CN114502550B - Tegafur co-crystal - Google Patents
Tegafur co-crystal Download PDFInfo
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- CN114502550B CN114502550B CN201980042572.7A CN201980042572A CN114502550B CN 114502550 B CN114502550 B CN 114502550B CN 201980042572 A CN201980042572 A CN 201980042572A CN 114502550 B CN114502550 B CN 114502550B
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- pyridyl
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- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 title claims abstract description 69
- 229960001674 tegafur Drugs 0.000 title claims abstract description 67
- 239000013078 crystal Substances 0.000 title claims abstract description 57
- 230000005496 eutectics Effects 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000004090 dissolution Methods 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 229910017488 Cu K Inorganic materials 0.000 claims abstract description 6
- 229910017541 Cu-K Inorganic materials 0.000 claims abstract description 6
- 230000005855 radiation Effects 0.000 claims abstract description 6
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 4
- 238000001228 spectrum Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 20
- MGFJDEHFNMWYBD-OWOJBTEDSA-N 4-[(e)-2-pyridin-4-ylethenyl]pyridine Chemical group C=1C=NC=CC=1/C=C/C1=CC=NC=C1 MGFJDEHFNMWYBD-OWOJBTEDSA-N 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 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 9
- 238000001035 drying Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000005259 measurement Methods 0.000 abstract 1
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- 238000007789 sealing Methods 0.000 description 15
- 238000012360 testing method Methods 0.000 description 10
- 238000000113 differential scanning calorimetry Methods 0.000 description 7
- 238000004080 punching Methods 0.000 description 7
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
- 238000001757 thermogravimetry curve Methods 0.000 description 6
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229930182555 Penicillin Natural products 0.000 description 4
- 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 4
- 238000002474 experimental method Methods 0.000 description 4
- 229960002949 fluorouracil Drugs 0.000 description 4
- 229940049954 penicillin Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- KFDVPJUYSDEJTH-UHFFFAOYSA-N 4-ethenylpyridine Chemical group C=CC1=CC=NC=C1 KFDVPJUYSDEJTH-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002447 crystallographic data Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 229940035893 uracil Drugs 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- DHMYGZIEILLVNR-UHFFFAOYSA-N 5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione;1h-pyrimidine-2,4-dione Chemical compound O=C1C=CNC(=O)N1.O=C1NC(=O)C(F)=CN1C1OCCC1 DHMYGZIEILLVNR-UHFFFAOYSA-N 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 101001037160 Xenopus laevis Homeobox protein Hox-D1 Proteins 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- XBCXJKGHPABGSD-UHFFFAOYSA-N methyluracil Natural products CN1C=CC(=O)NC1=O XBCXJKGHPABGSD-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 238000005303 weighing 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal, and relates to the technical field of crystal form drug molecules. The tegafur eutectic uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.26+/-0.2 degrees, 9.30+/-0.2 degrees, 11.89+/-0.2 degrees, 12.60+/-0.2 degrees, 14.79+/-0.2 degrees, 20.28+/-0.2 degrees, 23.98+/-0.2 degrees and 26.43+/-0.2 degrees; the crystallographic measurement parameters were: triclinic system, chiral space group is P-1; the unit cell parameters are: a= 5.1391 (4) a, b= 9.7392 (7) a, c= 13.9658 (10) a, α= 96.008 (6) °, β= 92.368 (7) °, γ= 103.481 (7) °, and unit cell volume v= 674.44 (9) a 3 The method comprises the steps of carrying out a first treatment on the surface of the Related methods of preparation and use are also provided. The tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal has good stability and higher solubility and dissolution rate.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a tegafur-1, 2-di (4-pyridyl) ethylene eutectic, a preparation method thereof and application thereof in preparing medicines for treating diseases.
Background
Tegafur (TF), chemical name 1- (tetrahydro-2-furanyl) -5-fluoro-2, 4 (1H, 3H) -pyrimidinedione, white or quasi-white crystalline powder, molecular formula C 8 H 9 FN 2 O 3 Molecular weight of200, the structural formula is shown as follows:
tegafur belongs to fluorouracil derivatives, and in 1968, the doctor Hiller of Su-Linked scientist successfully synthesized TF. TF acts by being degraded in vivo by liver drug metabolizing enzymes and the cytochrome P-450 system to fluorouracil, which acts the same as fluorouracil. TF has the advantages of high chemotherapeutic activity (twice that of 5-FU) and low toxicity (5-6 times lower than 5-FU), and is widely used for treating breast cancer and gastrointestinal cancer.
Although tegafur is widely used in anti-tumor treatment, it still has serious side effects such as bone marrow suppression and injury to human body, so researchers are still continuously researching and searching ways for reducing toxicity or improving bioavailability. The presence of 2'R and 2' S racemates of tegafur is described in patent No.855121, but studies have shown that both isomers are biologically active, toxic (YasumotoM.et al., "J.Med.chem.," 1977, vol.41, no.9, 1632-1635); uchida T et al studied the crystalline form of tegafur and successfully obtained four crystalline forms of α, β, γ, δ ("chem.pharm.Bull.", vol.41, no.9, 1623-1625). All of the above 4 crystalline forms can be obtained by a relatively simple method, such as: adding tegafur into acetone for hot-melting and cold-separating to obtain alpha crystal form; the saturated tegafur methanol solution is subjected to rotary evaporation to obtain a beta crystal form; the beta crystal form can be transformed into a gamma crystal form at 130 ℃; the delta crystal form can be obtained by recrystallizing tegafur in methanol solution and slowly evaporating at room temperature. Although four crystal forms were successfully prepared, the four crystal forms did not significantly improve the physicochemical properties of tegafur, nor did they greatly enhance its therapeutic effect.
In summary, configuration or crystal form screening does not better improve the efficacy or reduce the toxicity of tegafur, which is currently used in combination with uracil, e.g., kagaway et al demonstrate that tegafur and uracil are effective in improving the efficacy of tegafur when mixed in a molar ratio of 1:4 ("Cancer Investigation", vol.13, no.5, 470-474); sanchiz F et al invented a complex of tegafur, folic acid, and uracil ("Jpn. Journal Clin. Oncol.",1994, vol.24, no.6, 322-326) to increase the bioavailability of tegafur. Since uracil itself has some toxicity, fujita H et al indicated that tegafur was more significantly reduced in toxicity when used in combination with thymine, adenosine, thymidine, etc. (Experimental and Clinical Pharmacotherapy, issue 12, riga,1983, p.205). U.S. Pat. No.6,538,001 reports that the solubility and bioavailability of tegafur can be improved when tegafur forms a molecular complex with methyl uracil at 1:2 or 1:1. Srinivasu a. Et al report on the study of co-crystals of tegafur with nicotinamide, isonicotinamide, catechol, theophylline, p-hydroxybenzoic acid, which, although successfully prepared, did not show surprising physicochemical properties (Crystal Growth & Design 2014, 14, 12, 6557-6569). Currently, combination administration is an effective method for improving the bioavailability of tegafur, so that a compound sharing scheme for seeking tegafur needs to be developed, so that the dissolution (dissolution) and the solubility of tegafur are improved and/or the bioavailability of tegafur is improved, and the toxic and side effects of tegafur are reduced.
Summary of The Invention
Technical problem
Aiming at the problems in the prior art, the invention provides a tegafur-1, 2-di (4-pyridyl) ethylene eutectic with high stability and solubility, which has definite crystallographic main parameters and atomic space positions; in another aspect, the invention provides a method of preparing the co-crystal.
Solution to the problem
Technical solution
The specific technical content of the invention is as follows:
in a first aspect, the present invention provides a tegafur-1, 2-bis (4-pyridyl) ethylene co-crystal, wherein the molar ratio of tegafur to 1, 2-bis (4-pyridyl) ethylene in the co-crystal is 1:1, and a tegafur molecule and a 1, 2-bis (4-pyridyl) ethylene molecule form a basic structural unit of the co-crystal, and the specific structure is as shown in formula I:
preferably, the tegafur-1, 2-di (4-pyridyl) ethylene co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 6.26+/-0.2,9.30 +/-0.2 DEG, 11.89+/-0.2 DEG, 12.60+/-0.2 DEG, 14.79+/-0.2 DEG, 20.28+/-0.2 DEG and 23.98+/-0.2 deg.
Preferably, the tegafur-1, 2-di (4-pyridyl) ethylene co-crystal uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at 6.26+/-0.2 degrees, 9.30+/-0.2 degrees, 10.59+/-0.2 degrees, 11.89+/-0.2 degrees, 12.60+/-0.2 degrees, 14.79+/-0.2 degrees, 18.74+/-0.2 degrees, 19.14+/-0.2 degrees, 20.28+/-0.2 degrees, 21.39 +/-0.2 degrees, 22.32+/-0.2 degrees, 23.98+/-0.2 degrees and 26.43+/-0.2 degrees.
Preferably, the tegafur-1, 2-di (4-pyridyl) ethylene co-crystal uses Cu-K alpha radiation, and the characteristic peak accords with an X-ray powder diffraction pattern shown in figure 1.
Preferably, the tegafur-1, 2-di (4-pyridyl) ethylene co-crystal has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve, and the corresponding temperature range is 133.55-153.13 ℃, preferably 142.73 ℃.
Preferably, the tegafur-1, 2-di (4-pyridyl) ethylene co-crystal has the following crystallographic parameters: triclinic system, chiral space group is P-1; the unit cell parameters are: α= 96.008 (6) °, β= 92.368 (7) °, γ= 103.481 (7) °, unit cell volume +.>
In a second aspect, the invention provides a preparation method of tegafur-1, 2-di (4-pyridyl) ethylene eutectic, which comprises the following specific preparation steps:
adding tegafur and 1, 2-di (4-pyridyl) ethylene into the organic solvent A, heating, stirring, dissolving, continuing to perform heat preservation reaction, ending the reaction, filtering, volatilizing, crystallizing, filtering, and drying to obtain tegafur-1, 2-di (4-pyridyl) ethylene eutectic.
Preferably, the preparation steps comprise: adding tegafur and 1, 2-di (4-pyridyl) ethylene into the organic solvent A, heating, stirring, dissolving, continuing to perform heat preservation reaction, filtering after the reaction is finished, and slowly cooling the filtrate to room temperature; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing, filtering, and drying under reduced pressure to obtain tegafur-1, 2-di (4-pyridyl) ethylene eutectic.
Preferably, the feed molar ratio of tegafur to 1, 2-bis (4-pyridyl) ethylene is 1:1 to 1.5, preferably 1:1.1.
Preferably, the organic solvent A is one or two of acetonitrile, acetone, methanol and ethanol, preferably methanol.
Preferably, the mass-volume ratio of the tegafur to the organic solvent A is 1:80-120 g/ml.
Preferably, the heating dissolution temperature is 30 to 50 ℃.
Preferably, the incubation time is 1 to 3 hours; the temperature of the heat preservation reaction is 30-50 ℃.
In a preferred embodiment, the slow cooling mode of the filtrate is programmed cooling, preferably, the cooling rate is 0.5 ℃/min.
In a third aspect, the present invention provides a pharmaceutical composition comprising the tegafur-1, 2-bis (4-pyridinyl) ethylene co-crystal of the present invention and other pharmaceutically acceptable components.
Preferably, the other pharmaceutically acceptable components include other active ingredients, excipients, fillers, and the like, which may be used in combination.
Preferably, the pharmaceutical composition of the present invention can be prepared using the following method: the compounds of the present invention are formulated into useful dosage forms by combining them with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients, using standard and conventional techniques.
Preferably, the pharmaceutical composition is spray, tablet, capsule, powder injection, liquid injection and the like.
In a fourth aspect, the present invention provides an application of tegafur-1, 2-di (4-pyridyl) ethylene eutectic as an active ingredient in preparing an antitumor drug.
Confirmation of Crystal Structure
The X-ray crystal data were collected on a model of the japanese physics, xlab Synergy instrument, temperature 293 (2) K was tested, data were collected with CuKa radiation in an omega scan mode and Lp correction was performed. Analyzing the structure by a direct method, finding all non-hydrogen atoms by a difference Fourier method, obtaining all hydrogen atoms on carbon and nitrogen by theoretical hydrogenation, and finishing the structure by a least square method.
The crystallographic data obtained for testing and resolving the tegafur crystals prepared according to the invention are (table 1): the crystallographic parameters are: triclinic system, chiral space group is P-1; the unit cell parameters are: α= 96.008 (6) °, β= 92.368 (7) °, γ= 103.481 (7) °, unit cell volume +.> The molecular formula is: c (C) 20 H 19 FN 4 O 3 The molecular weight is: 382.28. the stacking diagram of the tegafur-1, 2-di (4-pyridyl) ethylene co-crystal is shown in figure 3. The ORTEP diagram (fig. 4) of the tegafur-1, 2-di (4-pyridyl) ethylene co-crystal of the present invention shows that the co-crystal of the present invention is formed by combining tegafur, a molecular active pharmaceutical ingredient, with 1, 2-di (4-pyridyl) ethylene, a molecular co-crystal ligand under N-h.
TABLE 1 principal crystallographic data of tegafur-1, 2-bis (4-pyridinyl) ethylene co-crystal
In the invention, an X-ray powder diffraction test instrument and test conditions are as follows: x-ray powder diffractometer: panalytics 1E; cu-K alpha; sample stage: a flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; divergence slit: 1/4; anti-scatter slit: 1, a step of; a cable pull slit: 0.04rad; step size: 0.5s; scanning range: 3-50 deg.
According to the crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-K alpha) are shown in the accompanying figure 1 and the table 2.
TABLE 2 PXRD peaks for tegafur-1, 2-bis (4-pyridinyl) ethylene cocrystal
The samples prepared by the scheme of the invention have the same crystallographic parameters and X-ray powder diffraction patterns.
TGA/DSC thermal analysis tester and test conditions in the invention: TGA/DSC thermal analyzer: METTLER TOLEDO TGA/DSC < 3+ >; dynamic temperature section: 30-300 ℃; heating rate: 10 ℃/min; procedure section gas N 2 The method comprises the steps of carrying out a first treatment on the surface of the Gas flow rate: 50mL/min; crucible: 40 μl of aluminum crucible.
The DSC/TGA spectrum result of the tegafur-1, 2-di (4-pyridyl) ethylene eutectic prepared by the method is shown in figure 2, only one endothermic peak exists in a Differential Scanning Calorimetry (DSC), the temperature range is 133.55-153.13 ℃, and the peak value is 142.73 ℃.
Advantageous effects of the invention
Advantageous effects
The invention provides a novel tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal, which has definite main crystallographic parameters and definite atomic space positions; the preparation method of the eutectic provided by the invention is simple to operate, and the prepared crystal has higher yield and purity; the tegafur-1, 2-di (4-pyridyl) ethylene eutectic crystal has good stability, higher solubility and dissolution rate, further can increase the bioavailability of tegafur, improves the drug effect, and is suitable for large-scale popularization and application.
Brief description of the drawings
Drawings
Figure 1X-ray powder diffraction pattern of tegafur co-crystals.
FIG. 2 is a Differential Scanning Calorimetry (DSC) and Thermogram (TGA) plot of tegafur co-crystals.
FIG. 3 single crystal diffraction stack of tegafur co-crystals.
FIG. 4 ORTEP diagram of tegafur co-crystals.
Inventive examples
Embodiments of the invention
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The tegafur raw material (beta crystal form, purity 99.91%) and 1, 2-di (4-pyridyl) ethylene used in the experiment of the invention are all commercial products, and tegafur-isonicotinamide eutectic crystal is prepared according to the method of example 1 disclosed in patent CN104496972 a.
Example 1
Tegafur (2.02 g) and 1, 2-bis (4-pyridyl) ethylene (2.01 g) are added into methanol (200 ml), after heating, stirring and dissolving at 40 ℃, the reaction is continued for 1 hour at 40 ℃, the reaction is finished, and the filtrate is filtered and cooled to room temperature at a speed of 0.5 ℃/min; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing for 1 day, filtering, and drying under reduced pressure to obtain tegafur-1, 2-di (4-pyridyl) ethylene eutectic, wherein the yield is 95%, and the purity is: 99.94%.
Example 2
Tegafur (2.04 g) and 1, 2-di (4-pyridyl) ethylene (1.82 g) are added into methanol (200 ml), after heating, stirring and dissolving at 40 ℃, the reaction is continued for 1 hour at 40 ℃, the reaction is finished, and the filtrate is filtered and cooled to room temperature at a speed of 0.5 ℃/min; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing for 1 day, filtering, and drying under reduced pressure to obtain tegafur-1, 2-di (4-pyridyl) ethylene eutectic, wherein the yield is 87%, and the purity is: 99.86%.
Example 3:
tegafur (2.05 g) and 1, 2-bis (4-pyridyl) ethylene (2.73 g) are added into methanol (240 ml), after heating, stirring and dissolving at 40 ℃, the reaction is continued for 1 hour at 40 ℃, the reaction is finished, and the filtrate is filtered and cooled to room temperature at a speed of 0.5 ℃/min; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing for 1 day, filtering, and drying under reduced pressure to obtain tegafur-1, 2-di (4-pyridyl) ethylene eutectic, wherein the yield is 90%, and the purity is: 99.88%.
Example 4
Tegafur (2.03 g) and 1, 2-di (4-pyridyl) ethylene (2.01 g) are added into acetone (160 ml), after heating, stirring and dissolving at 30 ℃, the reaction is continued for 1 hour at 30 ℃, the reaction is finished, and the filtrate is filtered and cooled to room temperature at the speed of 0.5 ℃/min; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing for 1 day, filtering, and drying under reduced pressure to obtain tegafur-1, 2-di (4-pyridyl) ethylene eutectic, wherein the yield is 92%, and the purity is: 99.91%.
Example 5
Tegafur (2.02 g) and 1, 2-di (4-pyridyl) ethylene (2.02 g) are added into ethanol (220 ml), after being heated and stirred at 45 ℃ to dissolve, the reaction is continued to be carried out for 2 hours at 45 ℃, the reaction is finished, and the filtrate is filtered and cooled to room temperature at the speed of 0.5 ℃/min; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing for 2 days, filtering, and drying under reduced pressure to obtain tegafur-1, 2-di (4-pyridyl) ethylene eutectic, wherein the yield is 91%, and the purity is: 99.92%.
Example 6
Tegafur (2.04 g) and 1, 2-di (4-pyridyl) ethylene (2.03 g) are added into acetonitrile (240 ml), after heating, stirring and dissolving at 50 ℃, the reaction is continued for 3 hours at 50 ℃, the reaction is finished, and the filtrate is filtered and cooled to room temperature at a speed of 0.5 ℃/min; placing the filtrate in a beaker, sealing by a sealing film, punching, volatilizing, crystallizing for 3 days, filtering, and drying under reduced pressure to obtain tegafur-1, 2-di (4-pyridyl) ethylene eutectic, wherein the yield is 89%, and the purity is: 99.90%.
Industrial applicability
Stability test
The specific stability test method is carried out by referring to the guidance method of stability investigation specified in the fourth section of the Chinese pharmacopoeia 2015, and specific experimental conditions and results are shown in Table 3.
TABLE 3 stability test results of tegafur crystalline forms
The experimental result shows that the purity and the appearance of the tegafur-1, 2-di (4-pyridyl) ethylene eutectic prepared by the invention are not obviously changed under the conditions of illumination, high temperature and high humidity, and the tegafur-1, 2-di (4-pyridyl) ethylene eutectic has better stability; the purity of the beta crystal form and the tegafur-isonicotinamide eutectic in the prior art is relatively and greatly reduced under the same experimental condition, and the impurity content is obviously increased. Inventive examples 1 to 6 have similar stability test results.
Solubility test
The solubility test method specifically comprises the following steps: respectively weighing 10ml of medium (water, 0.01mol/L HCl solution and phosphate buffer solution with pH=6.8) into a penicillin bottle, adding excessive sample to be tested, sealing the penicillin bottle, placing the penicillin bottle in a constant temperature water bath at 25 ℃ for stirring for 1 hour, filtering the penicillin bottle by a 0.45 mu m filter membrane, and taking filtrate; the absorbance was measured at 271nm wavelength, and the solubility was calculated by measuring the absorbance of the standard control by HPLC, and the results are shown in Table 4.
TABLE 4 solubility of tegafur polycrystals in different media (mg/ml)
The solubility test result shows that the solubility of the tegafur-1, 2-di (4-pyridyl) ethylene eutectic is obviously better than that of tegafur beta crystal forms and tegafur-isonicotinamide eutectic. Inventive examples 1-6 have similar solubility test results.
Dissolution Rate test
The experiment was performed in a VK7010 (valian company, usa) dissolution apparatus equipped with a heating circulator for VK750D, with approximately 500mg of sample compressed into 0.5cm 2 In the disc of (2), an electric rotary disc inner die certified by United states pharmacopoeia is adopted, and the disc is operated on a hydraulic machine with the pressure of 5 tons for 5 minutes. Only one side of the disk was exposed to the vehicle throughout the experiment, the surface of the disk being constant. The sample was placed in a tank containing 900mL of phosphate buffer (pH 6.8), preheated at 37℃and stirred at 50 rpm. At regular intervals, 2mL samples were manually drawn. The collected samples were filtered through a 0.4 μm nylon membrane and the calibration curve of each was analyzed using HPLC. Absorbance was measured at a wavelength of 271nm in phosphate buffer at ph=6.8.
TABLE 5 dissolution Rate of tegafur polycrystals in phosphate buffer
| Sample of | IDR(×10 -2 )(mg cm -2 min -1 ) |
| Example 1 | 6.7 |
| Beta crystal form | 3.5 |
| Tegafur-isonicotinamide co-crystals | 5.5 |
As can be seen from the dissolution rate test experiments, the tegafur-1, 2-di (4-pyridyl) ethylene eutectic phase prepared by the invention is faster in dissolution than tegafur beta crystal forms and tegafur-isonicotinamide eutectic phases disclosed by the prior art. Inventive examples 1-6 have similar dissolution rate test results.
In conclusion, the tegafur-1, 2-di (4-pyridyl) ethylene eutectic provided by the invention effectively improves the physicochemical property of tegafur, and provides possibility for reducing toxic and side effects of tegafur and improving the biological activity of tegafur.
Claims (7)
1. A tegafur co-crystal, characterized in that the co-crystal is composed of tegafur as an active pharmaceutical ingredient and 1, 2-bis (4-pyridyl) ethylene as a co-crystal ligand; wherein the eutectic basic unit consists of one tegafur molecule and one 1, 2-di (4-pyridyl) ethylene molecule, and the crystallographic parameters are: triclinic system, chiral space group is P-1; the unit cell parameters are: a= 5.1391 (4) a, b= 9.7392 (7) a, c= 13.9658 (10) a, α= 96.008 (6) °, β= 92.368 (7) °, γ= 103.481 (7) °, and unit cell volume v= 674.44 (9) a 3 The structure is as follows:
the method comprises the steps of carrying out a first treatment on the surface of the The eutectic uses Cu-K alpha radiation, and an X-ray diffraction spectrum expressed by 2 theta has characteristic peaks at 6.26+/-0.2 degrees, 9.30+/-0.2 degrees, 10.59+/-0.2 degrees, 11.89+/-0.2 degrees, 12.60+/-0.2 degrees, 14.79+/-0.2 degrees, 18.74+/-0.2 degrees, 19.14+/-0.2 degrees, 20.28+/-0.2 degrees, 21.39 +/-0.2 degrees, 22.32+/-0.2 degrees and 23.98+/-0.2 degrees, and 26.43+/-0.2 degrees.
2. Tegafur co-crystal according to claim 1, wherein the co-crystal has an X-ray powder diffraction pattern as shown in figure 1.
3. A process for preparing a tegafur co-crystal according to any one of claims 1-2, characterized in that it comprises the following steps: adding tegafur and 1, 2-di (4-pyridyl) ethylene into the organic solvent A, heating, stirring, dissolving, continuing to perform heat preservation reaction, ending the reaction, filtering, volatilizing, crystallizing, filtering, and drying to obtain tegafur-1, 2-di (4-pyridyl) ethylene eutectic.
4. The method for preparing tegafur co-crystals according to claim 3, wherein the molar ratio of tegafur to 1, 2-bis (4-pyridyl) ethylene is 1:1 to 1.5.
5. The method for preparing tegafur co-crystals according to claim 3, wherein the organic solvent a is one or two of acetonitrile, acetone, methanol and ethanol; the mass volume ratio of tegafur to the organic solvent A is 1:80-120, g/ml.
6. The method for preparing tegafur eutectic according to claim 3, wherein the heating dissolution temperature is 30-50 ℃; the temperature of the heat preservation reaction is 30-50 ℃.
7. Use of tegafur co-crystals according to any one of claims 1-2 as active ingredient for the preparation of an antitumor drug.
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|---|---|---|---|---|
| CN103159746A (en) * | 2011-12-12 | 2013-06-19 | 山东新时代药业有限公司 | Industrial tegafur synthesizing method |
| CN104496972A (en) * | 2014-12-04 | 2015-04-08 | 浙江大学 | Novel pharmaceutical tegafur co-crystal and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159746A (en) * | 2011-12-12 | 2013-06-19 | 山东新时代药业有限公司 | Industrial tegafur synthesizing method |
| CN104496972A (en) * | 2014-12-04 | 2015-04-08 | 浙江大学 | Novel pharmaceutical tegafur co-crystal and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| Crystal Engineering of Tegafur Cocrystals: Structural Analysis and Physicochemical Properties;Srinivasulu Aitipamula等;《Cryst.Growth Des.》;第14卷;第6557-6569页 * |
| Transferability of cocrystallization propensities between aromatic and heteroaromatic amides;Piotr Cysewski;《Struct Chem》;1-10 * |
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