CN106018618A - Escitalopram oxalate tablet composition and quality control method - Google Patents
Escitalopram oxalate tablet composition and quality control method Download PDFInfo
- Publication number
- CN106018618A CN106018618A CN201610517655.5A CN201610517655A CN106018618A CN 106018618 A CN106018618 A CN 106018618A CN 201610517655 A CN201610517655 A CN 201610517655A CN 106018618 A CN106018618 A CN 106018618A
- Authority
- CN
- China
- Prior art keywords
- isomer
- solution
- escitalopram
- test solution
- chromatogram
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- KTGRHKOEFSJQNS-BDQAORGHSA-N (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;oxalic acid Chemical compound OC(=O)C(O)=O.C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 KTGRHKOEFSJQNS-BDQAORGHSA-N 0.000 title claims abstract description 105
- 229960005086 escitalopram oxalate Drugs 0.000 title claims abstract description 104
- 239000007916 tablet composition Substances 0.000 title claims abstract description 44
- 238000003908 quality control method Methods 0.000 title claims abstract description 17
- 239000012535 impurity Substances 0.000 claims abstract description 111
- 238000000034 method Methods 0.000 claims abstract description 84
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 56
- 239000000203 mixture Substances 0.000 claims abstract description 54
- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 claims abstract description 33
- 229960004341 escitalopram Drugs 0.000 claims abstract description 32
- 239000000126 substance Substances 0.000 claims abstract description 31
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 28
- 230000000694 effects Effects 0.000 claims abstract description 15
- 239000003937 drug carrier Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 119
- 239000012085 test solution Substances 0.000 claims description 108
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 claims description 71
- 229960001653 citalopram Drugs 0.000 claims description 69
- 238000002360 preparation method Methods 0.000 claims description 49
- 238000007865 diluting Methods 0.000 claims description 31
- 239000007788 liquid Substances 0.000 claims description 30
- 238000003359 percent control normalization Methods 0.000 claims description 27
- 239000000843 powder Substances 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 238000000926 separation method Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000001514 detection method Methods 0.000 claims description 19
- 230000014759 maintenance of location Effects 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 18
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 14
- 238000005303 weighing Methods 0.000 claims description 14
- 229960000583 acetic acid Drugs 0.000 claims description 13
- 239000012362 glacial acetic acid Substances 0.000 claims description 13
- 239000000945 filler Substances 0.000 claims description 12
- 230000004044 response Effects 0.000 claims description 12
- WSEQXVZVJXJVFP-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 WSEQXVZVJXJVFP-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000337 buffer salt Substances 0.000 claims description 9
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 239000013558 reference substance Substances 0.000 claims description 9
- 239000012488 sample solution Substances 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 108010059993 Vancomycin Proteins 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 230000035945 sensitivity Effects 0.000 claims description 8
- 229960003165 vancomycin Drugs 0.000 claims description 8
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 6
- 239000000523 sample Substances 0.000 claims description 6
- 229910000077 silane Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 235000006408 oxalic acid Nutrition 0.000 claims description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 5
- 229960000281 trometamol Drugs 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000009210 therapy by ultrasound Methods 0.000 claims description 3
- 238000012360 testing method Methods 0.000 abstract description 50
- 239000003826 tablet Substances 0.000 description 71
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000009472 formulation Methods 0.000 description 13
- 241000700159 Rattus Species 0.000 description 12
- 239000008187 granular material Substances 0.000 description 9
- 238000005259 measurement Methods 0.000 description 8
- 239000000314 lubricant Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- 229920003081 Povidone K 30 Polymers 0.000 description 5
- 210000003754 fetus Anatomy 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- LYYWQJNKWCANAC-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carboxamide Chemical compound O1CC2=CC(C(N)=O)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 LYYWQJNKWCANAC-UHFFFAOYSA-N 0.000 description 4
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- -1 tablets thereof Chemical compound 0.000 description 4
- 208000008811 Agoraphobia Diseases 0.000 description 3
- 108010011485 Aspartame Proteins 0.000 description 3
- 208000020401 Depressive disease Diseases 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 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 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 229960004543 anhydrous citric acid Drugs 0.000 description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 3
- 239000000605 aspartame Substances 0.000 description 3
- 229960003438 aspartame Drugs 0.000 description 3
- 235000010357 aspartame Nutrition 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 3
- 230000003907 kidney function Effects 0.000 description 3
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000007968 orange flavor Substances 0.000 description 3
- 208000019906 panic disease Diseases 0.000 description 3
- 229960004793 sucrose Drugs 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 231100000820 toxicity test Toxicity 0.000 description 3
- 230000004584 weight gain Effects 0.000 description 3
- 235000019786 weight gain Nutrition 0.000 description 3
- ASGSMDPSNUXWMB-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-2-benzofuran-5-carbonitrile Chemical compound O1C(=O)C2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 ASGSMDPSNUXWMB-UHFFFAOYSA-N 0.000 description 2
- 206010007269 Carcinogenicity Diseases 0.000 description 2
- 208000031404 Chromosome Aberrations Diseases 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 102000019057 Cytochrome P-450 CYP2C19 Human genes 0.000 description 2
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010074268 Reproductive toxicity Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007670 carcinogenicity Effects 0.000 description 2
- 231100000260 carcinogenicity Toxicity 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 231100000005 chromosome aberration Toxicity 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 239000007938 effervescent tablet Substances 0.000 description 2
- 230000035558 fertility Effects 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 231100001052 maternal toxicity Toxicity 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 230000009984 peri-natal effect Effects 0.000 description 2
- 231100000372 reproductive toxicity Toxicity 0.000 description 2
- 230000007696 reproductive toxicity Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000007779 soft material Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 231100000039 Ames test Toxicity 0.000 description 1
- 102100039511 Chymotrypsin-C Human genes 0.000 description 1
- DIOGFDCEWUUSBQ-UHFFFAOYSA-N Citalopram N-oxide Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCC[N+](C)([O-])C)C1=CC=C(F)C=C1 DIOGFDCEWUUSBQ-UHFFFAOYSA-N 0.000 description 1
- KTGRHKOEFSJQNS-UHFFFAOYSA-N Citalopram Oxalate Chemical compound OC(=O)C(O)=O.O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 KTGRHKOEFSJQNS-UHFFFAOYSA-N 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 101000889306 Homo sapiens Chymotrypsin-C Proteins 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 102000018251 Hypoxanthine Phosphoribosyltransferase Human genes 0.000 description 1
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 1
- 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 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229940126600 bulk drug product Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007723 die pressing method Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000007674 genetic toxicity Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000013421 nuclear magnetic resonance imaging Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000007542 postnatal development Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 231100001055 skeletal defect Toxicity 0.000 description 1
- 208000014680 small intestine neoplasm Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an escitalopram oxalate tablet composition and a quality control method and in particular relates to a method for controlling quality of an escitalopram oxalate tablet composition. The method comprises the following steps: carrying out limitation test on escitalopram R-enantiomeric impurities in the composition, measuring the content of the escitalopram R-enantiomeric impurities in the composition and testing related substances in the composition. Furthermore, the invention also relates to an escitalopram oxalate tablet composition. The escitalopram oxalate tablet composition comprises an effective dose of escitalopram oxalate, magnesium stearate and optional pharmaceutically acceptable carriers. The method can implement the excellent technical effect as described in the description.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to an escitalopram oxalate tablet composition for treating depressive disorders and panic disorders accompanied or not accompanied by agoraphobia, and also relates to a quality control method of the escitalopram oxalate tablet composition. The method has excellent performance.
Background
Escitalopram Oxalate (Escitalopram Oxalate), its chemical name: s (+) -1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile oxalate of the formula: c20H21FN2O·C2H2O4Molecular weight: 414.43, having the chemical formula:
in the present invention escitalopram may also be referred to as S-citalopram or the S-isomer of citalopram, corresponding to the case where R-citalopram or the R-isomer of citalopram is an impurity which in some embodiments of the present invention is to be measured in the composition.
Escitalopram oxalate is an oral selective 5-hydroxytryptamine reuptake inhibitor (SSRI) and is clinically used for treating depressive disorders and panic disorders with or without agoraphobia. Escitalopram oxalate is the S-isomer (mono-isomer) of racemic citalopram (citalopram). Escitalopram oxalate tablets (trade name:) Marketed in the united states in 2002 and in china in 2005.
The former Beijing patent EP1414435 discloses a preparation method of escitalopram oxalate with an average particle size of 40-200 μm, the patent discloses that the granularity in the range is obtained to enable the product to be suitable for direct compression or direct powder encapsulation, and discloses a method for preparing escitalopram oxalate tablets by using a direct compression method by using escitalopram oxalate with the particle size range. But this particle size range must be obtained by a special crystallization process.
The minimum specification of the currently marketed escitalopram oxalate tablet is 5mg, the tablet weight is 65mg, and when the marked amount of each tablet is not more than 25mg or the content of the main drug is not more than 25% of the weight of each tablet according to the specification of the 2010 pharmacopeia appendix XE, the content uniformity needs to be checked so as to ensure the uniform and safe product quality. Meanwhile, the 65mg tablet weight has the main problems of high requirement on tabletting equipment in commercial production, because the tablet weight difference is difficult to control, the strength of the used small punch is low, and the tablet is easy to break in the production process, which all cause the difficulty of commercial production and increase the production cost of the escitalopram oxalate tablet.
Further, WO03/011278a1 discloses a problem arising when using large crystalline particles of escitalopram oxalate, i.e. that these large active ingredient particles no longer can be distributed as uniformly and consistently as desired in the tablet or the substance to be compressed to form the tablet, which has a negative effect on the bioavailability of escitalopram oxalate. When escitalopram oxalate in the form of large crystalline particles is used, it may happen that the dissolution of the active ingredient is delayed and thus the release of the active ingredient is delayed, which results in a slower absorption of the active ingredient in the body and thus in a later onset of the pharmacological efficacy.
Furthermore, solid formulations of escitalopram oxalate, such as tablets thereof, are usually prepared using conventional methods. For example, chinese patent application No. 201410724777.2 discloses escitalopram oxalate-containing tablets and a method for preparing the same. The escitalopram oxalate tablet disclosed by the invention uses hydroxypropyl cellulose as a binder, and uses escitalopram oxalate with the median particle size of less than or equal to 20 mu m, so that the prepared escitalopram oxalate tablet has the advantages of attractive surface and stable quality. The invention also provides a preparation method of the oral tablet, which is simple in process and suitable for commercial production. For another example, chinese patent application No. 201510732767.8 discloses a formulation and a preparation process of escitalopram oxalate effervescent tablets, wherein escitalopram oxalate effervescent tablets adopt a tabletting process that a formulation is composed of a main drug, a disintegrant, an aromatic agent and the like, and an acidic disintegrant and an alkaline disintegrant are respectively granulated. The formula and the process are easy to operate, the product quality is controllable, the taste is good, and the cost is low. For another example, chinese patent application No. 200910078081.6 discloses an escitalopram oxalate oral solid preparation and a preparation method thereof, wherein the oral solid preparation comprises the following raw materials: 2-40 parts of escitalopram oxalate, 5-60 parts of starch, 5-200 parts of microcrystalline cellulose, 5-60 parts of lactose, 0.05-5 parts of adhesive and 0.05-3 parts of lubricant; the adhesive is one or more of mixed aqueous solution or alcoholic solution of polyvinylpyrrolidone, hydroxyethyl methylcellulose, hydroxypropyl cellulose and ethyl cellulose, and the concentration of the adhesive is 0.1-10.0%; the lubricant is stearic acid, magnesium stearate, calcium stearate, talcum powder or superfine silica gel powder. These solid formulations generally require the addition of the lubricant magnesium stearate for formulation purposes.
Escitalopram oxalate, e.g. tablets thereof, has a number of quality control methods. For example, chinese patent application No. 201210589707.1 discloses a method for preparing escitalopram oxalate impurity a, which comprises reacting escitalopram with p-bromofluorobenzene grignard reagent to obtain escitalopram impurity a, wherein the impurity a can be used for quality control of escitalopram oxalate such as tablets thereof. For another example, chinese patent application No. 201310339936.2 relates to a novel method for synthesizing escitalopram oxalate with three impurities, which is of great significance for the synthesis of escitalopram oxalate with high purity. The invention mainly researches 1- [3- (dimethylamino) propyl ] -1- (4-fluorophenyl) -1, 3-dihydro-isobenzofuran-5-formamide (II) serving as a citalopram amide impurity and 1- [3- (dimethylamino) propyl ] -1- (4-fluorophenyl) -3-oxo-1, 3-dihydro-isobenzofuran-5-carbonitrile (III) serving as a citalopram lactone impurity, citalopram-N-oxide impurities 1- [3- (dimethylamino) propyl ] -1- (4-fluorophenyl) -1, 3-dihydroisophenylfuran-5-carbonitrile-N-oxide (IV) synthesis, which impurities are useful for quality control of escitalopram oxalate, e.g. tablets thereof. For another example, chinese patent application No. 201410049248.7 relates to escitalopram oxalate related substances and a method for preparing the same. The antidepressant drug escitalopram oxalate (namely (S) - (+) -1- [3- (dimethylamino) propyl ] -1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile oxalate) is synthesized by hydrolyzing, acylating, condensing, reducing, adding and oxidizing a compound (II) (namely (S) - (+) -1- [3- (dimethylamino) propyl ] -1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile) to obtain a target compound. The method obtains the compound (I) by chemical synthesis for the first time, can obtain a target compound by high-efficiency and quick separation, and the impurities can be used for controlling the quality of escitalopram oxalate such as tablets thereof.
In addition, chinese patent application No. 200810246555.9 (publication No. 101769904a) discloses a high performance liquid chromatography method for measuring escitalopram oxalate optical isomers, wherein a chromatographic column using vancomycin silane bonded silica gel as a filler is selected, and a mixed solvent of methanol, absolute ethanol, triethylamine and glacial acetic acid is used as a mobile phase, so that the method can be used for quality control of escitalopram oxalate optical isomers.
Unfortunately, however, the existing methods are limited in the quality control of escitalopram oxalate or formulations thereof, such as tablets, in particular in the quality control of its optical isomers. It would therefore be highly desirable to provide a method for the quality control of escitalopram oxalate or a formulation thereof, such as a tablet, and in particular for the quality control of the optical isomers thereof, to a person skilled in the art.
Disclosure of Invention
The invention aims to provide a method for controlling the quality of escitalopram oxalate or a preparation thereof, such as a tablet, and particularly for controlling the quality of an optical isomer of escitalopram oxalate. It is another object of the present invention to provide a formulation of escitalopram oxalate, such as a tablet composition. The inventors have surprisingly found that superior results of one or more aspects of the invention can be obtained using the method of the invention. The present invention has been completed based on this finding.
To this end, the present invention provides in a first aspect a method for the quality control of escitalopram oxalate tablet compositions, which method comprises the limit check of the R-isomer impurities of citalopram in the composition, comprising the steps of:
(1) taking a proper amount of the escitalopram oxalate tablet composition fine powder, wherein the content of the escitalopram oxalate tablet composition fine powder is 20-30 mg, precisely weighing, placing the obtained mixture into a 50ml measuring flask, adding a proper amount of a mobile phase, carrying out ultrasonic dissolution, cooling to room temperature, diluting to a scale with the mobile phase, shaking up, filtering, and taking a subsequent filtrate as a sample solution;
(2) precisely measuring 1ml of a test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 1.0% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 200ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.5% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 500ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.2% control solution;
(3) according to the specification of high performance liquid chromatography carried in 0512 of the fourth section 59 of the 2015 version of Chinese pharmacopoeia, vancomycin silane bonded silica gel is used as a filling agent, mixed solution of methanol-absolute ethyl alcohol-triethylamine-glacial acetic acid with the volume ratio of 50 to (40-60) to (0.05-0.15) is used as a mobile phase, the flow rate is 0.5-1.0 ml/min, and the detection wavelength is 230-240 nm;
(4) taking a proper amount of citalopram racemate, dissolving and diluting the citalopram racemate by using a mobile phase to prepare a solution containing 0.1mg in 1ml, taking 10 mu l of the solution as a system applicability solution, injecting the solution into a liquid chromatograph, recording a chromatogram, enabling an R-isomer and an S-isomer to flow out in sequence, and considering that the separation effect is acceptable (namely, the subsequent operation can be continuously carried out) when the separation degree between the two peaks is calculated to be more than 1.5 (the relative retention time of the R-isomer peak relative to the S-isomer peak is about 0.9), and considering that the theoretical plate number is acceptable (namely, the subsequent operation can be continuously carried out) when the calculated number is more than 2500 according to the escitalopram, namely the S-isomer;
(5) injecting 10 μ l of 1% control solution into liquid chromatograph, and adjusting detection sensitivity to make peak height of main component chromatographic peak 20% of full range; precisely measuring 10 μ l of the test solution, 1.0% of the control solution, 0.5% of the control solution and 0.2% of the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram;
(6) reading a chromatogram of the test solution, comparing the peak area of an R-isomer peak with the main peak area of control solutions with various concentrations if the R-isomer peak exists in the chromatogram, wherein the R-isomer impurity limit is less than 0.2% if the R-isomer peak area in the chromatogram of the test solution is less than 0.2% of the main peak area of the control solutions, the R-isomer impurity limit is less than 0.5% if the R-isomer peak area in the chromatogram of the test solution is less than 0.5% of the main peak area of the control solutions, and the R-isomer impurity limit is less than 1.0% if the R-isomer peak area in the chromatogram of the test solution is less than 1.0% of the main peak area of the control solutions; if the R-isomer peak area is greater than 1.0%, a control solution having a concentration of greater than 1.0% is prepared in step (2) in a similar manner thereto and similarly compared.
The method according to any of the embodiments of the first aspect of the present invention, further comprising determining the content of R-isomer impurities of citalopram in the composition, comprising the steps of:
reading the chromatogram of the test solution obtained in the step (5), if an R-isomer peak exists in the chromatogram, comparing the peak area with the main peak area in the chromatogram of the 1.0% control solution, and calculating the content of the R-isomer according to the following formula:
r-isomer content ═ 1.0% (R-isomer peak area in test solution chromatogram ÷ 1.0% main peak area in control solution chromatogram) ×
The process according to any of the embodiments of the first aspect of the present invention, wherein in step (1) the limit check of the R-isomer impurities of citalopram in the composition is performed, an appropriate amount of fine powder of escitalopram oxalate tablet composition containing 25mg of escitalopram, precision weighing and subsequent treatment.
The process according to any one of the embodiments of the first aspect of the present invention, wherein in step (3) the composition is checked for limitations on citalopram R-isomer impurities, said mobile phase is methanol-absolute ethanol-triethylamine-glacial acetic acid in a volume ratio of 50: 0.1.
It has been found that, although the use of the above-mentioned methanol-absolute ethanol-triethylamine-glacial acetic acid mixture can achieve good degrees of separation of R-isomer and S-isomer and the number of theoretical plates is ideal, the R-isomer peak area tends to decrease after the sample is left for a long period of time of 5 hours or longer. It has been found that the trend of the R-isomer peak area is probably due to the addition of magnesium stearate to the composition, so that tablets without magnesium stearate do not show such a phenomenon, and the R-isomer peak area is reduced along with the prolonging of the standing time of the test solution of the tablets with magnesium stearate. It has been surprisingly found that this phenomenon of smaller R-isomer peak areas is overcome when triethylamine in the mixed mobile phase is replaced with an equal amount of tromethamine, and it is also surprising that in the case of good separation of both R-and S-isomers, the retention time of the S-isomer can also be advanced, which is beneficial for improving the separation efficiency. Therefore, according to the method of any one of the embodiments of the first aspect of the present invention, in the step (3) of performing the limit check on the citalopram R-isomer impurities in the composition, the mixed solution of methanol-absolute ethanol-tromethamine-glacial acetic acid with the volume ratio of four is 50: 40-60: 0.05-0.15 as the mobile phase, for example, the mixed solution with the volume ratio of four is 50: 0.1 as the mobile phase.
The method according to any one of the embodiments of the first aspect of the present invention, wherein in step (3) the limit check is performed on citalopram R-isomer impurities in the composition, said flow rate is 0.6 ml/min.
The method according to any one of the embodiments of the first aspect of the present invention, wherein in step (3) the limit check is performed on citalopram R-isomer impurities in the composition, said detection wavelength is 238 nm.
The method according to any embodiment of the first aspect of the present invention, further comprising examining the composition for substances of interest, comprising the steps of:
(1) taking a proper amount of the fine powder of the escitalopram oxalate tablet composition, wherein the fine powder contains 50mg of escitalopram, precisely weighing, placing the fine powder into a 100ml measuring flask, adding 10ml of buffer salt solution, strongly shaking for 10min, adding 40ml of methanol, shaking for 10min, performing ultrasound treatment for 10min, cooling to room temperature, adding a mobile phase to dilute to a scale, shaking uniformly, filtering, and taking a subsequent filtrate as a test solution; the preparation method of the buffer salt solution comprises the following steps: weighing 1.5g anhydrous sodium acetate, adding 0.4ml glacial acetic acid, adding water to 1000ml, shaking, adjusting pH to 5.2 with 1M sodium hydroxide, and mixing;
(2) precisely measuring 1ml of a test solution, placing the test solution into a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 1.0% control solution (1.0%);
(3) according to the specification of high performance liquid chromatography carried by 0512 of section 59 of the fourth part of the 2015 edition of Chinese pharmacopoeia, octadecylsilane chemically bonded silica is used as a filler, the column length of a chromatographic column is 150mm, the inner diameter of the chromatographic column is 4.6mm, the particle size of the filler is 5 mu m, a mixed solution of buffer salt solution, methanol and acetonitrile in a volume ratio of 60: 33: 7 is used as a mobile phase, the flow rate is 1.0ml/min, the detection wavelength is 239nm, and the column temperature is 45 ℃;
(4) taking a proper amount of reference substance of escitalopram oxalate and reference substance of impurities C of escitalopram, dissolving and diluting the reference substances by using a mobile phase to prepare mixed solutions containing 1.0 mu g of escitalopram in each 1ml, taking 10 mu l of the mixed solutions as system applicability test solutions, injecting the mixed solutions into a liquid chromatograph, recording a chromatogram, and considering that the separation effect is acceptable when the separation degree of the peak of escitalopram and the impurities C is more than 3.0;
(5) taking 10 mu l of the control solution to carry out sample injection for 6 times, and considering the control solution to be acceptable when the relative standard deviation of the peak area of the main peak is less than 2.0 percent; injecting 10 μ l of the control solution into a liquid chromatograph, and adjusting detection sensitivity to make the peak height of the main component chromatographic peak 10% of the full scale; precisely measuring 10 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the retention time of the chromatogram until the main peak is 3.5 times;
(6) reading a chromatogram of the test solution, removing a solvent peak and an oxalic acid peak if an impurity peak exists in the chromatogram, and calculating the percentage of each known impurity, unknown impurity and total impurity according to the following formula:
impurity% (% A)x/Ar)×(1/F)×1/100×100
Wherein:
Ax: peak area of each impurity in test solution
Ar: peak area of escitalopram in control solution
F: relative response factor.
The method according to any one of the embodiments of the first aspect of the present invention, wherein the relative retention times of the respective impurities and their relative response factors when the relevant substances in the composition are examined are as follows:
| name (R) | Relative retention time | Relative response factor |
| Oxalic acid | 0.095 | - |
| Citalopram impurity A | 0.33 | 0.77 |
| Escitalopram impurity A | 0.42 | 0.88 |
| Citalopram impurity B | 0.56 | 0.78 |
| Citalopram impurity C | 0.80 | 0.51 |
| Escitalopram | 1.0 | - |
| Citalopram impurity E | 1.24 | 0.88 |
| Other single impurities | - | 1.0 |
| Total impurities | - | - |
The method according to any one of the embodiments of the first aspect of the present invention, wherein the chemical structure of citalopram impurity C is as follows when the relevant substances in the composition are examined:
the method according to any one of the embodiments of the first aspect of the present invention, wherein the chemical structure of citalopram impurity a when the relevant substances in the composition are examined is as follows:
the method according to any one of the embodiments of the first aspect of the present invention, wherein the escitalopram impurity a has the following chemical structure when the relevant substances in the composition are examined:
the method according to any one of the embodiments of the first aspect of the present invention, wherein the chemical structure of citalopram impurity B is as follows when the relevant substances in the composition are examined:
the method according to any one of the embodiments of the first aspect of the present invention, wherein the chemical structure of citalopram impurity E is as follows when the relevant substances in the composition are examined:
it is generally required in the art that the acceptability criterion for citalopram impurity A is < 0.2%, the acceptability criterion for escitalopram impurity A is < 0.1%, the acceptability criterion for citalopram impurity B is < 0.2%, the acceptability criterion for citalopram impurity C is < 0.4%, the acceptability criterion for citalopram impurity E is < 0.2%, the acceptability criterion for other individual impurities is < 0.1%, and the acceptability criterion for the total impurities is < 1.0%.
The method according to any one of the embodiments of the first aspect of the present invention, wherein said escitalopram oxalate tablet composition comprises a therapeutically effective amount of escitalopram oxalate, together with magnesium stearate, and optionally a pharmaceutically acceptable carrier.
Further, the second aspect of the present invention provides an escitalopram oxalate tablet composition comprising a therapeutically effective amount of escitalopram oxalate, together with magnesium stearate, and optionally a pharmaceutically acceptable carrier.
Since magnesium stearate is added as a lubricant in most commercially available escitalopram oxalate tablets, this very common lubricant provides the possibility of manufacturing tablets smoothly. It has been unexpectedly found that when isomer impurities are examined using certain flows against such tablet compositions with the addition of magnesium stearate, it is found that the quality control checks may be adversely affected by the presence of magnesium stearate. However, when the examination is carried out using some of the mobile phases mentioned in the present invention, the presence of magnesium stearate in the tablets does not adversely affect the examination method. Thus, escitalopram oxalate tablet compositions comprising magnesium stearate are also an aspect of the present invention.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
The column using vancomycin silane-bonded silica gel as a packing material used in the present invention is commercially available, for example, under the brand name of Astec CHIROBIOTIC V, and in the present invention, as not otherwise specified, the column using vancomycin silane-bonded silica gel as a packing material is under the brand name of Astec CHIROBIOTIC V, and has a column specification of 250X 4.6mm, 5 μm. It is well known that other column specifications are acceptable, such as 150X 4.6mm, 5 μm columns, 200X 4.6mm, 5 μm columns, etc., when the resolution and theoretical plate count requirements can be met.
The escitalopram oxalate tablets used clinically at present have the specifications of 5mg, 10mg, 20mg and the like, are orally taken and can be taken together with food.
In terms of dosage, depressive disorder: the daily dosage is 1 time, the common dosage is 10mg daily, the maximum daily dosage can be increased to 20mg according to individual response of patients, the antidepressant effect can be obtained usually for 2-4 weeks, and after the symptom is relieved, the treatment is continued for at least 6 months to consolidate the effect; panic disorder with or without agoraphobia: 1 time a day, a starting dose of 5mg daily is recommended, which increases to 10mg daily after a continuous week, and the dose may also continue to increase, depending on the individual response of the patient, to a maximum dose of 20mg daily; these doses usually achieve the best results for about 3 months of treatment, with a course of treatment generally lasting several months.
For elderly patients (> 65 years): it is recommended to start the treatment with half the above conventional starting dose, and the maximum dose should be reduced accordingly. For children and adolescents (< 18 years): the product is not suitable for children and teenagers under 18 years old.
For reduced renal function: patients with mild to moderate renal function reduction (CLCR < 30 ml/min) do not need to adjust the dosage, and patients with severe renal function reduction should be treated with caution.
For patients with reduced liver function: the initial dose is recommended to be 5mg daily for 2 weeks of treatment. The dose may be increased to 10mg daily, depending on the individual response of the patient.
For CYP2C19 slow metabolizers: for patients known to be slow metabolizing CYP2C19, a starting dose of 5mg daily is recommended for 2 weeks of treatment and the dose can be increased to 10mg daily depending on the individual response of the patient.
Withdrawal symptoms: when the treatment needs to be stopped, the dosage should be gradually reduced within 1 to 2 weeks so as to avoid the symptoms of drug withdrawal. The safety of doses above 20mg per day has not been proven.
Genetic toxicity: in the racemic citalopram Ames assay, 2 of the 5 tested strains (TA98 and TA1537) gave positive results in the absence of metabolic activator. In the racemic citalopram CHL chromosome aberration test, the result is positive whether a metabolic activator exists or not. The results of the racemic citalopram mouse lymphoma cell forward gene mutation test (HPRT), the rat liver cell program external DNA synthesis test (UDS), the human lymphocyte chromosome aberration test and the mouse micronucleus test are all negative.
Reproductive toxicity: in the fertility test, the rats orally administer the racemic citalopram 32, 48 and 72 mg/kg/day, the mating rate of each dose group is reduced, the fertility is reduced when the dose is more than or equal to 32 mg/kg/day, and the gestation time is prolonged when the dose is 48 mg/kg/day. In the embryo-fetus development toxicity test of rats, when the rats are orally administered with escitalopram 56, 112 and 150 mg/kg/day, and medium and high doses (calculated according to mg/m2, which is equivalent to that the maximum recommended dose [ MRHD ] of human is more than or equal to 56 times per day), the weight reduction and ossification delay of the fetus can be seen. The toxicity (clinical abnormal symptoms, weight gain reduction and food intake reduction) of the parent bodies can be seen in all the dose groups, and no teratogenic effect is seen. The development-free dose was 56 mg/kg/day, corresponding to approximately 28-fold MRHD. When 6, 12, 24, 48 mg/kg/day escitalopram was given to pregnant rats in perinatal period, the mortality of offspring was slightly increased and the growth was slightly delayed in the highest dose group (corresponding to about 24 times MRHD), and slight maternal toxicity was observed (clinically abnormal symptoms, weight gain reduction, and decrease in food intake). The 24mg/kg non-dose group showed a slight increase in progeny mortality. The non-affecting dose was 12 mg/kg/day, corresponding to approximately 6-fold MRHD.
In animal reproductive toxicity tests, racemic citalopram is seen to have adverse effects on embryonic/fetal self-life development and postnatal development, including teratogenicity at doses above those found in humans. In the embryo/fetus toxicity test of rats, the rats are orally administered with 32, 56 and 112 mg/kg/day of racemic citalopram, and the growth inhibition of the embryos/fetus, the reduction of the survival rate of the fetus, the increase of abnormal rate of the fetus (comprising cardiovascular and skeletal defects) and maternal toxicity (clinical abnormal normal and weight gain reduction) can be seen at high dose, and the non-influence dose of the development is 56 mg/kg/day. No abnormality is found when the dose of the racemic citalopram is orally given by the rabbits until the dose reaches 16 mg/kg/day. In perinatal toxicity test, rats are orally administered with 4.8, 12.8 and 32 mg/kg/day of racemic citalopram, and the high-dose group shows that the death rate of young rats is increased and the growth of the young rats is stopped within 4 days after birth. The non-affecting dose was 12.8 mg/kg/day.
Carcinogenicity: the NMRI/BOM mice and COBS WI rats were orally administered racemic citalopram for 18 and 24 months, respectively. Mice did not show carcinogenicity at doses up to 240 mg/kg/day. An increased incidence of small bowel tumors was seen in rats at doses of 8 or 24 mg/kg/day. The relevance of this phenomenon to humans is not clear.
The present invention has an excellent effect in that the quality control of escitalopram oxalate tablet compositions can be effectively performed by using a specific method.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it.
In the following examples, the following tests are for illustrative purposes and some specific descriptions are given based on the comparability of the examples, from which the person skilled in the art can fully generalize the method of the solution of the invention based on the prior knowledge. In the following various compositions were prepared, the total ingredient amount of each batch was an amount containing at least 50g of the active ingredient, and the shortage was proportionally increased to an amount of at least 50g of the active ingredient, as not otherwise specified. When the escitalopram oxalate bulk drug is used for preparing the tablet, the bulk drug is a bulk drug product which is produced by Hunan Dongting pharmaceutical industry GmbH and has the national drug standard of H20140130 and meets the medicinal standard.
Preparation of composition
Preparation example 1: preparation of escitalopram oxalate tablet composition
The formula is as follows:
the preparation method comprises the following steps: escitalopram oxalate API particle size median particle diameter D (V, 0.5) ═ 105 μm. The escitalopram oxalate and the talcum powder are sieved by a 30-mesh sieve and are uniformly mixed with the microcrystalline cellulose and the croscarmellose sodium in a single-arm mixing barrel. Magnesium stearate was added by sieving through a 30 mesh sieve and mixing was continued for 3 minutes and tabletting was performed using a rotary tablet press.
Preparation example 2: preparation of escitalopram oxalate tablet composition
The formula is as follows:
the preparation method comprises the following steps: escitalopram oxalate API particle size median particle diameter D (V, 0.5) ═ 11 μm. Premixing escitalopram oxalate, lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose and croscarmellose sodium in a high-shear granulator, adding purified water for granulation, carrying out wet granulation by using a rotary granulator, drying wet granules in a fluidized bed, carrying out dry granulation on the dried granules by using the rotary granulator to obtain dry granules, adding magnesium stearate into the dry granules, uniformly mixing in a single-arm hopper mixer, and tabletting by using a rotary tablet press.
Preparation example 3: preparation of escitalopram oxalate tablet composition
Formulation and preparation reference was made to preparation example 5 of the present invention, except that polyethylene glycol-6000 was replaced with 0.75g of magnesium stearate.
Preparation example 4: escitalopram oxalate tablets are provided
Commercially available escitalopram oxalate tablets are approved under the reference H20140121 (which may be abbreviated as #121 in the present invention), commercially available escitalopram oxalate tablets are approved under the reference H20143391 (which may be abbreviated as #391 in the present invention and manufactured by the pharmaceutical industry of hunan cavernosum), commercially available escitalopram oxalate tablets are produced in shandong province (which may be abbreviated as shandong tablets in the present invention), and commercially available escitalopram oxalate tablets are produced in Jilin province (which may be abbreviated as Jilin tablets in the present invention). The four commercial tablets were tested with magnesium stearate added.
Preparation example 5: preparation of escitalopram oxalate tablet composition
The formula is as follows:
3.34g of escitalopram oxalate, 17.75g of anhydrous citric acid, 29.75g of sodium bicarbonate, 26.62g of sucrose, 5.74g of orange flavor, 8.87g of aspartame, 7.83g of lubricant polyethylene glycol-6000 and 0.1g of PVP-K30;
the preparation method comprises the following steps:
crushing escitalopram oxalate, sodium bicarbonate, anhydrous citric acid, cane sugar and orange flavor essence by 80 meshes, and sieving aspartame and polyethylene glycol-6000 by using a 80-mesh sieve;
weighing escitalopram oxalate, anhydrous citric acid, aspartame and orange flavor according to the prescription amount, uniformly mixing, adding 38 percent of PVPK30 ethanol solution by mass, preparing a soft material, granulating by using a 20-mesh sieve, drying at 60 ℃ until the moisture of the granules is less than or equal to 1.0 percent, and finishing by using a 18-mesh sieve to obtain granules a;
thirdly, weighing sodium bicarbonate and cane sugar in the prescription amount, uniformly mixing, adding PVP-K30 ethanol solution with the total mass of 62%, making soft materials, granulating with a 20-mesh sieve, drying at 40 ℃ until the moisture of the granules is less than or equal to 1.0%, and finishing with a 18-mesh sieve to obtain granules b;
mixing the granules a and b with polyethylene glycol-6000 according to the prescription amount;
selecting a phi 8mm flat punching die pressing sheet with the theoretical weight of 191.6 mg.
The PVP-K30 ethanol solution is PVP-K30 in the prescription, and is prepared into a PVP-K30 ethanol solution with the mass fraction of 5% by using an ethanol solution with the volume fraction of 50%.
Preparation example 6: preparation of escitalopram oxalate tablet composition
Formulation and preparation reference is made to preparation example 1 of the present invention, except that magnesium stearate was removed therefrom.
Preparation example 7: preparation of escitalopram oxalate tablet composition
Formulation and preparation reference is made to preparation example 2 of the present invention, except that magnesium stearate was removed therefrom.
Preparation example 8: preparation of escitalopram oxalate tablet composition
Formulation and preparation reference is made to preparation example 1 of the present invention, except that the magnesium stearate therein is replaced with an equal amount of stearic acid.
Preparation example 9: preparation of escitalopram oxalate tablet composition
Formulation and preparation reference is made to preparation 2 of the invention, except that the magnesium stearate is replaced by an equal amount of talc.
Second, test example section
Test example 1 quality control-Limit check of citalopram R-isomer impurities in the composition
The method comprises the following steps:
(1) taking a proper amount of the escitalopram oxalate tablet composition fine powder, wherein the content of the escitalopram oxalate tablet composition fine powder is equal to 25mg of escitalopram, precisely weighing, placing the escitalopram oxalate tablet composition fine powder into a 50ml measuring flask, adding a proper amount of mobile phase, carrying out ultrasonic dissolution, cooling to room temperature, diluting to a scale with the mobile phase, shaking up, filtering, and taking a subsequent filtrate as a sample solution;
(2) precisely measuring 1ml of a test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 1.0% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 200ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.5% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 500ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.2% control solution;
(3) performing measurement according to the specification of high performance liquid chromatography carried in 0512 of section 59 of the fourth part of the 2015 edition of Chinese pharmacopoeia, taking vancomycin silane bonded silica gel as a filler, taking a mixed solution of methanol-absolute ethyl alcohol-triethylamine-glacial acetic acid with the volume ratio of 50: 0.1 as a mobile phase, wherein the flow rate is 0.6ml/min, and the detection wavelength is 238 nm;
(4) taking a proper amount of citalopram racemate, dissolving and diluting by using a mobile phase to prepare a solution containing 0.1mg in 1ml, taking 10 mu l of the solution as a system applicability solution, injecting into a liquid chromatograph, recording a chromatogram, enabling an R-isomer and an S-isomer to flow out in sequence, and considering that the separation effect is acceptable when the separation degree between two peaks is calculated to be more than 1.5 (the relative retention time of the R-isomer peak relative to the S-isomer peak is about 0.9), and considering that the theoretical plate number is acceptable when the calculation is more than 2500 according to the escitalopram, namely the S-isomer peak;
(5) injecting 10 μ l of 1% control solution into liquid chromatograph, and adjusting detection sensitivity to make peak height of main component chromatographic peak 20% of full range; precisely measuring 10 μ l of the test solution, 1.0% of the control solution, 0.5% of the control solution and 0.2% of the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram;
(6) reading a chromatogram of the test solution, comparing the peak area of an R-isomer peak with the main peak area of control solutions with various concentrations if the R-isomer peak exists in the chromatogram, wherein the R-isomer impurity limit is less than 0.2% if the R-isomer peak area in the chromatogram of the test solution is less than 0.2% of the main peak area of the control solutions, the R-isomer impurity limit is less than 0.5% if the R-isomer peak area in the chromatogram of the test solution is less than 0.5% of the main peak area of the control solutions, and the R-isomer impurity limit is less than 1.0% if the R-isomer peak area in the chromatogram of the test solution is less than 1.0% of the main peak area of the control solutions; if the R-isomer peak area is greater than 1.0%, a control solution having a concentration of greater than 1.0% is prepared in step (2) in a similar manner thereto and similarly compared.
Test example 2 quality control-Limit checks on the citalopram R-isomer impurities in the composition
The method comprises the following steps:
(1) taking a proper amount of the escitalopram oxalate tablet composition fine powder, wherein the content of the escitalopram oxalate tablet composition fine powder is equal to 20mg of escitalopram, precisely weighing, placing the escitalopram oxalate tablet composition fine powder into a 50ml measuring flask, adding a proper amount of mobile phase, carrying out ultrasonic dissolution, cooling to room temperature, diluting to a scale with the mobile phase, shaking up, filtering, and taking a subsequent filtrate as a sample solution;
(2) precisely measuring 1ml of a test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 1.0% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 200ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.5% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 500ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.2% control solution;
(3) performing measurement according to the specification of high performance liquid chromatography carried in 0512 of section 59 of the fourth part of the 2015 edition of Chinese pharmacopoeia, taking vancomycin silane bonded silica gel as a filler, taking a mixed solution of methanol-absolute ethyl alcohol-triethylamine-glacial acetic acid with the volume ratio of 50: 40: 0.15: 0.05 as a mobile phase, wherein the flow rate is 0.5ml/min, and the detection wavelength is 240 nm;
(4) taking a proper amount of citalopram racemate, dissolving and diluting by using a mobile phase to prepare a solution containing 0.1mg in 1ml, taking 10 mu l of the solution as a system applicability solution, injecting into a liquid chromatograph, recording a chromatogram, enabling an R-isomer and an S-isomer to flow out in sequence, and considering that the separation effect is acceptable when the separation degree between two peaks is calculated to be more than 1.5 (the relative retention time of the R-isomer peak relative to the S-isomer peak is about 0.9), and considering that the theoretical plate number is acceptable when the calculation is more than 2500 according to the escitalopram, namely the S-isomer peak;
(5) injecting 10 μ l of 1% control solution into liquid chromatograph, and adjusting detection sensitivity to make peak height of main component chromatographic peak 20% of full range; precisely measuring 10 μ l of the test solution, 1.0% of the control solution, 0.5% of the control solution and 0.2% of the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram;
(6) reading a chromatogram of the test solution, comparing the peak area of an R-isomer peak with the main peak area of control solutions with various concentrations if the R-isomer peak exists in the chromatogram, wherein the R-isomer impurity limit is less than 0.2% if the R-isomer peak area in the chromatogram of the test solution is less than 0.2% of the main peak area of the control solutions, the R-isomer impurity limit is less than 0.5% if the R-isomer peak area in the chromatogram of the test solution is less than 0.5% of the main peak area of the control solutions, and the R-isomer impurity limit is less than 1.0% if the R-isomer peak area in the chromatogram of the test solution is less than 1.0% of the main peak area of the control solutions; if the R-isomer peak area is greater than 1.0%, a control solution having a concentration of greater than 1.0% is prepared in step (2) in a similar manner thereto and similarly compared.
Test example 3 quality control-Limit checks on citalopram R-isomer impurities in the composition
The method comprises the following steps:
(1) taking a proper amount of the escitalopram oxalate tablet composition fine powder, wherein the content of the escitalopram oxalate tablet composition fine powder is 30mg, precisely weighing, placing the escitalopram oxalate tablet composition fine powder into a 50ml measuring flask, adding a proper amount of mobile phase, carrying out ultrasonic dissolution, cooling to room temperature, diluting to a scale with the mobile phase, shaking up, filtering, and taking a subsequent filtrate as a sample solution;
(2) precisely measuring 1ml of a test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 1.0% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 200ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.5% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 500ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.2% control solution;
(3) performing measurement according to the specification of high performance liquid chromatography carried in 0512 of section 59 of the fourth part of the 2015 edition of Chinese pharmacopoeia, taking vancomycin silane bonded silica gel as a filler, taking a mixed solution of methanol-absolute ethyl alcohol-triethylamine-glacial acetic acid with the volume ratio of 50: 60: 0.05: 0.15 as a mobile phase, wherein the flow rate is 1.0ml/min, and the detection wavelength is 230 nm;
(4) taking a proper amount of citalopram racemate, dissolving and diluting by using a mobile phase to prepare a solution containing 0.1mg in 1ml, taking 10 mu l of the solution as a system applicability solution, injecting into a liquid chromatograph, recording a chromatogram, enabling an R-isomer and an S-isomer to flow out in sequence, and considering that the separation effect is acceptable when the separation degree between two peaks is calculated to be more than 1.5 (the relative retention time of the R-isomer peak relative to the S-isomer peak is about 0.9), and considering that the theoretical plate number is acceptable when the calculation is more than 2500 according to the escitalopram, namely the S-isomer peak;
(5) injecting 10 μ l of 1% control solution into liquid chromatograph, and adjusting detection sensitivity to make peak height of main component chromatographic peak 20% of full range; precisely measuring 10 μ l of the test solution, 1.0% of the control solution, 0.5% of the control solution and 0.2% of the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram;
(6) reading a chromatogram of the test solution, comparing the peak area of an R-isomer peak with the main peak area of control solutions with various concentrations if the R-isomer peak exists in the chromatogram, wherein the R-isomer impurity limit is less than 0.2% if the R-isomer peak area in the chromatogram of the test solution is less than 0.2% of the main peak area of the control solutions, the R-isomer impurity limit is less than 0.5% if the R-isomer peak area in the chromatogram of the test solution is less than 0.5% of the main peak area of the control solutions, and the R-isomer impurity limit is less than 1.0% if the R-isomer peak area in the chromatogram of the test solution is less than 1.0% of the main peak area of the control solutions; if the R-isomer peak area is greater than 1.0%, a control solution having a concentration of greater than 1.0% is prepared in step (2) in a similar manner thereto and similarly compared.
Test example 4, quality control-limit check of citalopram R-isomer impurities in the composition: referring to the procedure of test example 1, except that triethylamine in the mixed mobile phase was replaced with an equal amount of tromethamine. Test example 5, quality control-limit check of citalopram R-isomer impurities in the composition: referring to the procedure of test example 2, except that triethylamine in the mixed mobile phase was replaced with an equal amount of tromethamine. Test example 6, quality control-limit check of citalopram R-isomer impurities in the composition: referring to the procedure of test example 3, except that triethylamine in the mixed mobile phase was replaced with an equal amount of tromethamine.
The escitalopram oxalate tablets provided in preparation examples 1 to 9 were examined for the impurities limitation of the R-isomer of citalopram using the methods of test examples 1 to 6, respectively.
As a result: test example 1-test example 6 the methods of all tablets tested, the degrees of separation between the S-isomer and the R-isomer were greater than 2.0, and all met the test requirements; when the method of test example 1-test example 6 is used for detecting all tablets, the theoretical plate number of S-isomer peaks is more than 3000, and the S-isomer peaks meet the measurement requirement; when all tablets are detected, the retention time of the three methods of the test example 4 to the test example 6 is basically the same as the retention time of the S-isomer, the retention time of the three methods of the test example 1 to the test example 3 is basically the same, and the retention time of the three methods of the test example 4 to the test example 6 is about 82 to 83 percent of the retention time of the three methods of the test example 1 to the test example 3, which indicates that the peak-off time of the test example 4 to the test example 6 is advanced, and the method is very valuable for completing the analysis task as soon as possible; the test solutions were tested on all tablets within 2 hours after the dosing, and the amount of the R isomer in each tablet was below the limit of 0.5%, and the amount of the R isomer in some commercially available tablets was even below the limit of 0.2% (for example, the test solutions were tested on all tablets by the method of test examples 1-6, and the test solutions were tested within 2 hours after the dosing, and the limits were below 0.2%); the limits of the amount of the R isomer measured using the six different methods of test example 1-test example 6 were essentially the same for the same tablet, with no significant difference, indicating that minor changes in the method did not have a significant effect on the results. When all tablets are tested by the methods of test example 1-test example 6, the test solution is injected into a liquid chromatograph for measurement after being placed at room temperature for 2, 5 and 10 hours after being prepared, and the results show that the measurement results of different tablets by different methods are remarkably different, specifically: experimental example 4-experimental example 6 three methods were performed on all the tablets provided in preparative examples 1-9, in which the sample solution was injected into the liquid chromatograph after dispensing and left at room temperature for 2, 5, and 10 hours, and the R isomer peak area of the same tablet measured by the same method did not change, that is, the R isomer peak area of the sample solution did not change after left for different times; experimental examples 1-experimental example 3 three methods for all tablets without magnesium stearate provided in experimental examples 5-9, the test solution was injected into the liquid chromatograph after being prepared and left at room temperature for 2, 5, and 10 hours, the R isomer peak area of the same tablet measured by the same method was unchanged, i.e. the R isomer peak area of the test solution was unchanged after being left for different periods of time, and the results of detection of these tablets by the three methods of experimental examples 4-6 were substantially the same; experimental examples 1 to 3 three methods of the present invention were carried out in such a manner that, in all tablets containing magnesium stearate provided in the preparation examples 1 to 4, the sample solution was injected into the liquid chromatograph after the solution preparation and left to stand at room temperature for 2, 5, and 10 hours, the R isomer peak area of the same tablet measured by the same method tended to decrease with the lapse of the standing time, while the R isomer peak area of 5 hours was 87 to 90% of the R isomer peak area of 2 hours and the R isomer peak area of 10 hours was 81 to 83% of the R isomer peak area of 2 hours for the same tablet measured by the respective methods; this shows that the peak area of the R isomer in the tablet containing magnesium stearate measured using triethylamine as one of the mobile phase components decreases with the time of standing of the test solution, but it cannot be explained that this tendency is not exhibited in the tablet containing no magnesium stearate measured, and this defect is well overcome when triethylamine is substituted with the same. Since magnesium stearate is an excellent tablet lubricant, the quality control methods provided by the present invention are very valuable because for large sample sizes, it is often necessary to wait a long time for sample solutions to be introduced into the liquid chromatograph during liquid chromatography.
Test example 7: quality control-determination of the content of citalopram R-isomer impurities in the composition
The methods of test examples 1 to 6 were used, respectively, but the procedure (6) was changed as follows: reading the chromatogram of the test solution obtained in the step (5), if an R-isomer peak exists in the chromatogram, comparing the peak area with the main peak area in the chromatogram of the 1.0% control solution, and calculating the content of the R-isomer according to the following formula:
r-isomer content ═ 1.0% (R-isomer peak area in test solution chromatogram ÷ 1.0% main peak area in control solution chromatogram) ×
All of the tablets of production examples 1 to 9 were subjected to R-isomer content measurement using the methods performed in reference test examples 1 to 6, respectively, and the sample preparation rate was controlled so that all of the test article solutions were injected into the liquid chromatograph within 2 hours after preparation (although this would reduce the working efficiency). The results show that for the same tablet, the R-isomer content measurements obtained using different methods are substantially the same, all tablets have an R-isomer content of less than 0.5%, some tablets have an R-isomer content in the range of 0.2-0.5%, and some tablets have an R-isomer content in the range of 0.05-0.2%, for example, tablets from Hunan Dongting pharmaceutical industry have an R-isomer content in the range of 0.08-0.13%, as measured using the methods performed in test examples 1-6, showing very low isomer impurities.
Test example 8: quality control-examination of the relevant substances in the composition
And (3) checking:
(1) taking a proper amount of the fine powder of the escitalopram oxalate tablet composition, wherein the fine powder contains 50mg of escitalopram, precisely weighing, placing the fine powder into a 100ml measuring flask, adding 10ml of buffer salt solution, strongly shaking for 10min, adding 40ml of methanol, shaking for 10min, performing ultrasound treatment for 10min, cooling to room temperature, adding a mobile phase to dilute to a scale, shaking uniformly, filtering, and taking a subsequent filtrate as a test solution; the preparation method of the buffer salt solution comprises the following steps: weighing 1.5g anhydrous sodium acetate, adding 0.4ml glacial acetic acid, adding water to 1000ml, shaking, adjusting pH to 5.2 with 1M sodium hydroxide, and mixing;
(2) precisely measuring 1ml of a test solution, placing the test solution into a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 1.0% control solution (1.0%);
(3) according to the specification of high performance liquid chromatography carried by 0512 of section 59 of the fourth part of the 2015 edition of Chinese pharmacopoeia, octadecylsilane chemically bonded silica is used as a filler, the column length of a chromatographic column is 150mm, the inner diameter of the chromatographic column is 4.6mm, the particle size of the filler is 5 mu m, a mixed solution of buffer salt solution, methanol and acetonitrile in a volume ratio of 60: 33: 7 is used as a mobile phase, the flow rate is 1.0ml/min, the detection wavelength is 239nm, and the column temperature is 45 ℃;
(4) taking a proper amount of reference substance of escitalopram oxalate and reference substance of impurities C of escitalopram, dissolving and diluting the reference substances by using a mobile phase to prepare mixed solutions containing 1.0 mu g of escitalopram in each 1ml, taking 10 mu l of the mixed solutions as system applicability test solutions, injecting the mixed solutions into a liquid chromatograph, recording a chromatogram, and considering that the separation effect is acceptable when the separation degree of the peak of escitalopram and the impurities C is more than 3.0;
(5) taking 10 mu l of the control solution to carry out sample injection for 6 times, and considering the control solution to be acceptable when the relative standard deviation of the peak area of the main peak is less than 2.0 percent; injecting 10 μ l of the control solution into a liquid chromatograph, and adjusting detection sensitivity to make the peak height of the main component chromatographic peak 10% of the full scale; precisely measuring 10 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the retention time of the chromatogram until the main peak is 3.5 times;
(6) reading a chromatogram of the test solution, removing a solvent peak and an oxalic acid peak if an impurity peak exists in the chromatogram, and calculating the percentage of each known impurity, unknown impurity and total impurity according to the following formula:
impurity% (% A)x/Ar)×(1/F)×1/100×100
Wherein:
Ax: peak area of each impurity in test solution
Ar: peak area of escitalopram in control solution
F: relative response factor.
The relative retention times of the various impurities and their relative response factors when examined are as follows:
| name (R) | Relative retention time | Relative response factor |
| Oxalic acid | 0.095 | - |
| Citalopram impurity A | 0.33 | 0.77 |
| Escitalopram impurity A | 0.42 | 0.88 |
| Citalopram impurity B | 0.56 | 0.78 |
| Citalopram impurity C | 0.80 | 0.51 |
| Escitalopram | 1.0 | - |
| Citalopram impurity E | 1.24 | 0.88 |
| Other single impurities | - | 1.0 |
| Total impurities | - | - |
The chemical structure of citalopram impurity C is as follows:
the chemical structure of citalopram impurity a is as follows:
escitalopram impurity a has the following chemical structure:
the chemical structure of citalopram impurity B is as follows:
the chemical structure of citalopram impurity E is as follows:
the tablets of preparation examples 1 to 9 were inspected for relevant substances by the method of this test example 8, and the results showed that for all tablets, citalopram impurity a was 0.2% or less, escitalopram impurity a was 0.1% or less, citalopram impurity B was 0.2% or less, citalopram impurity C was 0.4% or less, citalopram impurity E was 0.2% or less, other individual impurities were 0.1% or less, and total impurities were 1.0% or less; for example, the citalopram impurity A is less than or equal to 0.05 percent, the escitalopram impurity A is less than or equal to 0.02 percent, the citalopram impurity B is less than or equal to 0.05 percent, the citalopram impurity C is less than or equal to 0.1 percent, the citalopram impurity E is less than or equal to 0.05 percent, other single impurities are less than or equal to 0.01 percent, and the total impurities are less than or equal to 0.35 percent of the tablets produced by the Hunan Dongting pharmaceutical industry.
Industrial applicability
The above description is only a preferred embodiment of the present invention and should not be interpreted as limiting the scope of the present invention, and all equivalent modifications and variations made within the scope of the claims of the present invention are within the scope of the claims of the present invention.
Claims (10)
1. A method for the quality control of an escitalopram oxalate tablet composition comprising the limit checking of R-isomer impurities of citalopram in the composition comprising the steps of:
(1) taking a proper amount of the escitalopram oxalate tablet composition fine powder, wherein the content of the escitalopram oxalate tablet composition fine powder is 20-30 mg, precisely weighing, placing the obtained mixture into a 50ml measuring flask, adding a proper amount of a mobile phase, carrying out ultrasonic dissolution, cooling to room temperature, diluting to a scale with the mobile phase, shaking up, filtering, and taking a subsequent filtrate as a sample solution;
(2) precisely measuring 1ml of a test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 1.0% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 200ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.5% control solution; precisely measuring 1ml of the test solution, placing the test solution in a 500ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 0.2% control solution;
(3) the determination is carried out according to the specification of high performance liquid chromatography carried in 0512 of section 59 of the fourth part of 2015 edition of Chinese pharmacopoeia, vancomycin silane bonded silica gel is used as a filling agent, and the volume ratio of methanol-absolute ethyl alcohol-triethylamine-glacial acetic acid is 50: (40-60): (0.05-0.15): (0.05-0.15) taking the mixed solution as a mobile phase, wherein the flow rate is 0.5-1.0 ml/min, and the detection wavelength is 230-240 nm;
(4) taking a proper amount of citalopram racemate, dissolving and diluting the citalopram racemate by using a mobile phase to prepare a solution containing 0.1mg in 1ml, taking 10 mu l of the solution as a system applicability solution, injecting the solution into a liquid chromatograph, recording a chromatogram, enabling an R-isomer and an S-isomer to flow out in sequence, considering that the separation effect is acceptable when the separation degree between two peaks is calculated to be more than 1.5, and considering that the separation effect is acceptable when the theoretical plate number is calculated to be more than 2500 according to the escitalopram, namely the S-isomer peak;
(5) injecting 10 μ l of 1% control solution into liquid chromatograph, and adjusting detection sensitivity to make peak height of main component chromatographic peak 20% of full range; precisely measuring 10 μ l of the test solution, 1.0% of the control solution, 0.5% of the control solution and 0.2% of the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram;
(6) reading a chromatogram of the test solution, comparing the peak area of an R-isomer peak with the main peak area of control solutions with various concentrations if the R-isomer peak exists in the chromatogram, wherein the R-isomer impurity limit is less than 0.2% if the R-isomer peak area in the chromatogram of the test solution is less than 0.2% of the main peak area of the control solutions, the R-isomer impurity limit is less than 0.5% if the R-isomer peak area in the chromatogram of the test solution is less than 0.5% of the main peak area of the control solutions, and the R-isomer impurity limit is less than 1.0% if the R-isomer peak area in the chromatogram of the test solution is less than 1.0% of the main peak area of the control solutions; if the R-isomer peak area is greater than 1.0%, a control solution having a concentration of greater than 1.0% is prepared in step (2) in a similar manner thereto and similarly compared.
2. The method according to claim 1, further comprising determining the amount of R-isomer impurities of citalopram in the composition, comprising the steps of:
reading the chromatogram of the test solution obtained in the step (5), if an R-isomer peak exists in the chromatogram, comparing the peak area with the main peak area in the chromatogram of the 1.0% control solution, and calculating the content of the R-isomer according to the following formula:
the content of R-isomer is (R-isomer peak area in chromatogram of test solution divided by main peak area in chromatogram of 1.0% control solution) multiplied by 1.0%.
3. A process according to claim 1, wherein in the step (1) of limit checking the R-isomer impurities of citalopram in the composition, a suitable amount of fine powder of escitalopram oxalate tablet composition containing 25mg of escitalopram, is finely weighed and subsequently subjected to a subsequent treatment.
4. The method according to claim 1, wherein in the step (3) of limit checking the citalopram R-isomer impurities in the composition, the mobile phase is methanol-absolute ethanol-triethylamine-glacial acetic acid in a volume ratio of 50: 50: 0.1: 0.1.
5. a process according to any one of claims 1 to 4 wherein in step (3) of margin checking the R-isomer impurities of citalopram in the composition, the mobile phase is replaced with an equal amount of tromethamine for triethylamine.
6. The method according to claim 1, wherein in step (3) of limit checking the citalopram R-isomer impurities in the composition, said flow rate is 0.6 ml/min.
7. The method according to claim 1, wherein in step (3) of limit checking the citalopram R-isomer impurities in the composition, said detection wavelength is 238 nm.
8. A method according to any one of claims 1 to 7, further comprising the step of examining the composition for the substance of interest, comprising the steps of:
(1) taking a proper amount of the fine powder of the escitalopram oxalate tablet composition, wherein the fine powder contains 50mg of escitalopram, precisely weighing, placing the fine powder into a 100ml measuring flask, adding 10ml of buffer salt solution, strongly shaking for 10min, adding 40ml of methanol, shaking for 10min, performing ultrasound treatment for 10min, cooling to room temperature, adding a mobile phase to dilute to a scale, shaking uniformly, filtering, and taking a subsequent filtrate as a test solution; the preparation method of the buffer salt solution comprises the following steps: weighing 1.5g anhydrous sodium acetate, adding 0.4ml glacial acetic acid, adding water to 1000ml, shaking, adjusting pH to 5.2 with 1M sodium hydroxide, and mixing;
(2) precisely measuring 1ml of a test solution, placing the test solution into a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a 1.0% control solution (1.0%);
(3) according to the specification of high performance liquid chromatography carried by 0512 of section 59 of the fourth part of the 2015 edition, octadecylsilane chemically bonded silica is used as a filler, the column length of a chromatographic column is 150mm, the inner diameter of the chromatographic column is 4.6mm, the particle size of the filler is 5 mu m, and the volume ratio of buffer salt solution to methanol to acetonitrile is 60: 33: 7 is a mobile phase, the flow rate is 1.0ml/min, the detection wavelength is 239nm, and the column temperature is 45 ℃;
(4) taking a proper amount of reference substance of escitalopram oxalate and reference substance of impurities C of escitalopram, dissolving and diluting the reference substances by using a mobile phase to prepare mixed solutions containing 1.0 mu g of escitalopram in each 1ml, taking 10 mu l of the mixed solutions as system applicability test solutions, injecting the mixed solutions into a liquid chromatograph, recording a chromatogram, and considering that the separation effect is acceptable when the separation degree of the peak of escitalopram and the impurities C is more than 3.0;
(5) taking 10 mu l of the control solution to carry out sample injection for 6 times, and considering the control solution to be acceptable when the relative standard deviation of the peak area of the main peak is less than 2.0 percent; injecting 10 μ l of the control solution into a liquid chromatograph, and adjusting detection sensitivity to make the peak height of the main component chromatographic peak 10% of the full scale; precisely measuring 10 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the retention time of the chromatogram until the main peak is 3.5 times;
(6) reading a chromatogram of the test solution, removing a solvent peak and an oxalic acid peak if an impurity peak exists in the chromatogram, and calculating the percentage of each known impurity, unknown impurity and total impurity according to the following formula:
impurity% (% A)x/Ar)×(1/F)×1/100×100
Wherein:
Axpeak area of each impurity in test solution
ArPeak area of escitalopram in control solution
F: relative response factor.
9. The method of claim 8 wherein the relative retention times of the respective impurities and their relative response factors when the relevant substances in the composition are examined are as follows:
the chemical structure of citalopram impurity C is as follows:
the chemical structure of the citalopram impurity A is as follows:
the chemical structure of escitalopram impurity A is as follows:
the chemical structure of the citalopram impurity B is as follows:
the chemical structure of citalopram impurity E is as follows:
or,
the escitalopram oxalate tablet composition comprises escitalopram oxalate with effective treatment amount, magnesium stearate and optional pharmaceutically acceptable carriers.
10. An escitalopram oxalate tablet composition comprising a therapeutically effective amount of escitalopram oxalate together with magnesium stearate and optionally a pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610517655.5A CN106018618B (en) | 2016-07-05 | 2016-07-05 | Escitalopram oxalate tablet composition and quality control method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610517655.5A CN106018618B (en) | 2016-07-05 | 2016-07-05 | Escitalopram oxalate tablet composition and quality control method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106018618A true CN106018618A (en) | 2016-10-12 |
| CN106018618B CN106018618B (en) | 2018-06-22 |
Family
ID=57106458
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610517655.5A Active CN106018618B (en) | 2016-07-05 | 2016-07-05 | Escitalopram oxalate tablet composition and quality control method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106018618B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106568863A (en) * | 2016-11-04 | 2017-04-19 | 北京万全德众医药生物技术有限公司 | Method for separating and determining escitalopram oxalate intermediate and optical isomer thereof by using high-performance liquid chromatography |
| CN107941962A (en) * | 2017-12-28 | 2018-04-20 | 北京和合医学诊断技术股份有限公司 | Detect the liquid phase chromatography analytical method of escitalopram medicament contg in blood |
| CN111514110A (en) * | 2020-05-07 | 2020-08-11 | 福建海西新药创制有限公司 | Pharmaceutical composition containing escitalopram oxalate and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101474171A (en) * | 2009-02-13 | 2009-07-08 | 四川珍珠制药有限公司 | Oral solid preparation of escitalopram oxalate and preparation method thereof |
| CN101769904A (en) * | 2008-12-29 | 2010-07-07 | 北京德众万全药物技术开发有限公司 | Method utilizing HPLC (high performance liquid chromatography) to measure oxalate escitalopram optical isomer |
| CN103360353A (en) * | 2013-08-07 | 2013-10-23 | 中国药科大学 | Preparation methods for impurities of escitalopram oxalate |
| CN104523638A (en) * | 2014-11-28 | 2015-04-22 | 浙江华海药业股份有限公司 | Tablet containing escitalopram oxalate and preparation method thereof |
-
2016
- 2016-07-05 CN CN201610517655.5A patent/CN106018618B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101769904A (en) * | 2008-12-29 | 2010-07-07 | 北京德众万全药物技术开发有限公司 | Method utilizing HPLC (high performance liquid chromatography) to measure oxalate escitalopram optical isomer |
| CN101474171A (en) * | 2009-02-13 | 2009-07-08 | 四川珍珠制药有限公司 | Oral solid preparation of escitalopram oxalate and preparation method thereof |
| CN103360353A (en) * | 2013-08-07 | 2013-10-23 | 中国药科大学 | Preparation methods for impurities of escitalopram oxalate |
| CN104523638A (en) * | 2014-11-28 | 2015-04-22 | 浙江华海药业股份有限公司 | Tablet containing escitalopram oxalate and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| THE UNITED STATES PHARMACOPEIAL CONVENTION: "《USP35-NF30》", 30 November 2011, UNITED BOOK PRESS * |
| 杨庆云 等: "草酸艾司西酞普兰的有关物质检查及含量测定方法", 《中国药学杂志》 * |
| 车明徽 等: "HPLC法测定草酸艾司西酞普兰片的有关物质", 《黑龙江医药》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106568863A (en) * | 2016-11-04 | 2017-04-19 | 北京万全德众医药生物技术有限公司 | Method for separating and determining escitalopram oxalate intermediate and optical isomer thereof by using high-performance liquid chromatography |
| CN107941962A (en) * | 2017-12-28 | 2018-04-20 | 北京和合医学诊断技术股份有限公司 | Detect the liquid phase chromatography analytical method of escitalopram medicament contg in blood |
| CN111514110A (en) * | 2020-05-07 | 2020-08-11 | 福建海西新药创制有限公司 | Pharmaceutical composition containing escitalopram oxalate and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106018618B (en) | 2018-06-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6151727B2 (en) | Ulipristal acetate ester tablets | |
| RU2446800C2 (en) | Controlled-release preparative forms | |
| EP3981399A1 (en) | Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor | |
| TW200427448A (en) | Controlled release preparations comprising tramadol and topiramate | |
| KR101977785B1 (en) | Composite formulation for oral administration comprising ezetimibe and rosuvastatin and a process for the preparation thereof | |
| MX2009002336A (en) | Imatinib compositions. | |
| AU2010274589A1 (en) | Oral pharmaceutical composition of rasagiline and process for preparing thereof | |
| CN102247368B (en) | Compound acrivastine sustained release tablets, and preparation method thereof | |
| CN106018618A (en) | Escitalopram oxalate tablet composition and quality control method | |
| RU2700164C2 (en) | Solid preparations containing tofogliflozin, and method for production thereof | |
| EP3453384B1 (en) | Pharmaceutical tablet composition comprising bilastine | |
| CN102276516A (en) | Levamlodipine besylate crystals, preparation method thereof and brand-new medicinal composition containing crystals | |
| CN102764254B (en) | A kind of levetiracetam medicinal composition and preparation method thereof | |
| CN111773191A (en) | Compound solid preparation containing phenylephrine hydrochloride and preparation method thereof | |
| JP2007063217A (en) | Tablet containing pranlukast hydrate and method for producing the same | |
| KR101794573B1 (en) | Immediate-release solid preparations comprising choline alfoscerate and preparing method thereof | |
| EP3470062B1 (en) | Pharmaceutical tablet composition comprising bilastine polymorphic form 3 and magnesium aluminometasilicate | |
| KR20180052127A (en) | Tablets with medium independent active material transfer | |
| EP3087976A1 (en) | Stable crystal x-form agomelatine tablet and preparation method thereof | |
| JP2022517616A (en) | A method for producing a pharmaceutical composition containing nefopam and acetaminophen, and a pharmaceutical composition obtained thereby. | |
| EP3079672B1 (en) | Pharmaceutical composition comprising a pharmaceutically acceptable salt of rasagiline | |
| CN111603450A (en) | Isosorbide mononitrate tablet and preparation process thereof | |
| JP2001213890A (en) | Trehalose particle | |
| CN115666532B (en) | Sustained release preparation containing limaprost | |
| EP3641735B1 (en) | Pharmaceutical tablet composition comprising bilastine form 3 and a water-soluble filler |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |