CN103980278B - Eszopiclone microcrystalline and preparation method thereof - Google Patents
Eszopiclone microcrystalline and preparation method thereof Download PDFInfo
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- CN103980278B CN103980278B CN201210577013.6A CN201210577013A CN103980278B CN 103980278 B CN103980278 B CN 103980278B CN 201210577013 A CN201210577013 A CN 201210577013A CN 103980278 B CN103980278 B CN 103980278B
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- basifier
- eszopiclone
- water
- acidulant
- preparation
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- 229960001578 eszopiclone Drugs 0.000 title claims abstract description 140
- GBBSUAFBMRNDJC-INIZCTEOSA-N eszopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-INIZCTEOSA-N 0.000 title claims abstract description 127
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 62
- 238000003756 stirring Methods 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 31
- 239000002253 acid Substances 0.000 claims abstract description 25
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 72
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 52
- 239000003814 drug Substances 0.000 claims description 51
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 50
- 229940079593 drug Drugs 0.000 claims description 26
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 26
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 25
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 25
- 239000007864 aqueous solution Substances 0.000 claims description 24
- 235000011090 malic acid Nutrition 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 23
- 239000007787 solid Substances 0.000 claims description 22
- 238000005406 washing Methods 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical group OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000001630 malic acid Substances 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 15
- -1 eszopiclone D-malic acid salt Chemical class 0.000 claims description 15
- 230000003068 static effect Effects 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000012752 auxiliary agent Substances 0.000 claims description 10
- 230000006837 decompression Effects 0.000 claims description 10
- 239000001509 sodium citrate Substances 0.000 claims description 9
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 6
- 235000015165 citric acid Nutrition 0.000 claims description 6
- 239000011975 tartaric acid Substances 0.000 claims description 6
- 235000002906 tartaric acid Nutrition 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical group CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 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 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 239000000084 colloidal system Substances 0.000 claims description 3
- 239000003995 emulsifying agent Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 claims description 3
- 238000012545 processing Methods 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 claims description 3
- 229910001948 sodium oxide Inorganic materials 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical group O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 14
- 239000003960 organic solvent Substances 0.000 abstract description 14
- 239000002245 particle Substances 0.000 abstract description 14
- 238000009826 distribution Methods 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 230000003113 alkalizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 238000000034 method Methods 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000012065 filter cake Substances 0.000 description 15
- 238000004458 analytical method Methods 0.000 description 13
- 239000012535 impurity Substances 0.000 description 13
- 235000002639 sodium chloride Nutrition 0.000 description 13
- 235000011121 sodium hydroxide Nutrition 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000013081 microcrystal Substances 0.000 description 11
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical group C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 description 10
- 229960000820 zopiclone Drugs 0.000 description 9
- 239000008236 heating water Substances 0.000 description 8
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical class OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 235000011083 sodium citrates Nutrition 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 206010022437 insomnia Diseases 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000000147 hypnotic effect Effects 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- 241000238876 Acari Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000002535 acidifier Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940049920 malate Drugs 0.000 description 2
- 150000004701 malic acid derivatives Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000010603 pastilles Nutrition 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000010583 slow cooling Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 230000005059 dormancy Effects 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000003760 hair shine Effects 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical class [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an eszopiclone microcrystalline and a preparation method thereof. The preparation method comprises the following steps: (1) eszopiclone is dissolved in an acid solution containing an acidulant to obtain a medicated solution; or a water-soluble eszopiclone salt is dissolved in water to get a medicated solution; wherein the solvent of the acid solution containing the acidulant is a solvent A and / or water; the solvent A is an organic solvent capable of being mixedly dissolved in water in any proportion; and (2) under stirring, an alkalizing agent is added into the medicated solution. The eszopiclone microcrystalline prepared by the preparation method is free of residual organic solvent, microcrystalline particle size and particle size distribution are controllable, and the microcrystalline product can be directly used for the preparation of pharmaceutical formulations without further grinding, so that the dissolution rate and content uniformity of prepared pharmaceutical formulation products are increased, and bioavailability improvement and individual difference reduction can be facilitated.
Description
Technical field
The invention belongs to medicinal chemistry art, more particularly to a kind of eszopiclone crystallite and preparation method thereof.
Background technology
Modern society has that than more serious sleep-disorder the whole world has nearly 1/4 people to be subject to insomnia puzzlement, insomnia
Occur to increase as the age increases, the elderly for having more than 50% complains easily awake and early awakening, and insomnia and its treatment are increasingly received
To the concern of people.
Eszopiclone（Eszopiclone）It is zopiclone（zopiclone）Individual isomer, by the U.S.
The quick short-acting Non-benzodiazepine sedative hypnotics of Sepracor companies exploitation.Eszopiclone in 2005 is listed in the U.S.,
Completed clinical testing at that time is related to people more than 2000, for the treatment of short-term and chronic insomnia, preclinical and clinical research table
Bright eszopiclone to 50 times that the affinity of benzene ribavirin acceptor is left zopiclone, the LD of eszopiclone50For 1500mg/
Kg, levo form is 300mg/kg, and raceme is 850mg/kg.Eszopiclone has that curative effect is strong, the low advantage of toxicity.Right assistant
Clone's preparation is individual administration, and adult recommends initial dose for 2mg before falling asleep, and 3mg can more effectively extend and sleep
The dormancy time.
Eszopiclone and zopiclone belong to poorly water soluble drugs, are preparing eszopiclone or zopiclone（Referred to as
Medicine）Solid pharmaceutical preparation when need by medicine crush and cross be sieved to certain fineness, to ensure the dissolution rate of solid pharmaceutical preparation and contain
The amount uniformity.At present, it is general that diameter of aspirin particle is reduced using mechanical crushing and the method sieved.
US20030119841 discloses the method for preparing eszopiclone as raw material with zopiclone.Right assistant is first obtained
Clone's D-malic acid salt, heating eszopiclone D-malic acid salt, water and ethyl acetate mixtures are added in potassium carbonate and follow-up
Continuous heating, makes eszopiclone be dissolved in ethyl acetate layer, it is concentrated, cool down, be filtered, washed and dried after obtain right assistant gram
It is grand.
The method is one of main method of industrialization production eszopiclone, due to the finally crystallization from organic solvent,
There is the defect of organic solvent residual in product, and the eszopiclone particle diameter for obtaining is larger, further prepare pharmaceutical preparation
When also need to further crush to reduce diameter of aspirin particle.
CN101426794 is disclosed one kind and is crystallized using various organic solvents, prepares the right side of low organic solvent residual
The method of zopiclone A crystal formations.
CN102232953 discloses a kind of premixing method containing eszopiclone composition and accessory formula, will sieve
Afterwards the eszopiclone of 50～250 micron grain sizes progressively increases with dextrin equivalent and is mixed, and crosses 120 mesh sieves and disperses 3 times, to be had
There is the pharmaceutical composition of high-dissolution and uniformity of dosage units, routinely understand that the eszopiclone in the invention is general according to this area
Obtained by mechanical crushing.
Because the expression activitiy of such medicine is high, sucking the drug powder of relatively low-dose can quickly produce hypnotic effect,
When carrying out mechanical crushing and sieving process, easily there is the bad reaction that Sucked medicine powder causes the quick hypnosis of operating personnel,
Cause security incident.Many dust, pollution environment can be also produced when carrying out mechanical crushing and sieving and process and is lost big etc. many
Problem.Further, since all employ various organic solvents, generally existing organic solvent in the last crystallization stage for synthesizing the medicine
Residue problem, needs removal organic solvent residual of adopting various measures, and can otherwise affect drug quality and be related to drug safety.Cause
This, it is necessary to research can overcome the method for preparing eszopiclone medicine crystallite of drawbacks described above.
The content of the invention
The technical problem to be solved is to overcome in prior art to be needed to reduce eszopiclone diameter of aspirin particle
Carry out mechanical crushing and the bad reaction for causing the quick hypnosis of operating personnel is comprehended at the place of sieving, and existing preparation method is present
Organic solvent residual and affect the defect of drug safety etc., and provide a kind of eszopiclone crystallite and preparation method thereof, should
Eszopiclone crystallite obtained in method does not have organic solvent residual, and the particle diameter and particle diameter distribution of crystallite is controllable, and product need not enter
One step is crushed, can be directly used for preparing pharmaceutical preparation, further makes the dissolution rate and content of obtained drug product formulation uniform
Degree is improved, and is favorably improved bioavilability and is reduced individual difference.
The present inventor is through substantial amounts of experimental study, inventors have surprisingly discovered that using " Acid-Base dissolved crystallite method " to prepare
Eszopiclone, can directly be obtained the crystallite of eszopiclone, and obtained product cut size and particle diameter distribution are controllable, without the need for crushing
And be particularly suitable for directly preparing corresponding pharmaceutical preparation, the dissolution rate and uniformity of dosage units that can make obtained drug product formulation is carried
It is high.Further, the present inventor is also surprising that and adds certain auxiliary agent in preparation process, with reference to certain processing step
And associated process conditions, the surface nature of obtained eszopiclone crystallite can be further adjusted, to realize that superior technique is imitated
Really.
The final present invention solves above-mentioned technical problem by following technical proposals.
The preparation method of the eszopiclone crystallite of the present invention comprises the steps：
（1）Eszopiclone is dissolved in the acid solution containing acidulant and is obtained containing drug solns；Or；By right assistant gram
Grand water soluble salt is dissolved in the water and obtains containing drug solns；Wherein, the solvent in the described acid solution containing acidulant is molten
Agent A and/or water；Described solvent orange 2 A is organic solvent that can be miscible with water arbitrary proportion；
（2）Under agitation, by above-mentioned containing addition basifier in drug solns.
In the present invention, described eszopiclone is the eszopiclone described in the routine of this area, can for various crystal formations or
Amorphous state.
In the present invention, for dissolving the consumption of the water of the water soluble salt of described eszopiclone, can at least make medicine
It is dissolved completely in water and is defined, generally less than 50 times of the water soluble salt quality of eszopiclone, preferably less than 30 times,
More preferably less than 15 times.
In the present invention, the water soluble salt of described eszopiclone is the water of the conventional described eszopiclone in this area
Soluble, preferably eszopiclone hydrochloride and/or eszopiclone D- acylates.Wherein, described right assistant gram
Grand D- acylates are preferably eszopiclone D-malic acid salt.
In the present invention, described eszopiclone D-malic acid salt is preferably used in during synthesis eszopiclone and produces
Intermediate eszopiclone D-malic acid salt, be preferably obtained by following methods：According to method disclosed in US20030119841
Eszopiclone D-malic acid salt is prepared, eszopiclone D-malic acid salt is prepared as raw material with zopiclone and D-malic acid.
In the present invention, described acidulant is referred to can make complete drug dissolution in the solution containing acidulant or and medicine
Can be allowed to be dissolved in the acidic materials of water into after salt.According to the general knowledge of this area, described acidulant should be and pharmaceutically can be connect
Receive, and the acidic materials compatible with medicine.Wherein, described compatibility is referred to can coexist, and have no adverse effects.Described acidifying
Agent may be selected from various acid, such as inorganic acid, inorganic middle strong acid or organic monoacid, preferably malic acid, hydrochloric acid, citric acid,
One or more in tartaric acid, fumaric acid, butanedioic acid, maleic acid, lactic acid and acetic acid, more preferably malic acid, citric acid, salt
One or more in acid and tartaric acid, most preferably malic acid.
In the present invention, the amount of described acidulant can at least make the minimum of complete drug dissolution, and preferably this is most
1～1.2 times of a small amount of, more preferably 1～1.05 times.The amount of dissolvable medicine acidulant is relevant with factors, such as acidulant
Hydrogen ion number that can be in combination with the basic center of medicine in species, acidulant, quantity of solvent and the system bar in course of dissolution
Part（Such as temperature, compound method）Etc..Wherein, refer in eszopiclone can be with hydrogen in acidifying agent molecule for described basic center
The group of ions binding or position.Therefore, above-mentioned minimum referred under same solvent and pastille Acidic Liquid configuration condition, certain
Acidulant can be by the minimum of complete drug dissolution.The minimum can determine that by simple conventional method：In same solvent
Under pastille Acidic Liquid preparation condition, using the consumption dissolving eszopiclone for gradually increasing the acidulant, just it is completely dissolved
When, as minimum.The present inventor's Jing many experiments grope to draw, specifically, the mol ratio of acidulant and eszopiclone
Value generally 0.8～1.5, preferably 0.9～1.2.
In the present invention, the particularly preferred water of solvent in the described acid solution containing acidulant makes not organic in product
Dissolvent residual and improve drug safety.It is molten that described organic solvent is preferably the conventional water soluble alcohols of pharmaceutical arts
One or more in agent, such as ethanol, propane diols, glycerine and ethylene glycol, preferred alcohol.It is molten in the mixed liquor of water and solvent orange 2 A
The consumption of agent A can be selected arbitrarily.The amount of the solvent in the described acid solution containing acidulant is can at least make medicine completely molten
Xie Yu is defined in the solution containing acidulant, generally below the 50 of eszopiclone quality times, preferably less than 30 times, more preferably
For less than 15 times.
In the present invention, described basifier is referred to can be occurred neutralization reaction and make medicine form free state simultaneously in system
The material separated out from water.Such as inorganic strong alkali（Such as NaOH）, weak acid strong alkali salt（Such as potassium carbonate, sodium carbonate, saleratus
Etc.）, and the conjugate base of organic monoacid（Such as sodium citrate, sodium tartrate, natrium malicum and sodium acetate）.According to this area
General knowledge, described basifier should be pharmaceutically can be received and the alkaline matter compatible with medicine.Described basifier can
It is alternatively two or more into the compound basifier being grouped into, preferably potassium carbonate and saleratus, carbon for single basifier
Sour sodium and sodium acid carbonate, NaOH and sodium acid carbonate, NaOH and natrium malicum, NaOH and potassium carbonate or, hydrogen
Sodium oxide molybdena and sodium citrate, etc..
In the present invention, when obtaining in being dissolved in the acid solution containing acidulant for eszopiclone containing drug solns, enter one
The combination of step preferably following acidulants and basifier：
Acidulant is hydrochloric acid, and basifier is NaOH, potassium carbonate or sodium carbonate；Wherein, basifier and hydrochloric acid mole
Than being preferably 0.95～1.2, more preferably 0.99～1.1.
Acidulant is malic acid, and basifier is potassium carbonate or sodium carbonate；Wherein, potassium carbonate or sodium carbonate and malic acid rub
That ratio preferably 0.95～1.2, more preferably 0.99～1.1；
Acidulant is malic acid, and basifier is NaOH and sodium carbonate；Wherein, NaOH and sodium carbonate and malic acid
Mol ratio be preferably 0.95～1.2, more preferably 0.99～1.1；
Acidulant is malic acid or tartaric acid, and basifier is NaOH and potassium carbonate；Wherein, basifier and acidulant
Mol ratio is preferably 1.0～1.20；
Acidulant is citric acid, and basifier is sodium citrate；Wherein, basifier is preferably with the mol ratio of acidulant
1.0～1.20, more preferably 1.17.
In the present invention, when obtaining when being dissolved in the water for the water soluble salt of eszopiclone containing drug solns, basifier is preferred
For the combination of NaOH and sodium carbonate, potassium carbonate or sodium carbonate；Wherein, the water solubility of described basifier and eszopiclone
The mol ratio of salt is preferably 0.95～1.2, and more preferably 0.99～1.1.
Described containing preferably also containing auxiliary agent in drug solns in the present invention, described auxiliary agent is that water-solubility carrier, surface are lived
Property agent and solubilizer in one or more, be preferably applied to solubilising, stable and control the crystallite for separating out, the table for improving crystallite
The effect of face phenomenon（Such as particle diameter, form）With yield etc..The consumption of described auxiliary agent is generally the 0.1～10 of eszopiclone
Times, preferably the 0.5～5 of eszopiclone quality times.Preferably, the addition of described auxiliary agent is preferably described molten
Add while solution or after described in obtaining containing drug solns.
Wherein, described water-solubility carrier preferably includes mannitol, PVP, sucrose, polyethylene glycol, lactose, hydroxypropyl
One or more in group-beta-cyclodextrin and maltitol.The preferred polyethylene glycol range of number-average molecular weight of described polyethylene glycol
400-8000。
Wherein, described surfactant and solubilizer are pharmaceutically acceptable, preferably including poloxamer, poly- dimension
One or more in ketone, lauryl sodium sulfate, Emulsifier EL-60, Tween 80 and s6.
The present inventor has found through lot of experiments, when auxiliary agent is surfactant and/or solubilizer, is effectively increased
Eszopiclone solubility in an acidic solution, reduces solvent load, beneficial to the operation of subsequent step.
In the present invention, described dissolving can be heated in case of need to system, so that course of dissolution is rapider
With reduction quantity of solvent.When described solvent is water, the condition of described dissolving is preferably 30 DEG C～70 DEG C.When described molten
When agent is ethanol water, the condition of described dissolving is preferably 30 DEG C～60 DEG C.
In the present invention, the condition of described stirring refers generally to mixing speed faster, preferably linear velocity >=30 m/min
Clock, more preferably 50～150 ms/min of linear velocity.
In the present invention, basifier is preferably dissolved in after water and is used by described basifier.It is different according to the species of basifier,
The concentration of aqueous solution of described basifier is preferably 1%～30%, and more preferably 5%～20%, described percentage is basifier
Account for the mass percent of the aqueous solution total amount of basifier.
In the present invention, the feed postition of described basifier can be added once, also can be added above at twice, the speed of addition
Degree is unrestricted, can be to rapidly join, add at a slow speed or be spaced on a small quantity the modes such as addition.
In the present invention, separation of solid and liquid, washing and solid-liquid are routinely carried out according further to this area after described addition basifier
Separate, be dried, preferably suction filtration, washing, suction filtration and drying.
Wherein, the solvent of described washing uses the aqueous solution or water of basifier by this area.Described basifier
Basifier in the aqueous solution is step（2）In basifier.The concentration of aqueous solution of described basifier is preferably 0.1%～2%,
It is preferred that 0.5%～1%, described percentage accounts for the mass percent of the aqueous solution total amount of basifier for basifier.Described washing
The consumption of solvent be preferably 1～5 times of obtained eszopiclone crystallite quality.
Wherein, the number of times of described washing is preferably 1～3 time.
In the present invention, the drying means that described drying can adopt this area conventional is carried out, and such as static dry or dynamic is dry
It is dry.Wherein, it is preferably 40～80 DEG C, preferably 55～65 DEG C that described static state is dried, and drying under reduced pressure 3～12 hours, preferably 6～
8 hours.The vacuum condition of described drying under reduced pressure is preferably 450mmHg～76mmHg, more preferably for 150mmHg～
76mmHg.It is preferably to be vacuum dried in mixer in bipyramid at 40～70 DEG C, preferably 50～60 DEG C that described dynamic is dried
It is dried 3～8 hours, preferably 5～6 hours.
In the present invention, the step of described addition basifier after, the step of described separation of solid and liquid before, may be used also
Decentralized processing is carried out with colloid mill or homogenizer, with the particle diameter for further reducing and controlling medicine.
Eszopiclone crystallite obtained in the preparation method that aforementioned eszopiclone crystallite is also provided of the invention.
In the present invention, above-mentioned each optimum condition can be combined on the basis of common sense in the field is met, you can get Ben Fa
Bright each preferred embodiments.
The present invention is raw materials used can voluntarily to be prepared or be commercially available, and the material such as carrier is commercially available.
On the basis of common sense in the field is met, above-mentioned each optimum condition can be combined, and obtain final product each preferable reality of the present invention
Example.
Agents useful for same of the present invention and raw material are commercially available.
The present invention positive effect be：
1st, eszopiclone crystallite average grain diameter D [4,3] obtained in the preparation method of eszopiclone crystallite of the invention
Up to less than 50 microns, also can control average volume particle diameter D [4,3] less than 20 microns, even less than 10 microns of right assistant gram
Grand crystallite, can directly using avoid prepare follow-up preparation when the defect brought of mechanical pulverization process, while improve system
The dissolution rate and uniformity of dosage units of agent product, is favorably improved bioavilability and reduces individual difference.
2nd, the obtained Eszopiclone crystallite organic solvent-free residual of the present invention, Functionality, quality and appealing design is safe.
3rd, the present invention prepare eszopiclone crystallite method operation it is few, easy to operate, low cost, pollute and be lost it is little,
Heating, concentration, the troublesome operation of recycling solvent are avoided, the labor for thoroughly having prevented the operation is prevented and potential safety hazard, thoroughly
The organic solvent residuals such as ethyl acetate in raw material are solved the problems, such as, industrialized production is easily applied to.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Among applying a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product specification is selected.Room temperature is 10-30 DEG C.
Comparative example 1 prepares eszopiclone
The method announced by US20030119841, puts into 40g zopiclones, D-malic acid in the reaction bulb of 2L
13.4g, 406ml methyl alcohol, 754ml acetone, oil bath heating to 56 DEG C are reacted 30 minutes, and then slow cooling is to 45-47 DEG C of insulation
30 minutes, and 0.1g eszopiclone D malates are put into as crystal seed, it is cooled to 40 DEG C and is incubated 1 hour, it is cooled to 10-
15 DEG C are incubated 3 hours, close stirring, and at 10-15 DEG C 30 minutes are stood, and suction filtration uses methyl alcohol（2*50ml, 0-5 DEG C）Washing filter cake,
Drying under reduced pressure obtains eszopiclone D malates（22.1g, yield 41.1%, 97.2%ee）.
Eszopiclone D malate 10g, 20ml water and 150ml ethyl acetate, oil bath are put in 250ml reaction bulbs
It is heated to 30-40 DEG C.40wt% solution of potassium carbonate 8g were slowly added in 5 minutes, then solution is heated to into 60-65 DEG C, separation has
Machine phase, and with 100ml water washing organic phases, with 20ml ethyl acetate washings phases, and is concentrated into 70-80ml by organic phase, cold
But 2 hours are incubated to 0-5 DEG C, suction filtration, and use ethyl acetate（20ml, 0-5 DEG C）Washing filter cake, drying under reduced pressure obtains right assistant gram
It is grand（6.3g, yield 84.7%）.
Sample analysis：Eszopiclone content 99.5%, total impurities 0.05%, ethyl acetate residual 0.2%.
Comparative example 2 prepares eszopiclone
40g zopiclones, D-malic acid 13.4g, 243g methyl alcohol, 413g acetone are put in reaction bulb, oil bath heating is extremely
Backflow（56℃）Reaction 30 minutes, then slow cooling is to 10-15 DEG C, stands 8 hours, and suction filtration obtains crude salt, by upper step gained
In crude salt, 168g methyl alcohol, 247g acetone input reaction bulb, oil bath heating is to backflow（56℃）Reaction 30 minutes, then slowly drops
Temperature stands 8 hours to 10-15 DEG C, and suction filtration uses acetone（2*20ml, 0-5 DEG C）Washing filter cake, drying under reduced pressure obtains right assistant gram
Grand D malic acid refined salt（21.9g, 40.7%, 99.0%ee）.
Eszopiclone D malate 10g, 40ml water and 142g ethyl acetate are put in 250ml reaction bulbs, it is slow to add
Enter potassium carbonate 2.8g, solution is heated to into back flow reaction 30 minutes, separate organic phase, and use 2*40ml saturated aqueous common salts（70-80
℃）Washing organic phase, and organic phase is concentrated into into 60-70ml, it is cooled to 5-10 DEG C and stands 8 hours, suction filtration, and use ethyl acetate
（20ml, 0-5 DEG C）Washing filter cake, drying under reduced pressure obtains eszopiclone（6.4g, yield 86.1%）.
Sample analysis：Eszopiclone content 99.6%, total impurities 0.04%, ethyl acetate residual 0.2%.
Embodiment 1 prepares eszopiclone crystallite
Take the eszopiclone D-malic acid salt intermediate 30g as obtained in the preparation method of comparative example 1（57.4mmol）, input
In reaction bulb, add water 700g, open stirring, after eszopiclone D-malic acid salt it is complete it is molten after, adjustment speed of agitator to 60 meters/
Minute, pour 10wt% wet chemical 85g into（61.6mmol, 1.07 times of medicine）, continue to stir 1 hour, filter, use
1wt% wet chemicals washing filter cake for several times, after the wet brilliant 60 DEG C of decompressions static state of gained is dried 8 hours white micro-crystals solid is obtained
19.83g, yield 88.9%.
Sample analysis：Eszopiclone content is 99.5%, total impurities 0.03%, without ethyl acetate residual.
Embodiment 2 prepares eszopiclone crystallite
By eszopiclone 30g（77.2mmol）In input reaction bulb, 370g water and 10% aqueous hydrochloric acid solution 30g are added
（84.5mmol, 1.10 times of medicine）, stirring is opened, heating water bath after Eszopiclone is entirely molten, removes water-bath to 60 DEG C
Heating, adjustment speed of agitator to 50 ms/min, 10% sodium hydrate aqueous solution 34g（85mmol, 1.01 times of acid）, continue to stir
1 hour, filter, filter cake 2 times wash with 0.1wt% sodium hydrate aqueous solution 60g, it is some to obtain wet crystalline substance, 60 DEG C of decompression static state dryings 8
White micro-crystals solid 26.42g, yield 88.1% are obtained after hour.
Sample analysis：Content is 98.8%, total impurities 0.09%, without ethyl acetate residual.
Embodiment 3 prepares eszopiclone crystallite
Take the eszopiclone D-malic acid refined salt intermediate 30g as obtained in the preparation method of comparative example 2
（57.4mmol）, in input reaction bulb, water 450g is added, stirring is opened, after eszopiclone D-malic acid salt is entirely molten, input
15g PVP K30s, continue to stir entirely molten to solid, and adjustment speed of agitator pours 10wt% wet chemicals into 80 ms/min
95g（68.8mmol, 1.20 times of medicine）, continue to stir 1 hour, filter, filter cake 3 times is washed with 1% wet chemical 90g,
Wet brilliant the decompression after static state is dried 8 hours in 60 DEG C, 150mmHg of gained is obtained into white micro-crystals solid 20.45g, yield：91.7%.
Sample analysis：Eszopiclone content is 99.6%, total impurities 0.04%, without ethyl acetate residual.
Embodiment 4 prepares eszopiclone crystallite
By 30g（57.4mmol）In eszopiclone D-malic acid salt input reaction bulb, water 600g is added, opens stirring,
After eszopiclone D-malic acid salt is entirely molten, 300g sucrose is put into, continue to stir entirely molten to solid, adjustment speed of agitator to 50
M/min, pour 20% aqueous sodium carbonate 33g into（62.3mmol, 1.09 times of medicine）, continue to stir 1 hour, filter, use
2wt% wet chemicals 150g washing filter cakes 3 times, by gained it is wet it is brilliant in 80 DEG C, 76mmHg decompressions are static be dried 3 hours after
White micro-crystals solid 20.1g, yield 90.1%.
Sample analysis：Eszopiclone content is 99.1%, total impurities 0.06%, without ethyl acetate residual.
Embodiment 5 prepares eszopiclone crystallite
By 30g（57.4mmol）In eszopiclone D-malic acid salt input reaction bulb, water 150g is added, opens stirring,
Heated solution after eszopiclone D-malic acid salt is entirely molten, removes heating water bath to 70 DEG C, and input 3g poloxamers and 3g tell
Temperature 80, continues to stir entirely molten to solid, and adjustment speed of agitator is slowly added to 10wt% wet chemical 76g to 60 ms/min
（55.1mmol, 0.96 times of medicine）, continue to stir 1 hour, filter, filter cake 1 time wash with 1% wet chemical 30g, general
Gained it is wet it is brilliant in 60 DEG C, 450mmHg decompressions are static be dried 12 hours after white micro-crystals solid 20.3g, yield 91.0%.
Sample analysis：Eszopiclone content is 99.1%, total impurities 0.02%, without ethyl acetate residual.
Embodiment 6 prepares eszopiclone crystallite
By 30g（70.7mmol）In eszopiclone hydrochloride input beaker, water 450g is added, open stirring, treat right assistant
Clone's D-malic acid salt it is complete it is molten after, input 30g Macrogol 6000s and 3g lauryl sodium sulfate continue to stir complete to solid
Molten, to 150 ms/min, point 3 minor ticks pour 10wt% wet chemical 103g into adjustment speed of agitator（74.6mmol, medicine
1.06 times）, continue to stir 1 hour, stop stirring, filter, filter cake 2 times is washed with 1wt% wet chemical 60g, by gained
Wet brilliant 70 DEG C are dried 3 hours in bipyramid vacuum drying mixer dynamic, obtain white micro-crystals solid 25.3g, yield 91.9%.
Sample analysis：Eszopiclone content is 99.9%, total impurities 0.04%, without ethyl acetate residual.
Embodiment 7 prepares zopiclone crystallite
By 30g（77.2mmol）In zopiclone input reaction bulb, 5wt% aqueous solution of citric acid 280g is added
（72.9mmol, the 0.95 of medicine）, stirring is opened, heating water bath after zopiclone is entirely molten, removes heating water bath to 30 DEG C,
60g lactose and 15g HP-β-CDs, adjustment speed of agitator is added to be slowly added to 10wt% sodium citrates to 50 ms/min
Aqueous solution 220g（85.3mmol, 1.17 times of acid）, continue to stir 1 hour, filter, washed with 1wt% sodium citrate aqueous solution 60g
Wash filter cake 2 times, it is some to obtain wet crystalline substance, 60 DEG C of decompressions are static be dried 8 hours after white micro-crystals solid 26.17g, yield 87.2%.
Sample analysis：Eszopiclone content is 99.0%, total impurities 0.06%, without ethyl acetate residual.
Embodiment 8 prepares eszopiclone crystallite
By 30g（77.2mmol）In eszopiclone input reaction bulb, water 150g, ethanol 45g and 10wt% hydrochloric acid water are added
Solution 33g（93.0mmol, the 1.20 of medicine）, stirring is opened, heating water bath after eszopiclone is entirely molten, is removed to 60 DEG C
Heating water bath, dissolves in 10g PEG 8000s and 6g Emulsifier EL-60s, and adjustment speed of agitator is poured into 100 ms/min
30wt% aqueous sodium carbonate 31g（87.7mmol, 0.94 times of acid）, continue to stir 1 hour, by mixed liquor homogenizer homogeneous 5
Minute, filter, filter cake 1 time wash with 1wt% aqueous sodium carbonate 45g, by gained it is wet brilliant 60 DEG C in bipyramid vacuum drying mixer
Dynamic is dried 6 hours, obtains white micro-crystals solid 26.81g, yield 89.4%.
Sample analysis：Eszopiclone content is 99.2%, total impurities 0.06%, without ethyl acetate residual.
Embodiment 9 prepares eszopiclone crystallite
By 30g（77.2mmol）In eszopiclone input reaction bulb, water 200g and D-malic acid 11g is added
（82.1mmol, 1.06 times of medicine）, stirring is opened, heating water bath after eszopiclone is entirely molten, removes water-bath and adds to 40 DEG C
Heat, dissolves in 15g PVP K30s, and to 80 ms/min, point 2 minor ticks pour NaOH containing 5wt% and 5wt% into adjustment speed of agitator
The aqueous solution 51g of potassium carbonate（63.8mmol+18.5mmol, 1.00 times of acid）, continue to stir 1 hour, filter, use 1wt% carbonic acid
Aqueous solutions of potassium 60g washing filter cakes 2 times, by gained it is wet it is brilliant in 60 DEG C, 225mmHg decompressions are static be dried 8 hours after white micro-crystals
Solid 27.03g, yield 90.1%.
Sample analysis：Eszopiclone content is 99.0%, total impurities 0.03%, without ethyl acetate residual.
Embodiment 10 prepares eszopiclone crystallite
By 30g（77.2mmol）In eszopiclone input reaction bulb, water 480g and tartaric acid 11.5g is added
（76.7mmol, 0.99 times of medicine）, stirring is opened, heating water bath after eszopiclone is entirely molten, dissolves in 90g sweet to 30 DEG C
Dew alcohol, 6g PEG400s and 6g s6s, adjustment speed of agitator pours hydrogen containing 8wt% into 135 ms/min
The aqueous solution 36g of sodium oxide molybdena and 8wt% potassium carbonate（72.0mmol+20.8mmol, 1.21 times of acid）, continue to stir 1 hour, will
Mixed liquor milling treatment of colloid 10 minutes, filters, and filter cake 3 times is washed with 0.5wt% sodium hydrate aqueous solution 90g,
Wet brilliant the decompression after static state is dried 7 hours in 60 DEG C, 150mmHg of gained is obtained into white micro-crystals solid 26.56g, yield
88.5%。
Sample analysis：Eszopiclone content is 99.4%, total impurities 0.07%, without ethyl acetate residual.
Embodiment 11 prepares eszopiclone crystallite
By 30g（77.2mmol）In eszopiclone input reaction bulb, water 150g and 10% hydrochloric acid 27g is added
（76.1mmol, 0.99 times of medicine）, stirring is opened, heated solution after eszopiclone is entirely molten, removes water-bath and adds to 60 DEG C
Heat, puts into 5g poloxamers, continues to stir entirely molten to solid, and adjustment speed of agitator is slowly added to 1wt% carbon to 120 ms/min
Acid sodium aqueous solution 960g（90.6mmol, 1.19 times of acid）, continue to stir 1 hour, filter, with 1wt% wet chemical 90g
Washing filter cake 2 times, by gained it is wet it is brilliant in 60 DEG C, 150mmHg decompressions are static be dried 6 hours after white micro-crystals solid 24.75g,
Yield 82.5%.
Sample analysis：Eszopiclone content is 99.6%, total impurities 0.02%, without ethyl acetate residual.
Effect example
Eszopiclone crystallite prepared by embodiment 6 prepares eszopiclone piece, while using conventional eszopiclone
Prepare eszopiclone piece as a comparison case 3（3mg/ pieces）（Unit：Gram）
The particle diameter test result of effect example 1 is relatively
Determining instrument：Instrument BT-9300S types laser fineness gage and BT-800 type automatic cycle sampling systems（Dandong
Special Instrument Ltd. of city hundred）.
Assay method：Take sample appropriate, add circulation sample injection system（Decentralized medium is 1% wet chemical, and volume is about
For 570ml, RCF is 143 × g）, the system absorbance of making reaches（15±10）%, ultrasonic wave dispersion 3min, continuous 6 times
Sampling test and calculating, obtain D [4,3], D10、D50And D90。
Particle diameter tests relative result table：
The dissolution rate comparative experiments of effect example 2
Dissolution determination method：Sample shines dissolution method（Chinese Pharmacopoeia two methods of annex X C the 3rd of version in 2010）,
With 200ml water as solvent, rotating speed is 50 turns per minute, is operated in accordance with the law.By UV-VIS spectrophotometry（Chinese Pharmacopoeia 2010
Year two annex IV A of version）, the mensuration absorbance at the wavelength of 304nm；It is another to prepare contrast solution.It is measured in the same method, calculates dissolution
Amount.
Claims (23)
1. a kind of preparation method of eszopiclone crystallite, it is characterised in that it comprises the steps：
(1) eszopiclone is dissolved in the acid solution containing acidulant and is obtained containing drug solns；Or；By eszopiclone
Water soluble salt is dissolved in the water and obtains containing drug solns；Wherein, the solvent in the described acid solution containing acidulant is solvent orange 2 A
And/or water；Described solvent orange 2 A is one or more in ethanol, propane diols, glycerine and ethylene glycol；Described right assistant gram
Grand water soluble salt is eszopiclone hydrochloride and/or eszopiclone D-malic acid salt；
(2) under agitation, by above-mentioned containing addition basifier in drug solns；The condition of described stirring is linear velocity
50～150 ms/min；Described basifier is NaOH, potassium carbonate, sodium carbonate, saleratus, sodium citrate, tartaric acid
One or more in sodium, natrium malicum and sodium acetate；Described basifier is that basifier is dissolved in after water to use；Described
The concentration of aqueous solution of basifier is 1%～30%, and described percentage accounts for the quality of the aqueous solution total amount of basifier for basifier
Percentage；
When obtaining in being dissolved in the acid solution containing acidulant for eszopiclone containing drug solns, described acidulant and alkalization
Agent is combined as following arbitrary groups：
Acidulant is hydrochloric acid, and basifier is NaOH, potassium carbonate or sodium carbonate；Wherein, basifier is with the mol ratio of hydrochloric acid
0.95～1.2；
Acidulant is malic acid, and basifier is potassium carbonate or sodium carbonate；Wherein, the mol ratio of potassium carbonate or sodium carbonate and malic acid
For 0.95～1.2；
Acidulant is malic acid, and basifier is NaOH and sodium carbonate；Wherein, NaOH and sodium carbonate and malic acid rub
You are than being 0.95～1.2；
Acidulant is malic acid or tartaric acid, and basifier is NaOH and potassium carbonate；Wherein, basifier and acidulant mole
Than for 1.0～1.20；
Acidulant is citric acid, and basifier is sodium citrate；Wherein, basifier and the mol ratio of acidulant are 1.0～1.20；
When obtaining when being dissolved in the water for the water soluble salt of eszopiclone containing drug solns, basifier is NaOH and sodium carbonate
Combination, potassium carbonate or sodium carbonate, wherein, described basifier and the mol ratio of the water soluble salt of eszopiclone be 0.95～
1.2。
2. preparation method as claimed in claim 1, it is characterised in that the amount of described acidulant is to make eszopiclone complete
1～1.2 times of the minimum of dissolving；Acidulant is 0.8～1.5 with the molar ratio of eszopiclone；It is described for dissolving
The consumption of the water of the water soluble salt of eszopiclone is less than 50 times of the water soluble salt quality of eszopiclone.
3. preparation method as claimed in claim 2, it is characterised in that the amount of described acidulant is to make eszopiclone complete
1～1.05 times of the minimum of dissolving；And/or, described acidulant and the molar ratio of eszopiclone is 0.9～1.2；
And/or, the consumption of the described water for dissolving the water soluble salt of described eszopiclone is the water solubility of eszopiclone
Less than 30 times of salt quality.
4. preparation method as claimed in claim 3, it is characterised in that the described water for dissolving described eszopiclone
The consumption of the water of soluble is less than 15 times of the water soluble salt quality of eszopiclone.
5. preparation method as claimed in claim 1, it is characterised in that the solvent in the described acid solution containing acidulant
Measure as less than 50 times of eszopiclone quality.
6. preparation method as claimed in claim 5, it is characterised in that the solvent in the described acid solution containing acidulant
Measure as less than 30 times of eszopiclone quality.
7. preparation method as claimed in claim 6, it is characterised in that the solvent in the described acid solution containing acidulant
Measure as less than 15 times of eszopiclone quality.
8. preparation method as claimed in claim 1, it is characterised in that described basifier is potassium carbonate and saleratus, hydrogen
Sodium oxide molybdena and natrium malicum, NaOH and potassium carbonate or, NaOH and sodium citrate.
9. preparation method as claimed in claim 1, it is characterised in that when being dissolved in containing acidifying for eszopiclone containing drug solns
When obtaining in the acid solution of agent, described acidulant and basifier are combined as following arbitrary groups：
Acidulant is hydrochloric acid, and basifier is NaOH, potassium carbonate or sodium carbonate；Wherein, basifier and hydrochloric acid mole is
0.99～1.1；
Acidulant is malic acid, and basifier is potassium carbonate or sodium carbonate；Wherein, the mol ratio of potassium carbonate or sodium carbonate and malic acid
For 0.99～1.1；
Acidulant is malic acid, and basifier is NaOH and sodium carbonate；Wherein, NaOH and sodium carbonate and malic acid rub
You are than being 0.99～1.1；
Acidulant is citric acid, and basifier is sodium citrate；Wherein, basifier and the mol ratio of acidulant are 1.17；
When obtaining when being dissolved in the water for the water soluble salt of eszopiclone containing drug solns, basifier is NaOH and sodium carbonate
Combination, potassium carbonate or sodium carbonate；Wherein, the mol ratio of the water soluble salt of described basifier and eszopiclone be 0.99～
1.1。
10. preparation method as claimed in claim 1, it is characterised in that described containing auxiliary agent is also contained in drug solns, described helps
Agent is one or more in water-solubility carrier, surfactant and solubilizer；The consumption of described auxiliary agent is eszopiclone
0.1～10 times of quality.
11. preparation methods as claimed in claim 10, it is characterised in that the consumption of described auxiliary agent is eszopiclone quality
0.5～5 times；And/or, described auxiliary agent is incorporated as while described dissolving or is obtaining described containing drug solns
Add afterwards；And/or, described water-solubility carrier include mannitol, PVP, sucrose, polyethylene glycol, lactose, hydroxy propyl-Beta-
One or more in cyclodextrin and maltitol；And/or, described surfactant and solubilizer includes poloxamer, gathers
One or more in dimension ketone, lauryl sodium sulfate, Emulsifier EL-60, Tween 80 and s6.
12. preparation methods as claimed in claim 11, it is characterised in that described polyethylene glycol selects polyethylene glycol number to divide equally
Son amount scope 400-8000.
13. preparation methods as claimed in claim 1, it is characterised in that when described solvent is water, the condition of described dissolving
For 30 DEG C～70 DEG C；When described solvent is ethanol water, the condition of described dissolving is 30 DEG C～60 DEG C.
14. preparation methods as claimed in claim 1, it is characterised in that the concentration of aqueous solution of described basifier be 5%～
20%, described percentage accounts for the mass percent of the aqueous solution total amount of basifier for basifier.
15. preparation methods as claimed in claim 1, it is characterised in that solid-liquid point is also carried out after described addition basifier
From, washing and separation of solid and liquid, drying；The solvent of described washing is the aqueous solution or water of basifier；The solvent of described washing
Consumption be 1～5 times of obtained eszopiclone crystallite quality；Basifier in the aqueous solution of described basifier is step
(2) basifier in.
16. preparation methods as claimed in claim 15, it is characterised in that when the solvent of described washing is the water-soluble of basifier
During liquid, the concentration of aqueous solution of described basifier is 0.1%～2%, and described percentage accounts for the water-soluble of basifier for basifier
The mass percent of liquid total amount；The number of times of described washing is 1～3 time.
17. preparation methods as claimed in claim 16, it is characterised in that when the solvent of described washing is the water-soluble of basifier
During liquid, the concentration of aqueous solution of described basifier is 0.5%～1%, and described percentage accounts for the water-soluble of basifier for basifier
The mass percent of liquid total amount.
18. preparation methods as claimed in claim 15, it is characterised in that described drying is dried or dynamic dry for static.
19. preparation methods as claimed in claim 18, it is characterised in that it is 40～80 DEG C that described static state is dried, and decompression is dry
Dry 3～12 hours；And/or, described dynamic is dried little to be dried 3～8 in bipyramid vacuum drying mixer at 40～70 DEG C
When.
20. preparation methods as claimed in claim 19, it is characterised in that the temperature that described static state is dried is 55～65 DEG C；
And/or, the time of the drying under reduced pressure that described static state is dried is 6～8 hours；And/or, the temperature that described dynamic is dried is 50
～60 DEG C；And/or, described dynamic is dried and is vacuum dried the time dry in mixer for 5～6 hours in bipyramid.
21. preparation methods as described in claim 19 or 20, it is characterised in that the vacuum condition of described drying under reduced pressure is
450mmHg～76mmHg.
22. preparation methods as claimed in claim 21, it is characterised in that the vacuum condition of described drying under reduced pressure is
150mmHg～76mmHg.
23. preparation methods as claimed in claim 15, it is characterised in that after the step of described addition basifier,
Before the step of described separation of solid and liquid, also decentralized processing is carried out with colloid mill or homogenizer.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210577013.6A CN103980278B (en) | 2012-12-26 | 2012-12-26 | Eszopiclone microcrystalline and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210577013.6A CN103980278B (en) | 2012-12-26 | 2012-12-26 | Eszopiclone microcrystalline and preparation method thereof |
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| CN103980278B true CN103980278B (en) | 2017-05-10 |
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| US6339086B1 (en) * | 1999-05-14 | 2002-01-15 | Swpracor, Inc. | Methods of making and using N-desmethylzopiclone |
| CN101426794A (en) * | 2006-04-20 | 2009-05-06 | 特瓦制药工业有限公司 | Methods for preparing eszopiclone crystalline form A, substantially pure eszopiclone and optically enriched eszopiclone |
| CN101607961B (en) * | 2008-06-18 | 2011-08-10 | 天津天士力集团有限公司 | Eszopiclone crystal and composition thereof |
| EP2345654A1 (en) * | 2010-01-05 | 2011-07-20 | LEK Pharmaceuticals d.d. | Eszopiclone particles and a process for their preparation |
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