the following steps:
step 1, weighing and dissolving the methanesulfonic acid lunvatinib and the gallic acid in a molar ratio of 1:2 in an organic solvent to obtain a clear and transparent solution;
step 2, filtering the solution obtained in the step 1 to a crystallizing dish, standing, and volatilizing the solvent until the solvent is dry;
and 3, drying the product obtained in the step 2 in vacuum to remove residual solvent, thus obtaining the eutectic.
5. The method of claim 4, wherein: in the step 1, the organic solvent is one or a mixed solvent of methanol, acetonitrile and ethanol.
6. The method of claim 4, wherein: in the step 2, the standing condition is 20-30 ℃.
7. The method of claim 4, wherein: in the step 3, the temperature of vacuum drying is 20-30 ℃ and the time is 12-48 h.
8. A pharmaceutical composition comprising the co-crystal of claim 1.
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Publication number | Priority date | Publication date | Assignee | Title |
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WO2018196687A1 (en) * | 2017-04-25 | 2018-11-01 | 苏州科睿思制药有限公司 | New crystal form of lenvatinib methanesulfonate and preparation method thereof |
CN109867626A (en) * | 2019-04-18 | 2019-06-11 | 安礼特(上海)医药科技有限公司 | A kind of methanesulfonic acid logical sequence is cut down for Buddhist nun's polymorph and preparation method thereof |
WO2019228485A1 (en) * | 2018-06-01 | 2019-12-05 | 成都苑东生物制药股份有限公司 | New crystal form of lenvatinib mesylate and preparation method therefor |
CN111574359A (en) * | 2019-02-19 | 2020-08-25 | 愈磐生物科技(苏州)有限公司 | Levatinib-gallic acid eutectic crystal form and application thereof |
WO2021213453A1 (en) * | 2020-04-24 | 2021-10-28 | 成都苑东生物制药股份有限公司 | Lenvatinib mesylate crystal form xi and preparation method therefor |
CN113831283A (en) * | 2021-11-04 | 2021-12-24 | 南京科默生物医药有限公司 | Preparation method of amorphous matter of Ranuncutinib salt |
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WO2019228485A1 (en) * | 2018-06-01 | 2019-12-05 | 成都苑东生物制药股份有限公司 | New crystal form of lenvatinib mesylate and preparation method therefor |
CN111574359A (en) * | 2019-02-19 | 2020-08-25 | 愈磐生物科技(苏州)有限公司 | Levatinib-gallic acid eutectic crystal form and application thereof |
CN109867626A (en) * | 2019-04-18 | 2019-06-11 | 安礼特(上海)医药科技有限公司 | A kind of methanesulfonic acid logical sequence is cut down for Buddhist nun's polymorph and preparation method thereof |
WO2021213453A1 (en) * | 2020-04-24 | 2021-10-28 | 成都苑东生物制药股份有限公司 | Lenvatinib mesylate crystal form xi and preparation method therefor |
CN113831283A (en) * | 2021-11-04 | 2021-12-24 | 南京科默生物医药有限公司 | Preparation method of amorphous matter of Ranuncutinib salt |
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