CN113372401A - Novel crystal form of cytarabine and preparation method thereof - Google Patents
Novel crystal form of cytarabine and preparation method thereof Download PDFInfo
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- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 title claims abstract description 88
- 229960000684 cytarabine Drugs 0.000 title claims abstract description 87
- 239000013078 crystal Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 20
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 14
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 208000032839 leukemia Diseases 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 5
- 229940045145 uridine Drugs 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 230000001939 inductive effect Effects 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 238000000354 decomposition reaction Methods 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000004090 dissolution Methods 0.000 abstract description 3
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 238000006731 degradation reaction Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 12
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 208000031637 Erythroblastic Acute Leukemia Diseases 0.000 description 2
- 208000036566 Erythroleukaemia Diseases 0.000 description 2
- 208000035561 Leukaemic infiltration brain Diseases 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 208000021841 acute erythroid leukemia Diseases 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 239000001177 diphosphate Substances 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 235000011180 diphosphates Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- ZWIADYZPOWUWEW-XVFCMESISA-N CDP Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O1 ZWIADYZPOWUWEW-XVFCMESISA-N 0.000 description 1
- PCDQPRRSZKQHHS-CCXZUQQUSA-N Cytarabine Triphosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 PCDQPRRSZKQHHS-CCXZUQQUSA-N 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- FTDHDKPUHBLBTL-SHYZEUOFSA-K dCDP(3-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 FTDHDKPUHBLBTL-SHYZEUOFSA-K 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/09—Pyrimidine radicals with arabinosyl as the saccharide radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- 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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- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
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Abstract
The invention provides a novel crystal form of cytarabine, wherein an X-ray powder diffraction pattern has diffraction peaks at the positions of 2 theta +/-0.2 degrees, and the 2 theta is 13.151, 15.879, 16.310, 19.763 and 26.975. The novel crystal form of cytarabine provided by the invention has the characteristics of good batch-to-batch consistency, good stability under storage conditions, high dissolution speed, reduction of degradation risk in the production process of a preparation and the like, and is more suitable for the use of the preparation. The preparation method of the novel cytarabine crystal form has the characteristics of strong environmental friendliness, simpler operation, controllable quality, low toxicity and harmlessness of a used solvent and the like, and is more suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, and in particular relates to a novel cytarabine crystal form and a preparation method thereof.
Background
Cytarabine, chemically known as 1- β -D-arabinofuranosyl-4-amino-2 (1H) -pyrimidinone, was first synthesized in 1959 by RichardWalwick, Walden Roberts and Charles Dekker, university of California, Berkeley.
Cytarabine for injection was first marketed in the United states by Upjohn (Pfizer, the genus) 6 months in 1969 under the name of
The specifications on the market are 100mg, 500mg, 1g and 2g, which are the reference formulations recommended by the American orange book, but are currently on the market (for reasons of non-safety and effectiveness). HOSPIRA was approved by the FDA in 1990 to market a 20MG/ML injection, recommended as RS.
France: in 1985, Pfizer marketed cytarabine for injection in france under the name of marketed product
The specification is 500mg, 1.0g and 2.0g are newly increased in 1987, and 100mg is newly increased in 1997.
Italy: pfizer is marketed in Italy as injectable cytarabine under the trade name Pfizer
The specification was 100mg (with 5ml solvent), 500mg (with 10ml solvent), and time to first market/re-registration was 2010.
Spain: in 1970, Pfizer marketed Spain with 100mg specification for injection, and newly increased 500mg specification in 1984.
The product is prepared by firstly approving the Japan neo-medicine company in 1971 at 4 months, wherein the product is prepared by キロサイド -injection of 20mg, and then sequentially marketing 40mg, 60mg, 100mg, 200mg, 400mg and 1g of the preparation in specification, which are all injections. Wutian 1248686is approved in 2013 by Tokayao K.K. of バファーマ, and the commercial specification is 400mg and 1g of intravenous injection.
Cytarabine can be used alone or in combination with other chemotherapeutic drugs, and is suitable for induced remission of leukemia, especially acute myelocytic leukemia in adults or children. Can also be used for inducing and relieving acute lymphocytic leukemia, chronic myelocytic leukemia and erythroleukemia, and can be used for treating and maintaining meningeal leukemia and other meningeal malignant tumors.
Cytarabine is a pyrimidine antimetabolite which mainly acts on the proliferation stage of cells S and interferes with the proliferation of cells by inhibiting the synthesis of cell DNA. Cytarabine enters a human body and is converted into cytarabine triphosphate and cytarabine diphosphate after phosphorylation by kinase, the cytarabine can strongly inhibit the synthesis of DNA polymerase, and the cytarabine diphosphate can inhibit the conversion of the cytidine diphosphate into the deoxycytidine diphosphate, so that the DNA polymerization and the synthesis of cells are inhibited.
The published synthetic route of cytarabine is as follows:
the post-treatment of the route requires resin purification, generates a large amount of ammonia water eluent, requires concentration, and is time-consuming and energy-consuming.
Therefore, a cytarabine refining process more suitable for industrial production is developed and improved, and a new crystal form of a cytarabine raw material medicine which can be used for the cytarabine for injection is found, so that the cytarabine for injection has important practical significance.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a novel crystalline form of cytarabine and a preparation method thereof, wherein the novel crystalline form of cytarabine is obtained through preparation, and the preparation method is simple in operation and high in yield and purity.
In order to achieve the aim, the invention provides a novel crystal form of cytarabine, wherein an X-ray powder diffraction pattern has diffraction peaks at the positions of 2 theta +/-0.2 degrees, and the 2 theta is 13.151, 15.879, 16.310, 19.763 and 26.975.
The diffraction peak is a characteristic powder diffraction peak, and the detection precision is +/-1 degrees.
More preferably, the 2 θ is 11.130, 13.151, 15.272, 15.879, 16.310, 16.838, 19.426, 19.763, 21.020, 21.767, 23.133, 23.859, 24.184, 26.975, 27.529, 29.338.
In the invention, the new crystal form of cytarabine has an obvious exothermic peak at 224 +/-1 ℃, and the decomposition temperature is deduced to be 224 +/-1 ℃.
In the invention, the initial melting temperature of the new crystal form of cytarabine is 220 +/-1 ℃.
The invention provides a preparation method of the cytarabine new crystal form, which comprises the following steps:
s1) reacting imidazole uridine shown in the formula I with ammonia water in a solvent, and then carrying out reduced pressure concentration on the system to remove the solvent and redundant ammonia water;
s2) adding methanolic ammonia into a reaction system for reaction, and then separating to obtain a solid;
s3) mixing the solid obtained in S2) with ammonia water for reaction, then carrying out reduced pressure concentration on the system, removing redundant ammonia water, then adding a solvent for pulping to obtain a crude product of cytarabine;
s4) mixing the cytarabine crude product with a refined solvent, stirring for dissolving, carrying out hot filtration, then cooling for crystallization, and separating solids to obtain a new cytarabine crystal form;
preferably, in step S1), the solvent is dioxane.
The reaction temperature in the step S1) is preferably 20-25 ℃, and the reaction time is preferably 10-14 h.
The temperature of the reduced pressure concentration is preferably 60 ℃, and the reduced pressure concentration is carried out until no liquid is distilled.
Then adding methanol ammonia into the reaction system to continue the reaction.
The amount of the methanolic ammonia added is preferably VMethanol ammonia：MIntermediate IV＝10mL:1g。
The M isIntermediate IVRefers to the quality of the product obtained in step S1).
The reaction temperature is preferably 25-30 ℃, and the reaction time is preferably 20-30 h.
After the reaction was complete, a solid was isolated.
The method of separation in the present invention is not particularly limited, and may be a separation method known to those skilled in the art, and the present invention includes, but is not limited to, a suction filtration method and the like.
The resulting solid was then mixed with aqueous ammonia for reaction.
The amount of the ammonia water is preferably VAqueous ammonia：MCrude product＝(3～5)mL：1g。
The M isCrude productRefers to the mass of the solid obtained in step S2).
The reaction temperature is preferably 30-40 ℃, and the reaction time is preferably 10-15 h.
And then carrying out reduced pressure concentration on the system, removing redundant ammonia water, adding a solvent, and pulping to obtain a cytarabine crude product.
The solvent is preferably an alcohol solvent, more preferably ethanol.
And then mixing the crude cytarabine product with a refined solvent, stirring for dissolving, carrying out hot filtration, cooling for crystallization, and separating a solid to obtain a new cytarabine crystal form.
The refining solvent is preferably one or more of water, ammonia water, methanol, ethanol and isopropanol, and more preferably a methanol/water mixed solvent, an ethanol/water mixed solvent or water.
In the methanol/water mixed solvent, the volume ratio of methanol to water is preferably 2-4: 1, and more preferably 3: 1.
In the ethanol/water mixed solvent, the volume ratio of ethanol to water is preferably 2-4: 1, and more preferably 3: 1.
The ratio of the mass of the crude cytarabine to the volume of the refined solvent is preferably 1 Kg: (1-40) L, more preferably 1 Kg: (2-40) L, or preferably 1 Kg: (1-3) L.
The stirring and dissolving temperature is preferably 60-65 ℃.
The temperature of the hot filtration is preferably 60-65 ℃.
Specifically, the refined solvent is preheated to 60-65 ℃, and then is mixed with the crude cytarabine.
The cooling crystallization temperature is preferably 20-30 ℃, and the cooling crystallization time is preferably 2-3 h.
The solid obtained by separation is shown as the first discovery by an X-ray powder diffraction spectrum.
The cytarabine new crystal form obtained by the invention has the characteristics that the cytarabine new crystal form is dissolved within 2 minutes at the temperature of 20-30 ℃ at the concentration of 0.1g/ml, and impurities are not changed before and after the dissolution.
Through detection, the purity of the obtained new crystal form of the cytarabine reaches the use standard of the cytarabine for injection, and the new crystal form of the cytarabine can be directly used as a raw material medicament.
According to the method, the refining process of the cytarabine is simplified, the obtained product is pure white, activated carbon decolorization is not needed, resin column chromatography purification operation is not needed, large-scale concentration equipment is avoided, the synthetic operation of the cytarabine is simpler, the yield is higher, the production cost is reduced, the method is more suitable for industrial production, and a new crystal form of a cytarabine raw material is obtained.
The invention provides an application of the cytarabine new crystal form or the cytarabine new crystal form prepared by the preparation method in preparing a leukemia induction and remission medicine.
In particular, the leukemia includes, but is not limited to, acute myeloid leukemia in adults or children. Acute lymphocytic leukemia, chronic myelogenous leukemia, and erythroleukemia.
The new crystal form of cytarabine is also suitable for treating and maintaining meningeal leukemia and other meningeal malignant tumors.
The invention provides a pharmaceutical preparation, which comprises the novel crystal form of cytarabine or the novel crystal form of cytarabine prepared by the preparation method and pharmaceutically acceptable auxiliary agents.
The dosage form of the pharmaceutical preparation provided by the invention comprises but is not limited to injection.
The novel crystal form of cytarabine provided by the invention can be combined with other medicines.
Based on the above, the invention provides a pharmaceutical composition, which comprises the new crystal form of cytarabine or the new crystal form of cytarabine prepared by the preparation method, and other drugs for inducing and relieving leukemia.
Compared with the prior art, the invention provides a new crystal form of cytarabine, an X-ray powder diffraction pattern has diffraction peaks at the positions of 2 theta +/-0.2 degrees, and the 2 theta is 13.151, 15.879, 16.310, 19.763 and 26.975. The novel crystal form of cytarabine provided by the invention has the characteristics of good batch-to-batch consistency, good stability under storage conditions, high dissolution speed, reduction of degradation risk in the production process of a preparation and the like, and is more suitable for the use of the preparation.
The preparation method of the novel cytarabine crystal form has the characteristics of strong environmental friendliness, simpler operation, controllable quality, low toxicity and harmlessness of a used solvent and the like, and is more suitable for industrial production.
Drawings
FIG. 1 is a powder derivatization pattern of cytarabine crystalline form 1 prepared in example 1 of the present invention;
FIG. 2 is a liquid phase diagram of cytarabine crystalline form 1 prepared in example 1 of the present invention;
FIG. 3 is a powder diffraction pattern of cytarabine crystalline form 2 prepared in example 2 of the present invention;
figure 4 is a DSC profile of cytarabine crystalline form 2 prepared in example 2 of the present invention;
FIG. 5 is a powder diffraction pattern of cytarabine crystalline form 3 prepared in example 3 of the present invention;
figure 6 is a DSC profile of cytarabine crystalline form 3 prepared in example 3 of the present invention.
Detailed Description
In order to further illustrate the present invention, the novel crystalline form of cytarabine and the preparation method thereof provided by the present invention are described in detail below with reference to examples.
Example 1
Adding 138.0g of dioxane into a reaction bottle, adding 27.0g of cytarabine intermediate (imidazole uridine) and 80ml of ammonia water, stirring and reacting for 12 hours at 20-25 ℃, concentrating under reduced pressure at 60 ℃ until no liquid is distilled off, adding 270ml of methanol ammonia, stirring and reacting for 24 hours at 25-30 ℃, carrying out suction filtration on reaction liquid, adding 80ml of ammonia water into solid, stirring and reacting for 15 hours at 30-40 ℃, concentrating under reduced pressure at 60 ℃ until the solid is dried, pulping with absolute ethyl alcohol, and carrying out suction filtration to obtain a crude product.
And adding the crude product into 50ml of ethanol/water (3: 1) preheated to 60-65 ℃, stirring for dissolving, performing hot filtration, cooling to room temperature, stirring for 2-3 h, performing suction filtration, and performing forced air drying on the solid at 60 ℃ for 24h to obtain a refined cytarabine product, namely a crystal form 1, wherein the yield is 75.5%, and the purity is 99.9%.
Taking 5.0g of the cytarabine new crystal form raw material, adding purified water to prepare a solution with the concentration of 0.1g/ml, stirring at the temperature of 20-30 ℃, completely dissolving and clarifying within 2 minutes, and ensuring that the clarity meets the standard.
The product is characterized by powder diffraction and liquid chromatography, and the results are shown in figures 1-2, which shows that the new crystal form of cytarabine is obtained.
Example 2
Adding 138.0g of dioxane into a reaction bottle, adding 27.0g of cytarabine intermediate (imidazole uridine) and 80ml of ammonia water, stirring and reacting for 12 hours at 20-25 ℃, concentrating under reduced pressure at 60 ℃ until no liquid is distilled off, adding 270ml of methanol ammonia, stirring and reacting for 24 hours at 25-30 ℃, carrying out suction filtration on reaction liquid, adding 80ml of ammonia water into solid, stirring and reacting for 15 hours at 30-40 ℃, concentrating under reduced pressure at 60 ℃ until the solid is dried, pulping with absolute ethyl alcohol, and carrying out suction filtration to obtain a crude product.
And adding the crude product into 50ml of methanol/water (3: 1) preheated to 60-65 ℃, stirring for dissolving, performing hot filtration, cooling to room temperature, stirring for 2-3 h, performing suction filtration, and performing forced air drying on the solid at 60 ℃ for 24h to obtain a refined cytarabine product, namely a crystal form 2, wherein the yield is 75.1%, and the purity is 99.9%.
Taking 5.0g of the cytarabine new crystal form raw material, adding purified water to prepare a solution with the concentration of 0.1g/ml, stirring at the temperature of 20-30 ℃, completely dissolving and clarifying within 2 minutes, and ensuring that the clarity meets the standard.
The product is characterized by powder diffraction and differential scanning calorimetry, and the results are shown in figures 3-4, which shows that the new crystal form of cytarabine is obtained.
Example 3
Adding 138.0g of dioxane into a reaction bottle, adding 27.0g of cytarabine intermediate (imidazole uridine) and 80ml of ammonia water, stirring and reacting for 12 hours at 20-25 ℃, concentrating under reduced pressure at 60 ℃ until no liquid is distilled off, adding 270ml of methanol ammonia, stirring and reacting for 24 hours at 25-30 ℃, carrying out suction filtration on reaction liquid, adding 80ml of ammonia water into solid, stirring and reacting for 15 hours at 30-40 ℃, concentrating under reduced pressure at 60 ℃ until the solid is dried, pulping with absolute ethyl alcohol, and carrying out suction filtration to obtain a crude product.
And adding the crude product into 30ml of preheated water at the temperature of 60-65 ℃, stirring for dissolving, carrying out hot filtration, cooling to room temperature, stirring for 2-3 h, carrying out suction filtration, and carrying out forced air drying on the solid at the temperature of 60 ℃ for 24h to obtain a refined cytarabine product, namely a crystal form 3, wherein the yield is 46.0%, and the purity is 99.9%.
Taking 3.0g of the cytarabine new crystal form raw material, adding purified water to prepare a solution with the concentration of 0.1g/ml, stirring at the temperature of 20-30 ℃, completely dissolving and clarifying within 2 minutes, and ensuring that the clarity meets the standard.
The product is characterized by powder diffraction and differential scanning calorimetry, and the results are shown in figures 5-6, which shows that the new crystal form of cytarabine is obtained.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A novel crystal form of cytarabine is characterized in that an X-ray powder diffraction pattern has diffraction peaks at 2 theta +/-0.2 degrees, and the 2 theta is 13.151, 15.879, 16.310, 19.763 and 26.975.
2. The novel crystalline form of cytarabine of claim 1, wherein the 2 Θ is 11.130, 13.151, 15.272, 15.879, 16.310, 16.838, 19.426, 19.763, 21.020, 21.767, 23.133, 23.859, 24.184, 26.975, 27.529, 29.338.
3. The novel crystalline form of cytarabine of claim 1, wherein the novel crystalline form of cytarabine has a decomposition temperature of 224 ± 1 ℃; the initial melting temperature is 220 +/-1 ℃.
4. A process for the preparation of a new crystalline form of cytarabine as claimed in any of claims 1 to 3 comprising the steps of:
s1) reacting imidazole uridine shown in the formula I with ammonia water in a solvent, and then carrying out reduced pressure concentration on the system to remove the solvent and redundant ammonia water;
s2) adding methanolic ammonia into a reaction system for reaction, and then separating to obtain a solid;
s3) mixing the solid obtained in S2) with ammonia water for reaction, then carrying out reduced pressure concentration on the system, removing redundant ammonia water, then adding a solvent for pulping to obtain a crude product of cytarabine;
s4) mixing the cytarabine crude product with a refined solvent, stirring for dissolving, carrying out hot filtration, then cooling for crystallization, and separating solids to obtain a new cytarabine crystal form;
5. the method according to claim 4, wherein the amount of ammonia used in step S3) is VAqueous ammonia：MCrude product＝(3～5)mL：1g；
The reaction temperature is 30-40 ℃, and the reaction time is 10-15 h.
6. The preparation method according to claim 4, wherein in the step S4), the refining solvent is one or more of water, ammonia water, methanol, ethanol and isopropanol.
7. The production method according to claim 6, wherein the refining solvent is a methanol/water mixed solvent, an ethanol/water mixed solvent, or water.
8. Use of the novel crystal form of cytarabine as claimed in any one of claims 1 to 3 or the novel crystal form of cytarabine as prepared by the preparation method as claimed in any one of claims 4 to 7 in the preparation of a medicament for inducing and relieving leukemia.
9. A pharmaceutical preparation, which comprises the novel crystalline form of cytarabine as claimed in any one of claims 1 to 3 or the novel crystalline form of cytarabine as prepared by the preparation method as claimed in any one of claims 4 to 7, and pharmaceutically acceptable adjuvants.
10. A pharmaceutical composition, which comprises the novel cytarabine crystal form as described in any one of claims 1 to 3 or the novel cytarabine crystal form prepared by the preparation method as described in any one of claims 4 to 7, and other drugs for inducing and relieving leukemia.
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| CN1583776A (en) * | 2003-08-22 | 2005-02-23 | 浙江海正药业股份有限公司 | Preparing method for cytarabine |
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| CN1583776A (en) * | 2003-08-22 | 2005-02-23 | 浙江海正药业股份有限公司 | Preparing method for cytarabine |
| CN101948492A (en) * | 2010-08-20 | 2011-01-19 | 河南师范大学 | Technology for producing cytarabine through chemical synthesis method |
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