CN102516338B - Capecitabine compound, pharmaceutical composition and preparation method thereof - Google Patents
Capecitabine compound, pharmaceutical composition and preparation method thereof Download PDFInfo
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- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 229960004117 capecitabine Drugs 0.000 title claims abstract description 97
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims description 27
- -1 Capecitabine compound Chemical class 0.000 title description 5
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims abstract description 93
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 32
- 239000013078 crystal Substances 0.000 claims abstract description 24
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 21
- 229920002472 Starch Polymers 0.000 claims abstract description 21
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 21
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 21
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 18
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 16
- 229940042238 capecitabine oral tablet Drugs 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 11
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims abstract description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910017488 Cu K Inorganic materials 0.000 claims abstract description 4
- 229910017541 Cu-K Inorganic materials 0.000 claims abstract description 4
- 230000005260 alpha ray Effects 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 235000019890 Amylum Nutrition 0.000 claims description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000012046 mixed solvent Substances 0.000 claims description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 11
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 10
- 238000013019 agitation Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 239000011812 mixed powder Substances 0.000 claims description 6
- 239000012047 saturated solution Substances 0.000 claims description 6
- 239000013081 microcrystal Substances 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 238000005070 sampling Methods 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 abstract 1
- 238000005259 measurement Methods 0.000 abstract 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 abstract 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 abstract 1
- 239000008107 starch Substances 0.000 abstract 1
- 235000019698 starch Nutrition 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 11
- 238000003860 storage Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 102000005497 Thymidylate Synthase Human genes 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 230000003578 releasing effect Effects 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- WAVYAFBQOXCGSZ-UHFFFAOYSA-N 2-fluoropyrimidine Chemical compound FC1=NC=CC=N1 WAVYAFBQOXCGSZ-UHFFFAOYSA-N 0.000 description 1
- 229920003110 Primojel Polymers 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940085837 capecitabine 150 mg Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical group 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- KRPAJLYSLFNDOA-UHFFFAOYSA-N mephenesin carbamate Chemical group CC1=CC=CC=C1OCC(O)COC(N)=O KRPAJLYSLFNDOA-UHFFFAOYSA-N 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000007898 rapid-disintegration tablet Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
Belonging to the technical field of medicines, the invention specifically relates to capecitabine, which is a crystal. Cu-K alpha ray measurement of the capecitabine crystal can obtain X-ray powder diffraction, which shows a characteristic peak at positions where 2theta is 8.3 degrees, 13.2 degrees, 16.5 degrees, 22.2 degrees, 23.3 degrees, 26.1 degrees, 27.2 degrees, 31.1 degrees, 31.9 degrees, 35.6 degrees, and 36.7 degrees. The invention also relates to a capecitabine pharmaceutical composition, which is a capecitabine oral tablet composed of 100-600 parts of capecitabine, 30-150 parts of compressible starch, 20-160 parts of microcrystalline cellulose, 25-90 parts of sodium carboxymethylcellulose, 50-200 parts of low-substituted hydroxypropyl cellulose, 15-105 parts of cross-linked polyvinylpyrrolidone, and 3-8 parts of magnesium stearate.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of capecitabine compound, its pharmaceutical composition and preparation method thereof.
Background technology
Capecitabine (capecitabine, CAP), chemistry CAP by name, belongs to thymidylate synthase (thymidylate synthase, TS) Depressant, and molecular formula is: C
15h
22fN
3o
6, molecular weight: 359.35, fusing point: 110-121 ℃, water-soluble, solubleness 26mg/ml (20 ℃).Capecitabine is by chemical process, Fluracil (fluorouracil, FU) to be done to chemical structure transformation to form prodrug (prodrug), and it can be absorbed rapidly by intestinal mucosa with complete molecular form because containing mephenesin Carbamate structure.Capecitabine is a kind of oral fluoropyrimidine nucleoside analogue with good target effect, can be in tumor tissues selectivity be activated and produce the active cells poisonous substance matter of high density, thereby improve the tolerance of tumour patient, and antitumour activity is maximized.But capecitabine poor stability is easily degraded, its preparation needs (to be generally 2-8 ℃) at low temperatures, and lucifuge protection against the tide close drying stores storage condition requirement harshness, and its its related substances is higher in long-time storage.
CN102260309A discloses a kind of preparation method of high purity capecitabine, comprise capecitabine crude product is dissolved in to the organic solvent that is selected from ethers or haloalkane hydro carbons at least one, in the solution obtaining, add alkanes organic solvent, thereby separate out white solid, be capecitabine, fusing point is 112.5-113.5 ℃.The process for purification of this capecitabine obviously improves capecitabine purity, and yield significantly improves, and compares with process for refining in the past, has that the impurity of removing is effective, yield is high, simple and safe operation, is easy to the advantages such as large-scale industrial production.
CN101433546A discloses oral controlled release agent of a kind of capecitabine and preparation method thereof, this oral controlled release agent contains following composition by weight percentage: (1) capecitabine, or its pharmacy acceptable salt, or the amount of its ester derivative is 50-90%; (2) the pharmaceutically acceptable auxiliary material of 10-50%, comprising the auxiliary material of pharmaceutically acceptable slow-releasing and controlled-releasing action of 4-44%.This patent adopts the pharmaceutical excipient having gone on the market, and active constituents of medicine content high (weight percent > 50%), can delay controlled release 12 to 24 hours.
CN101522168A discloses a kind of capecitabine pediatric tablets, it is film coating pharmaceutical composition, described composition comprises capecitabine and at least one disintegrating agent, described disintegrating agent is selected from and comprises following group: croscarmellose sodium, primojel, low-substituted hydroxypropyl cellulose, Pharmaburst C or these arbitrary combination, form rapid disintegration tablet together with other pharmaceutical excipient.Described composition is being less than disintegration in 2 minutes in USP disintegration device in 37 ℃ of water, and described composition has the hardness of 8-13scu.
In order to find the better capecitabine of a kind of stability and pharmaceutical composition thereof, special proposition the present invention.
Summary of the invention
The first object of the present invention is to provide the better capecitabine compound of a kind of stability.
The second object of the present invention is to provide a kind of pharmaceutical composition that contains above-mentioned capecitabine, and this pharmaceutical composition disintegration is faster, and extended storage stability is better.
The 3rd object of the present invention is to provide the preparation method of the pharmaceutical composition of above-mentioned capecitabine.
In order to realize foregoing invention object, the present invention takes following technical scheme:
A kind of capecitabine, described capecitabine is crystal, and the X-ray powder diffraction that described capecitabine crystal is used Cu-K alpha-ray to measure is 8.3 °, 13.2 °, 16.5 °, 22.2 °, 23.3 °, 26.1 °, 27.2 °, 31.1 °, 31.9 °, 35.6 °, 36.7 ° at 2 θ and locates to show characteristic peak.
According to foregoing capecitabine, the fusing point of described capecitabine is 131-133 ℃.
Capecitabine provided by the present invention, X-ray powder diffraction shows that its crystalline structure is different from the capecitabine of prior art, the stability of the capecitabine of new crystal provided by the invention is more good, stores for a long time that capecitabine content is little, its related substances is few.
The preparation method of above-mentioned capecitabine provided by the invention comprises: get capecitabine bulk drug, be dissolved in methyl alcohol and acetonitrile by 1～2: in the mixed solvent that 1 volume ratio is made into, with triethylamine, regulate pH to 8-9, be heated to 60～65 ℃ and make saturated solution, continue to be heated to 65-70 ℃, add medical active carbon decoloring, stir, filter, under agitation condition, drip normal heptane and be cooled to 0-5 ℃ with the speed of 1-1.5 ℃/min, filter, obtain white micro-crystals powder, by methanol wash, drying under reduced pressure.
Same compound, different crystal formations causes inner solid-state structure different, causes its lattice energy different, and lattice energy is higher larger to the constraint of compound molecule, and crystalline structure is more stable, and this compound is more stable.It is raw material that commercially available capecitabine crude product is take in the present invention, through experiment repeatedly, finally in change, comprise kind and proportioning, the pH of solvent and regulate the alkaline matter of pH, under the crystallization conditions such as the kind of anti-solvent, temperature, crystallization rate, prepare a kind of capecitabine with new crystal formation, the fusing point of the capecitabine of this crystal formation is 131-133 ℃, compared with prior art, capecitabine lattice energy of the present invention is relatively high, and crystalline structure is more stable.
In the preparation method of above-mentioned capecitabine, the mixed solvent that methyl alcohol and acetonitrile are preferably made into by the volume ratio of 2: 1.
In the preparation method of above-mentioned capecitabine, make after saturated solution, preferably continue to be heated to 70 ℃.
In the preparation method of above-mentioned capecitabine, under agitation condition, drip normal heptane and lower the temperature with the speed of 1.5 ℃/min.
In the preparation method of above-mentioned capecitabine, the 3-5 of the volume that the consumption of normal heptane is mixed solvent doubly.
In the preparation method of above-mentioned capecitabine, adding decolorizing with activated carbon is this area common technology means, can process referring to any decolouring, those skilled in the art are without paying any creative work, the prior art that can grasp according to himself is carried out appropriate selection, and realizes the object of the invention.
In order further to improve formulation products quality, the present invention also can be preferably filtered into use ultrafiltration membrance filter after decolouring.
The particle diameter of the capecitabine crystal that the preparation method of above-mentioned capecitabine obtains is 150-250 μ m.
The present invention also provides a kind of pharmaceutical composition that contains foregoing capecitabine.
According to foregoing pharmaceutical composition, described pharmaceutical composition is capecitabine oral tablet.
According to foregoing pharmaceutical composition, by weight, described capecitabine oral tablet comprises 100～600 parts of capecitabines, 30～150 parts of amylum pregelatinisatums, 20～160 parts of Microcrystalline Celluloses, 25～90 parts of Xylo-Mucines, 50～200 parts of low-substituted hydroxypropyl celluloses, 15～105 parts of cross-linked polyvinylpyrrolidones, 3～8 parts of Magnesium Stearates.
According to foregoing pharmaceutical composition, by weight, described capecitabine oral tablet comprises 100 parts of capecitabines, 30 parts of amylum pregelatinisatums, 40 parts of Microcrystalline Celluloses, 25 parts of Xylo-Mucines, 50 parts of low-substituted hydroxypropyl celluloses, 25 parts of cross-linked polyvinylpyrrolidones, 3 parts of Magnesium Stearates.
According to foregoing pharmaceutical composition, by weight, described capecitabine oral tablet comprises 125 parts of capecitabines, 45 parts of amylum pregelatinisatums, 38 parts of Microcrystalline Celluloses, 29 parts of Xylo-Mucines, 60 parts of low-substituted hydroxypropyl celluloses, 30 parts of cross-linked polyvinylpyrrolidones, 3 parts of Magnesium Stearates.
According to foregoing pharmaceutical composition, by weight, described capecitabine oral tablet comprises 150 parts of capecitabines, 50 parts of amylum pregelatinisatums, 40 parts of Microcrystalline Celluloses, 35 parts of Xylo-Mucines, 65 parts of low-substituted hydroxypropyl celluloses, 35 parts of cross-linked polyvinylpyrrolidones, 4 parts of Magnesium Stearates.
According to foregoing pharmaceutical composition, by weight, described capecitabine oral tablet comprises 175 parts of capecitabines, 60 parts of amylum pregelatinisatums, 45 parts of Microcrystalline Celluloses, 40 parts of Xylo-Mucines, 75 parts of low-substituted hydroxypropyl celluloses, 40 parts of cross-linked polyvinylpyrrolidones, 4 parts of Magnesium Stearates.
Contriver has done the stability experiment of a series of pharmaceutical compositions that contain foregoing capecitabine, its result shows, the good stability of the capecitabine in pharmaceutical composition, this pharmaceutical composition has extraordinary stability in storage, the long-time its related substances of placing is low, be convenient to very much transportation, store, greatly improved patient's drug safety.
The present invention also provides the preparation method of above-mentioned capecitabine oral tablet, and described preparation method comprises the following steps:
(1) capecitabine and amylum pregelatinisatum, Microcrystalline Cellulose, Xylo-Mucine, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, Magnesium Stearate are sieved respectively, standby;
(2) Microcrystalline Cellulose, amylum pregelatinisatum, croscarmellose sodium and Magnesium Stearate are dried 1～2 hour respectively under 60～80 ℃ of conditions, cross 60～80 mesh sieves, standby;
(3) by recipe quantity, take above-mentioned standby pharmaceutical excipient, by capecitabine, amylum pregelatinisatum, Microcrystalline Cellulose, Xylo-Mucine, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, adopt the equivalent method of progressively increasing to mix, the Magnesium Stearate that adds again recipe quantity, mix, and control mixing time again in 5min, obtain mixed powder;
(4) after sampling detects, open tabletting machine, mixed powder is carried out to direct pressed powder, dressing, obtain.Capecitabine provided by the invention and pharmaceutical composition tool thereof have the following advantages:
(1) capecitabine good stability of the present invention, is placed with for a long time related substance and changes little;
(2) capecitabine pharmaceutical composition of the present invention has extraordinary stability in storage, stronger to the tolerance of storage environment, places for a long time its related substances low, is convenient to very much transportation, stores, and has greatly improved patient's drug safety.
Accompanying drawing explanation
Fig. 1 is the X-RD spectrogram of the capecitabine crystal of embodiment 1 preparation.
Embodiment
Specific embodiment of the invention method only limits to further explain and explanation the present invention, not to Composition of contents restriction of the present invention.
Embodiment 1
The preparation of capecitabine crystal: the mixed solvent that methyl alcohol and acetonitrile are made into by the volume ratio of 2: 1, and be heated to 65 ℃, get capecitabine bulk drug 100g and be placed in Agitation Tank, add mixed solvent and stir, until make saturated solution, with triethylamine, regulate pH to 8, continue to be heated to 70 ℃, add medicinal carbon 10g decolouring, stir, filter, under agitation condition, drip normal heptane and be cooled to 0 ℃ with the speed of 1.5 ℃/min, the consumption of normal heptane is 5 times of volume of mixed solvent, filter, obtain white micro-crystals powder, by methanol wash 3 times, drying under reduced pressure 3h, obtain described capecitabine crystal, particle diameter is 150-250 μ m.Yield 81.9%, HPLC content 99.66%, mp131～133 ℃.
The X-ray powder diffraction that the capecitabine crystal obtaining is used Cu-K alpha-ray to measure is 8.3 °, 13.2 °, 16.5 °, 22.2 °, 23.3 °, 26.1 °, 27.2 °, 31.1 °, 31.9 °, 35.6 °, 36.7 ° at 2 θ and locates to show characteristic peak.
Embodiment 2
The preparation of capecitabine crystal: the mixed solvent that methyl alcohol and acetonitrile are made into by the volume ratio of 1: 1, and be heated to 60 ℃, get capecitabine bulk drug 100g and be placed in Agitation Tank, add mixed solvent and stir, until make saturated solution, with triethylamine, regulate pH to 9, continue to be heated to 65 ℃, add medicinal carbon 10g decolouring, stir, filter, under agitation condition, drip normal heptane and be cooled to 5 ℃ with the speed of 1 ℃/min, the consumption of normal heptane is 3 times of volume of mixed solvent, filter, obtain white micro-crystals powder, by methanol wash 3 times, drying under reduced pressure 4h, obtain described capecitabine crystal, particle diameter is 150-250 μ m.Yield 79.5%, HPLC content 99.58%, mp131～133 ℃.
The X-ray powder diffraction collection of illustrative plates of the capecitabine crystal obtaining and embodiment 1 product has identical parameters.
Embodiment 3
The preparation of capecitabine crystal: the mixed solvent that methyl alcohol and acetonitrile are made into by the volume ratio of 1.5: 1, and be heated to 65 ℃, get capecitabine bulk drug 100g and be placed in Agitation Tank, add mixed solvent and stir, until make saturated solution, with triethylamine, regulate pH to 8, continue to be heated to 70 ℃, add medicinal carbon 10g decolouring, stir, filter, under agitation condition, drip normal heptane and be cooled to 0 ℃ with the speed of 1.5 ℃/min, the consumption of normal heptane is 4 times of volume of mixed solvent, filter, obtain white micro-crystals powder, by methanol wash 3 times, drying under reduced pressure 4h, obtain described capecitabine crystal, particle diameter is 150-250 μ m.Yield 80.7%, HPLC content 99.69%, mp131～133 ℃.
The X-ray powder diffraction collection of illustrative plates of the capecitabine crystal obtaining and embodiment 1 product has identical parameters.
Embodiment 4
Prescription:
Table 1
| First group | Second group | The 3rd group | The 4th group | The 5th group | The 6th group | |
| Capecitabine | 100g | 125g | 150g | 175g | 100g | 600g |
| Amylum pregelatinisatum | 30g | 45g | 50g | 60g | 30g | 150g |
| Microcrystalline Cellulose | 40g | 38g | 40g | 45g | 20g | 160g |
| Xylo-Mucine | 25g | 29g | 35g | 40g | 25g | 90g |
| Low-substituted hydroxypropyl cellulose | 50g | 60g | 65g | 75g | 60g | 200g |
| Cross-linked polyvinylpyrrolidone | 25g | 30g | 35g | 40g | 15g | 105g |
| Magnesium Stearate | 3g | 3g | 4g | 4g | 3g | 8g |
Make altogether 1000
Preparation method: capecitabine and amylum pregelatinisatum, Microcrystalline Cellulose, Xylo-Mucine, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, Magnesium Stearate are sieved respectively; Microcrystalline Cellulose, amylum pregelatinisatum, croscarmellose sodium and Magnesium Stearate are dried 1～2 hour respectively under 60～80 ℃ of conditions, cross 60～80 mesh sieves; The bulk drug taking by the prescription of table 1, adopt the equivalent method of progressively increasing to mix amylum pregelatinisatum, Microcrystalline Cellulose, Xylo-Mucine, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, add again Magnesium Stearate, mix, and control mixing time again in 5min, obtain mixed powder; After sampling detects, open tabletting machine, mixed powder is carried out to 1000 of direct pressed powders, dressing, obtain.
Experimental example 1
This test example detects related substance in the prepared capecitabine tablet of embodiment 4, and this test is carried out according to 2010 editions second appendix VIIIP residual solvent assay method of Chinese Pharmacopoeia, appendix XIXF medicine impurity analysis governing principle, and it the results are shown in Table 2:
The assay of table 2 related substance
| Preparation | Methyl alcohol | Acetonitrile | Normal heptane | Other related substance |
| First group | Up to specification | Up to specification | Up to specification | Up to specification |
| Second group | Up to specification | Up to specification | Up to specification | Up to specification |
| The 3rd group | Up to specification | Up to specification | Up to specification | Up to specification |
| The 4th group | Up to specification | Up to specification | Up to specification | Up to specification |
| The 5th group | Up to specification | Up to specification | Up to specification | Up to specification |
| The 6th group | Up to specification | Up to specification | Up to specification | Up to specification |
Experimental example 2
This test example has been investigated the stability of capecitabine crystal provided by the invention
This test is carried out according to 2005 editions second appendix XIX C medicine stability test governing principle of Chinese Pharmacopoeia, and result is as follows:
Table 3, accelerated test result
| |
0 month | 1 month | 2 months | 3 months | 6 months |
| 1 | 99.9％ | 99.9％ | 99.8％ | 99.6％ | 99.4％ |
| 2 | 100.0％ | 100.0％ | 99.9％ | 99.7％ | 99.5％ |
| 3 | 99.9％ | 99.9％ | 99.8％ | 99.6％ | 99.4％ |
| 4 | 100.3％ | 100.1％ | 99.8％ | 99.4％ | 98.3％ |
| 5 | 100.1％ | 100.0％ | 99.6％ | 99.1％ | 98.2％ |
Table 4, long-term test results
| |
0 month | 3 months | 6 months | 9 months | 12 months | 18 months |
| 1 | 99.9％ | 99.9％ | 99.9％ | 99.8％ | 99.7％ | 99.5％ |
| 2 | 100.0％ | 100.0％ | 99.9％ | 99.8％ | 99.7％ | 99.6％ |
| 3 | 99.9％ | 99.9％ | 99.8％ | 99.7％ | 99.6％ | 99.5％ |
| 4 | 100.3％ | 100.2％ | 99.9％ | 99.6％ | 99.1％ | 98.6％ |
| 5 | 100.1％ | 100.0％ | 99.7％ | 99.5％ | 99.1％ | 98.7％ |
Wherein sample 1 is the product of embodiment 1, and sample 2 is the product of embodiment 2, and sample 3 is the product of embodiment 3;
Sample 4 is for getting commercially available capecitabine bulk drug, the capecitabine obtaining with reference to the method for patent CN102260309A embodiment 1;
Sample 5 is for getting commercially available capecitabine bulk drug, the capecitabine obtaining by re-crystallizing in ethyl acetate.
This experimental example explanation, capecitabine crystal stability provided by the invention is good, accelerate, test of long duration capecitabine purity content is little, and the common capecitabine crystal stability of prior art is poor, and accelerated test and test of long duration capecitabine content are large.
Experimental example 3
This test example has been investigated the stability of capecitabine pharmaceutical composition provided by the invention
This test is carried out according to 2005 editions second appendix XIX C medicine stability test governing principle of Chinese Pharmacopoeia, and result is as follows:
Table 5, accelerated test result
Table 6, long-term test results
Wherein sample 6 is the product of first group in embodiment 4, and sample 7 is the product of second group in embodiment 4, and sample 8 is the product of the 3rd group in embodiment 4, and sample 9 is the product of the 4th group in embodiment 4;
Sample 11 is commercially available capecitabine sheet, originates from Shanghai company limited of Roche Group, and every containing capecitabine 150mg;
This experimental example high spot reviews capecitabine the tablet content of capecitabine and changing conditions of its related substances in accelerating experiment and long-term experiment, investigate presentation of results, capecitabine tablet with respect to prior art, in capecitabine tablet provided by the invention, capecitabine content is little, stability is better, the content variation few, related substance of related substance is little, has greatly improved patient's drug safety.
Other embodiments of the invention product has also carried out identical experiment, and obtains the experimental result of same trend, but length limits, and the present invention will not enumerate.
Claims (10)
1. a capecitabine, it is characterized in that, described capecitabine is crystal, and the X-ray powder diffraction that described capecitabine crystal is used Cu-K alpha-ray to measure is 8.3 °, 13.2 °, 16.5 °, 22.2 °, 23.3 °, 26.1 °, 27.2 °, 31.1 °, 31.9 °, 35.6 °, 36.7 ° at 2 θ and locates to show characteristic peak.
2. the preparation method of a capecitabine as claimed in claim 1, it is characterized in that, described preparation method comprises: get capecitabine bulk drug, be dissolved in methyl alcohol and acetonitrile by 1～2: in the mixed solvent that 1 volume ratio is made into, with triethylamine, regulate pH to 8-9, be heated to 60～65 ℃ and make saturated solution, continue to be heated to 65-70 ℃, add medical active carbon decoloring, stir, filter, under agitation condition, drip normal heptane and be cooled to 0-5 ℃ with the speed of 1-1.5 ℃/min, filter, obtain white micro-crystals powder, by methanol wash, drying under reduced pressure.
3. a pharmaceutical composition that contains capecitabine claimed in claim 1.
4. pharmaceutical composition according to claim 3, is characterized in that, described pharmaceutical composition is capecitabine oral tablet.
5. pharmaceutical composition according to claim 4, it is characterized in that, by weight, described capecitabine oral tablet comprises 100～600 parts of capecitabines, 30～150 parts of amylum pregelatinisatums, 20～160 parts of Microcrystalline Celluloses, 25～90 parts of Xylo-Mucines, 50～200 parts of low-substituted hydroxypropyl celluloses, 15～105 parts of cross-linked polyvinylpyrrolidones, 3～8 parts of Magnesium Stearates.
6. pharmaceutical composition according to claim 5, it is characterized in that, by weight, described capecitabine oral tablet comprises 100 parts of capecitabines, 30 parts of amylum pregelatinisatums, 40 parts of Microcrystalline Celluloses, 25 parts of Xylo-Mucines, 50 parts of low-substituted hydroxypropyl celluloses, 25 parts of cross-linked polyvinylpyrrolidones, 3 parts of Magnesium Stearates.
7. pharmaceutical composition according to claim 5, it is characterized in that, by weight, described capecitabine oral tablet comprises 125 parts of capecitabines, 45 parts of amylum pregelatinisatums, 38 parts of Microcrystalline Celluloses, 29 parts of Xylo-Mucines, 60 parts of low-substituted hydroxypropyl celluloses, 30 parts of cross-linked polyvinylpyrrolidones, 3 parts of Magnesium Stearates.
8. pharmaceutical composition according to claim 5, it is characterized in that, by weight, described capecitabine oral tablet comprises 150 parts of capecitabines, 50 parts of amylum pregelatinisatums, 40 parts of Microcrystalline Celluloses, 35 parts of Xylo-Mucines, 65 parts of low-substituted hydroxypropyl celluloses, 35 parts of cross-linked polyvinylpyrrolidones, 4 parts of Magnesium Stearates.
9. pharmaceutical composition according to claim 5, it is characterized in that, by weight, described capecitabine oral tablet comprises 175 parts of capecitabines, 60 parts of amylum pregelatinisatums, 45 parts of Microcrystalline Celluloses, 40 parts of Xylo-Mucines, 75 parts of low-substituted hydroxypropyl celluloses, 40 parts of cross-linked polyvinylpyrrolidones, 4 parts of Magnesium Stearates.
10. a preparation method for the capecitabine oral tablet described in claim 4-9 any one, is characterized in that, described preparation method comprises the following steps:
(1) capecitabine and amylum pregelatinisatum, Microcrystalline Cellulose, Xylo-Mucine, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, Magnesium Stearate are sieved respectively, standby;
(2) Microcrystalline Cellulose, amylum pregelatinisatum, croscarmellose sodium and Magnesium Stearate are dried 1～2 hour respectively under 60～80 ℃ of conditions, cross 60～80 mesh sieves, standby;
(3) by recipe quantity, take above-mentioned standby pharmaceutical excipient, by capecitabine, amylum pregelatinisatum, Microcrystalline Cellulose, Xylo-Mucine, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, adopt the equivalent method of progressively increasing to mix, the Magnesium Stearate that adds again recipe quantity, mix, and control mixing time in 5min, obtain mixed powder;
(4) after sampling detects, open tabletting machine, mixed powder is carried out to direct pressed powder, dressing, obtain.
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