CN102627660B - Cefmetazole aseptic powder and its preparation method - Google Patents
Cefmetazole aseptic powder and its preparation method Download PDFInfo
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- CN102627660B CN102627660B CN201210078280.9A CN201210078280A CN102627660B CN 102627660 B CN102627660 B CN 102627660B CN 201210078280 A CN201210078280 A CN 201210078280A CN 102627660 B CN102627660 B CN 102627660B
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- cefmetazole
- cefmetazole sodium
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- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 title claims abstract description 132
- 239000000843 powder Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 229960003585 cefmetazole Drugs 0.000 title abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 47
- 238000002347 injection Methods 0.000 claims abstract description 43
- 239000007924 injection Substances 0.000 claims abstract description 43
- 238000001035 drying Methods 0.000 claims abstract description 7
- 229960002676 cefmetazole sodium Drugs 0.000 claims description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000001914 filtration Methods 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 19
- 238000010521 absorption reaction Methods 0.000 claims description 19
- 239000013078 crystal Substances 0.000 claims description 19
- 239000000706 filtrate Substances 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 7
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000003610 charcoal Substances 0.000 claims description 5
- 239000012467 final product Substances 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- 239000012982 microporous membrane Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 11
- 238000001953 recrystallisation Methods 0.000 abstract description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 4
- 239000012046 mixed solvent Substances 0.000 abstract description 2
- 239000002510 pyrogen Substances 0.000 abstract 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 229920000642 polymer Polymers 0.000 description 26
- 238000004128 high performance liquid chromatography Methods 0.000 description 25
- 230000014759 maintenance of location Effects 0.000 description 18
- 238000000034 method Methods 0.000 description 16
- 239000012535 impurity Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 238000002425 crystallisation Methods 0.000 description 13
- 230000008025 crystallization Effects 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 206010002198 Anaphylactic reaction Diseases 0.000 description 6
- 230000036783 anaphylactic response Effects 0.000 description 6
- 208000003455 anaphylaxis Diseases 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 5
- 150000003952 β-lactams Chemical class 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 3
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 2
- 230000002052 anaphylactic effect Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
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- 235000019837 monoammonium phosphate Nutrition 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WFIYPADYPQQLNN-UHFFFAOYSA-N 2-[2-(4-bromopyrazol-1-yl)ethyl]isoindole-1,3-dione Chemical compound C1=C(Br)C=NN1CCN1C(=O)C2=CC=CC=C2C1=O WFIYPADYPQQLNN-UHFFFAOYSA-N 0.000 description 1
- XOHZHMUQBFJTNH-UHFFFAOYSA-O 4-methyl-1h-tetrazol-1-ium-5-thione Chemical compound CN1NN=[NH+]C1=S XOHZHMUQBFJTNH-UHFFFAOYSA-O 0.000 description 1
- 241000606124 Bacteroides fragilis Species 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 206010067268 Post procedural infection Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 238000010669 acid-base reaction Methods 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 239000013566 allergen Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 1
- 229960004755 ceftriaxone Drugs 0.000 description 1
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229940124585 oral penicillin Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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- 210000002345 respiratory system Anatomy 0.000 description 1
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 1
- 229940041007 third-generation cephalosporins Drugs 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutics, specifically to cefmetazole aseptic powder and its preparation method. The preparation method comprises: employing a mixed solvent to recrystallize cefmetazole, using a good solvent to dissolve the cefmetazole raw material, adding activated carbon for injection to remove a pyrogen, then adding a poor solvent for recrystallization, and conducting drying at a low temperature, thus obtaining the cefmetazole aseptic powder with no pyrogen and high purity. Characterized by simple operation and high yield, the preparation method of the invention can prepare cefmetazole aseptic powder with high purity, safe and reliable quality, thus being suitable for preparing cefmetazole aseptic powder injections and widely applicable in large scale production of cefmetazole aseptic powder injections.
Description
Technical field
The invention belongs to pharmaceutics field, relate to specifically a kind of cefmetazole sodium aseptic powder and preparation method thereof.
Background technology
Cefmetazole sodium, English name Cefmetazole, chemistry 6R by name, 7S-7-[2-[(cyanogen methyl) sulfo-] acetamido]-7-methoxyl group-3-[[(1-methyl isophthalic acid H-tetrazolium-5-yl) sulfo-] methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt, molecular formula is C
15h
16n
7naO
5s
3, molecular weight is 493.52, structural formula is as follows:
Cefmetazole sodium claims again cefmotazole, Cefmetazole, cefmotazole, developed by Japanese Sankyo (three are total to Pharmaceutical Co., Ltd), a kind of wide spectrum, efficient, low toxicity microbiotic, its antimicrobial spectrum is similar to the western spit of fland of cephalo, and performance and second generation cephalosporin are close.Cefmetazole sodium is in April, 1980 first in Japan's listing, and the domestic hour of log-on of import is first 1992.A large amount of clinical trials show, cefmetazole sodium all has good antibacterial efficacy to gram-positive and negative bacterium, methicillin-resistant staphylococcus aureus (MRSA), bacteroides fragilis and anerobe are also had to good anti-microbial activity, various β-lactamases are had to very strong tolerance and stability, in body, distribute, untoward reaction is few, can be used for responsive microbial respiratory system infection, biliary tract infection, urinary system infection, the infection of Obstetric and Gynecologic Department bacterium, skin soft-tissue infection and hand postoperative infection prevention etc.
But as β-lactam antibitics medicine, cefmetazole sodium also has the defect of antibiotic medicine, more easily there is untoward reaction.According to bibliographical information, antibiotics is one of medicine more easily occurring untoward reaction, the more common badness reaction of clinical middle antibacterials is the anaphylaxis of drug-induced, β-lactam antibitics, aminoglycoside and Comprecin all can inducing different types anaphylaxis, but the most serious with β-lactam antibitics.But years of researches prove, the anaphylaxis of β-lactam antibitics is not due to medicine itself, but relevant with micro-macromolecule impurity contained in medicine.China scientific research personnel is through further investigation, from four kinds of third generation cephalosporins such as cefotaxime, cefoperazone, ceftriaxone, ceftazime separated and collected to cause animal anaphylactoid substantially without the superpolymer of anti-microbial activity, utilize the oral active anaphylaxis model of animal, having confirmed the anaphylactoid main allergens of oral penicillin such as causing potassium v calcium, amoxycilline Trihydrate bp is their high molecular polymer, gastrointestinal absorption does not change its supersensitivity, and cynnematin and penicillin itself does not cause anaphylaxis.Confirm thus, β-lactam antibitics anaphylaxis is relevant with quality product.
In addition in " quality of cefmetazole sodium and stability study " literary composition of delivering in " external medical microbiotic fascicle " according to Zhang Chunran and Tang Kehui,, report: by two annex XIX C medicine stability experiment instruction principles of Chinese Pharmacopoeia version in 2000, self-control cefmetazole sodium is carried out to study on the stability.Illumination 10d is found in test, and content slightly reduces, and total impurities slightly raises; Place 10d content for 60 DEG C and reduce approximately 40%, related substance increases approximately 12%; Under 75% and 92.5% relative humidity, place 10d, become yellow jelly, total impurities increases respectively 23.5% and 33.5%, and content reduces by 23.5% and 35.2%.This shows that cefmetazole sodium is to light, thermally labile, high temperature, humidity all can make it that chemical reactions such as oxygenolysis occur, and cefmetazole sodium content is reduced, and total impurities increases, and has increased untoward reaction chance.Therefore the control of the quality control to cefmetazole sodium, especially macromolecule impurity seems extremely important.
Lot of domestic and foreign patent and periodical have been reported preparation method and the process for purification of cefmetazole sodium.
Chinese patent CN 102180892.A discloses a kind of purification process of cefmetazole sodium: 1) by soluble in water raw material cefmetazole sodium, add with the immiscible organic solvent of water and extract, then separate the organic phase that contains impurity, obtain the water that contains cefmetazole sodium; 2) in above-mentioned water, add basic metal or alkaline-earth metal alkyl oxide to process, the sedimentation and filtration of separating out is fallen, obtain filtrate; 3) in this aqueous solution, add ethanol or acetone to carry out recrystallization, by the crystal off-line washing of separating out, the dry cefmetazole sodium that obtains refining purification.But the cefmetazole sodium purity that the method makes is not high, the content that high performance liquid chromatography records cefmetazole is 94.3%, can't meet the requirement of the national drug standards.
Chinese patent CN 101787039A discloses a kind of preparation method of cefmetazole sodium compound, pass through acid-base reaction, macroporous adsorbent resin and charcoal absorption, obtain highly purified cefmetazole sodium compound, utilizing the cefmetazole sodium HPLC purity that the method prepares is 99.7%, but the cefmetazole sodium that the method makes does not carry out the control of polymkeric substance, and need to, at 40～50 DEG C of scope inner dryings, easily produce polymkeric substance in the method.
Chinese patent CN 101623285A discloses a kind of Cefmetazole sodium medicament and preparation method thereof, it is in preparation process, utilize water for injection and alcohol mixed solution to carry out recrystallization, then through washing with alcohol, filtration, the dry cefmetazole sodium sterilized powder that obtains.It is 0.59% that the cefmetazole sodium maximum making by the method is singly mixed, and always mixing is 1.79%, and the content of superpolymer is 0.014%.Can find out that from this cefmetazole sodium that utilizes the method to make is always assorted higher.
There is at present the production listing of the lyophilized injectable powder of cefmetazole sodium.But cefmetazole sodium is extremely unstable in the aqueous solution, its aqueous solution is degraded very soon at ambient temperature, finds that after testing in the aqueous solution, its side chain 5-sulfydryl-1-methyl tetrazolium increases, and cefmetazole sodium content reduces.And the Chinese patent that is 200910305622.4 according to application number report, there is following shortcoming in the aseptic freeze-dried powder that uses superfreeze forming technique to prepare: lyophilized powder is inhomogeneous, color and luster is poor, pure loading amount there are differences, clarity has problems, the product purity stability problem lower, material of preparation is not solved completely, be still difficult for preserving for a long time etc., and freeze-dried powder technique more complicated, cost is higher.Therefore cefmetazole sodium freezing-dried powder injection very easily produces impurity in process of production, may produce drug safety problem.Therefore cefmetazole sodium aseptic powder injection preparation more and more receives publicity.
The domestic main method that adopts solvent crystal is at present produced cefmetazole sodium aseptic powder injection preparation, and the solvent crystal method of bibliographical information is mainly to utilize second alcohol and water, or methyl alcohol and ether.But the former utilizes ethanol and water solvent crystal, under the condition existing at water, cefmetazole sodium is unstable, easily decompose, and in follow-up drying step, the temperature needing is higher, easily causes cefmetazole sodium to decompose; And utilize methyl alcohol and ether recrystallization, although do not need to contact with water, but the boiling point of ether is lower, velocity of evaporation is fast, in the time that crystallization is filtered, moisture can be condensed on plane of crystal, make cefmetazole sodium unstable, and temperature is higher when dry, easily causes the related substances such as high molecular polymer to increase.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of yield is high, purity is high cefmetazole sodium aseptic powder and preparation method thereof.
For realizing object of the present invention, the present invention adopts following technical scheme:
A preparation method for cefmetazole sodium aseptic powder, comprising:
Step 1: cefmetazole sodium is dissolved with good solvent, be heated to dissolve, add injection charcoal absorption, filter;
Step 2: get step 1 gained filtrate, add poor solvent, heated and stirred is dissolved, positive press filtration;
Step 3: get step 2 gained filtrate and be refrigerated to-5～5 DEG C of crystallizatioies, collect gained crystal, after filtration, drying under reduced pressure at 15～30 DEG C, after pulverizing and get final product;
Wherein, described good solvent is alcoholic solvent or ketones solvent, and described poor solvent is ether solvent or esters solvent.
Cefmetazole sodium of the present invention refers to and adopts the cefmetazole sodium compound that the synthetic or solid phase synthesis cefmetazole sodium compound that obtain, that not yet pass through refinement treatment of liquid phase or purity can not fulfilling medicinal.
Preparation method of the present invention adopts good solvent to dissolve cefmetazole sodium raw materials, and described good solvent is alcoholic solvent or ketones solvent.Wherein, described alcoholic solvent can be methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol, and described ketones solvent can be acetone, butanone, ethyl methyl ketone or metacetone.
As preferably, described good solvent is acetone, methyl alcohol or ethanol.Preferred, be acetone.Wherein, as preferably, add the consumption of good solvent to count 2～5 times of cefmetazole sodium by g/mL, every 1g cefmetazole sodium adds optimum solvent described in 2～5mL.
In the cefmetazole sodium that preparation method of the present invention is dissolved at good solvent, add injection charcoal absorption then to filter, to remove thermal source wherein.As preferably, described injection is used by the add-on of gac by g/mL, is 0.1%～0.5% of good solvent consumption, and more preferably 0.2%～0.3%, be that optimum solvent adds described injection to use by gac 1g～5g, more preferably 2g～3g described in every 100mL.。
Described absorption is preferably and adds injection heating activated carbon to reflux 30 minutes.
The gained filtrate that preparation method's step 2 of the present invention is got step 1 filtering thermal source adds after poor solvent heating for dissolving, positive press filtration degerming.Described poor solvent is ether solvent or esters solvent.Wherein, described ether solvent can be ether, isopropyl ether, methyl tertiary butyl ether or tetrahydrofuran (THF), and described esters solvent can be ethyl formate, ethyl acetate, isopropyl acetate, n-butyl acetate or tert.-butyl acetate.As preferably, described poor solvent is isopropyl ether, methyl tertiary butyl ether, ethyl acetate or ethyl formate, preferred, is methyl tertiary butyl ether.
Wherein, as preferably, the volume ratio of described poor solvent and good solvent is (1～3): 1.
As preferably, described positive press filtration is below 0.1Mpa, with 0.22 μ m filtering with microporous membrane.
Preparation method's step 3 of the present invention is got step 2 filtration sterilization gained filtrate low temperature crystallization, and gained crystal drying and crushing obtains cefmetazole sodium aseptic powder.
Preparation method of the present invention adopts good solvent to dissolve cefmetazole sodium raw materials, adds injection gac except thermal source, then adds poor solvent to carry out recrystallization, dry at low temperatures pyrogen-free and the high cefmetazole sodium aseptic powder of purity of obtaining.Compared with prior art, preparation method of the present invention has avoided cefmetazole sodium to contact with water, has solved the problem of the oxidizable generation impurity of cefmetazole sodium in cefmetazole sodium freeze-dried powder.And selected poor solvent and the boiling point of good solvent are all lower, acetone boiling point is 56 DEG C, methyl alcohol is 64 DEG C, ethanol is 78 DEG C, and isopropyl ether is 68.5 DEG C, and methyl tertiary butyl ether is 55.2 DEG C, ethyl formate is 54 DEG C, 77 DEG C of ethyl acetate, therefore recrystallization and vacuum-drying temperature are all relatively low, therefore utilize mixed solvent cefmetazole sodium to be carried out recrystallization and can not caused the decomposition of cefmetazole sodium.And the boiling point of solvent is all more than 50 DEG C, evaporation rate of solvent can be too not fast, can not have the problem occurring while using ether recrystallization in the time that crystallization is filtered.In addition, adopt preparation method of the present invention to prepare the yield of cefmetazole sodium aseptic powder higher, reach more than 90%, and purity is also very high, reaches 99.3～99.7%, high molecular polymer is below 0.1%.
The present invention also provides the cefmetazole sodium being made by above-mentioned preparation method aseptic powder.
The present invention also provides a kind of cefmetazole preparation of sodium, and it contains the cefmetazole sodium aseptic powder that preparation method of the present invention makes.
As preferably, described cefmetazole preparation of sodium is aseptic powder injection injection.
In an embodiment, the cefmetazole sodium aseptic powder direct packaging that aseptic powder injection injection of the present invention is made by preparation method of the present invention obtains.
Brief description of the drawings
Fig. 1 shows the purity HPLC color atlas of the cefmetazole sodium raw materials in the embodiment of the present invention 1～5, the absorption peak that the peak that wherein relative retention time is 12.689min is cefmetazole sodium, and the peak of all the other relative retention times is impurity peaks;
Fig. 2 shows the HPLC detection figure of the high molecular polymer of the cefmetazole sodium raw materials in the embodiment of the present invention 1～5, and the peak that wherein relative retention time is 12.974min is the absorption peak of high molecular polymer in cefmetazole sodium;
Fig. 3 shows the purity HPLC color atlas of the cefmetazole sodium aseptic powder that the embodiment of the present invention 1 makes, the absorption peak that the peak that wherein relative retention time is 10.252min is cefmetazole sodium, and the peak of all the other relative retention times is impurity peaks;
Fig. 4 shows the HPLC detection figure of the high molecular polymer of the cefmetazole sodium aseptic powder that the embodiment of the present invention 1 makes, and the peak that wherein relative retention time is 13.079min is the absorption peak of high molecular polymer in cefmetazole sodium;
Fig. 5 shows the purity HPLC color atlas of the cefmetazole sodium aseptic powder that the embodiment of the present invention 2 makes, the absorption peak that the peak that wherein relative retention time is 11.031min is cefmetazole sodium, and the peak of all the other relative retention times is impurity peaks;
Fig. 6 shows the HPLC detection figure of the high molecular polymer of the cefmetazole sodium aseptic powder that the embodiment of the present invention 2 makes, and the peak that wherein relative retention time is 13.151min is the absorption peak of high molecular polymer in cefmetazole sodium;
Fig. 7 shows the purity HPLC color atlas of the cefmetazole sodium aseptic powder that the embodiment of the present invention 3 makes, the absorption peak that the peak that wherein relative retention time is 10.999min is cefmetazole sodium, and the peak of all the other relative retention times is impurity peaks.
Fig. 8 shows the HPLC detection figure of the high molecular polymer of the cefmetazole sodium aseptic powder that the embodiment of the present invention 3 makes, and the peak that wherein relative retention time is 12.773min is the absorption peak of high molecular polymer in cefmetazole sodium;
Fig. 9 shows the purity HPLC color atlas of the cefmetazole sodium aseptic powder that the embodiment of the present invention 4 makes, the absorption peak that the peak that wherein relative retention time is 10.252min is cefmetazole sodium, and the peak of all the other relative retention times is impurity peaks.
Figure 10 shows the HPLC detection figure of the high molecular polymer of the cefmetazole sodium aseptic powder that the embodiment of the present invention 4 makes, and the peak that wherein relative retention time is 12.686min is the absorption peak of high molecular polymer in cefmetazole sodium;
Figure 11 shows the purity HPLC color atlas of the cefmetazole sodium aseptic powder that the embodiment of the present invention 5 makes, the absorption peak that the peak that wherein relative retention time is 10.252min is cefmetazole sodium, and the peak of all the other relative retention times is impurity peaks;
Figure 12 shows the HPLC detection figure of the high molecular polymer of the cefmetazole sodium aseptic powder that the embodiment of the present invention 5 makes, and the peak that wherein relative retention time is 13.218min is the absorption peak of high molecular polymer in cefmetazole sodium.
Embodiment
The embodiment of the invention discloses a kind of cefmetazole sodium aseptic powder and preparation method thereof.Those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Product of the present invention and method are described by preferred embodiment, related personnel obviously can, not departing from content of the present invention, spirit and scope product as herein described and method is changed or suitably change and combination, realize and apply the technology of the present invention.
For realizing object of the present invention, the present invention adopts following technical scheme:
A preparation method for cefmetazole sodium aseptic powder, comprising:
Step 1: by acetone, methyl alcohol or dissolve with ethanol for cefmetazole sodium, be heated to reflux, add injection charcoal absorption, filter;
Step 2: get step 1 gained filtrate, add isopropyl ether, methyl tertiary butyl ether, ethyl acetate or ethyl formate, heated and stirred is dissolved, positive press filtration;
Step 3: get step 2 gained filtrate and be refrigerated to-5～5 DEG C of crystallizatioies, collect gained crystal, after filtration, drying under reduced pressure at 15～30 DEG C, after pulverizing and get final product.
In order further to understand the present invention, below in conjunction with embodiment, the present invention is described in detail.
Wherein, cefmetazole sodium purity HPLC testing conditions is chromatographic column: Ecosil C18 5 μ 250mm × 4.6mm; Moving phase: taking ammonium dihydrogen phosphate with methyl alcohol, tetrahydrofuran (THF) and 10% TBAH volume ratio as 700: 280: 20: 12.8 mix, then use 10% phosphoric acid solution adjust pH to 4.5, for moving phase, described ammonium dihydrogen phosphate, for getting primary ammonium phosphate 5.75g, is dissolved in water and is diluted to 700mL; Detect wavelength: 254nm; Flow velocity: 1.0mL/min.
Cefmetazole sodium high molecular polymer testing conditions is chromatographic column: Sephadex G-10 50～60 μ m 15.0mm × 300mm (Dalian Yi Lite); Moving phase: taking the 0.02mol/L phosphate buffered saline buffer of pH7.0 as mobile phase A, taking water as Mobile phase B, described 0.02mol/L phosphate buffered saline buffer is the mixing solutions that 0.02mol/L disodium phosphate soln and 0.02mol/L sodium dihydrogen phosphate volume ratio are 61: 39; Detect wavelength: 254nm; Flow velocity: 1.5mL/min.
Embodiment 1: the preparation of cefmetazole sodium aseptic powder injection injection
(1) take 500g cefmetazole sodium raw materials, its HPLC purity is 94.0%, and high molecular polymer content is 1.22%, adds in reactor, adds the acetone of 1L, is heated to dissolve;
(2) after cefmetazole sodium material dissolution, add 2.5g injection gac, reflux was filtered after 30 minutes;
(3) after having filtered, in filtrate, add 2L methyl tertiary butyl ether, heated and stirred is dissolved;
(4) after dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration;
(5), after having filtered, filtrate is refrigerated to 0 DEG C, and low temperature crystallization 2 hours;
(6) after crystallization completes, filter, and by gained crystal 15 DEG C of vacuum-dryings 4 hours;
(7) after dry, crystal is pulverized, obtained white cefmetazole sodium aseptic powder 453.5g, yield is that 90.7%, HPLC purity is 99.6%, and high molecular polymer is 0.013%;
(8), by cefmetazole sodium aseptic powder direct packaging, obtain cefmetazole for inj aseptic powder injection injection.
Embodiment 2: the preparation of cefmetazole sodium aseptic powder injection injection
(1) take 500g cefmetazole sodium raw materials, its HPLC purity is 94.0%, and high molecular polymer content is 1.22%, adds in reactor, adds the ethanol of 1.5L, reflux;
(2) after cefmetazole sodium dissolves, add 7.5g injection gac, reflux was filtered after 30 minutes;
(3) after having filtered, in filtrate, add 1.5L ethyl acetate, heated and stirred is dissolved;
(4) after dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration;
(5), after having filtered, filtrate is refrigerated to 5 DEG C, and low temperature crystallization 2 hours;
(6) after crystallization completes, filter, and by gained crystal 30 DEG C of vacuum-dryings 3 hours;
(7) after dry, crystal is pulverized, obtained white cefmetazole sodium aseptic powder 456.5g, yield 91.3%, HPLC purity is 99.5%, high molecular polymer is 0.012%;
(8), by aseptic subpackaged cefmetazole sodium aseptic powder, obtain cefmetazole for inj aseptic powder injection injection.
Embodiment 3: the preparation of cefmetazole sodium aseptic powder injection injection
(1) take 500g cefmetazole sodium raw materials, its HPLC purity is 94.0%, and high molecular polymer content is 1.22%, adds in reactor, adds the methyl alcohol of 2L, reflux;
(2) after cefmetazole sodium dissolves, add 6g injection gac, reflux was filtered after 30 minutes;
(3) after having filtered, in filtrate, add 6L ethyl formate, heated and stirred is dissolved;
(4) after dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration;
(5), after having filtered, filtrate is refrigerated to-5 DEG C, and low temperature crystallization 2 hours;
(6) after crystallization completes, filter, and by gained crystal 25 DEG C of vacuum-dryings 3 hours;
(7) after dry, crystal is pulverized, obtained white cefmetazole sodium aseptic powder 463.5g, yield 92.7%, HPLC purity is 99.3%, high molecular polymer is 0.024%;
(8), by aseptic subpackaged cefmetazole sodium aseptic powder, obtain cefmetazole for inj aseptic powder injection injection.
Embodiment 4: the preparation of cefmetazole sodium aseptic powder injection injection
(1) take 500g cefmetazole sodium raw materials, its HPLC purity is 94.0%, and high molecular polymer content is 1.22%, adds in reactor, adds the acetone of 2L, reflux;
(2) after cefmetazole sodium dissolves, add 4g injection gac, reflux was filtered after 30 minutes;
(3) after having filtered, in filtrate, add 2L ethyl formate, heated and stirred is dissolved;
(4) after dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration;
(5), after having filtered, filtrate is refrigerated to 0 DEG C, and low temperature crystallization 2 hours;
(6) after crystallization completes, filter, and by gained crystal 25 DEG C of vacuum-dryings 2.5 hours;
(7) after dry, crystal is pulverized, obtained white cefmetazole sodium aseptic powder 461.0g, yield 92.2%, HPLC purity is 99.5%, high molecular polymer is 0.018%;
(8), by aseptic subpackaged cefmetazole sodium aseptic powder, obtain cefmetazole for inj aseptic powder injection injection.
Embodiment 5: the preparation of cefmetazole sodium aseptic powder injection injection
(1) take 500g cefmetazole sodium raw materials, its HPLC purity is 94.0%, and high molecular polymer content is 1.22%, adds in reactor, adds the methyl alcohol of 1.5L, reflux;
(2) after cefmetazole sodium dissolves, add 2g injection gac, reflux was filtered after 30 minutes;
(3) after having filtered, in filtrate, add 2L isopropyl ether, heated and stirred is dissolved;
(4) after dissolving, below 0.1Mpa, with the millipore filtration of 0.22 μ m, positive press filtration;
(5), after having filtered, filtrate is refrigerated to-5 DEG C, and low temperature crystallization 2 hours;
(6) after crystallization completes, filter, and by gained crystal 25 DEG C of vacuum-dryings 2.5 hours;
(7) after dry, crystal is pulverized, obtained white cefmetazole sodium aseptic powder 463.38g, yield 92.7%, HPLC purity is 99.7%, high molecular polymer is 0.011%;
(8), by aseptic subpackaged cefmetazole sodium aseptic powder, obtain cefmetazole for inj aseptic powder injection injection.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (4)
1. a preparation method for cefmetazole sodium aseptic powder, is characterized in that, comprising:
Step 1: cefmetazole sodium is dissolved with good solvent, be heated to reflux, add injection charcoal absorption, filter;
Step 2: get step 1 gained filtrate, add poor solvent, heated and stirred is dissolved, positive press filtration;
Step 3: get step 2 gained filtrate and be refrigerated to-5～5 DEG C of crystallizatioies, collect gained crystal, after filtration, drying under reduced pressure at 15～30 DEG C, after pulverizing and get final product;
Wherein, described good solvent is acetone, methyl alcohol or ethanol, and described poor solvent is isopropyl ether, methyl tertiary butyl ether, ethyl acetate or ethyl formate.
2. preparation method according to claim 1, is characterized in that, the consumption of described good solvent is counted 2～5 times of cefmetazole sodium by g/mL.
3. preparation method according to claim 1, is characterized in that, the volume ratio of described poor solvent and good solvent is (1～3): 1.
4. preparation method according to claim 1, is characterized in that, described positive press filtration is below 0.1Mpa, with 0.22 μ m filtering with microporous membrane.
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