CN116509810B - Montelukast sodium tablet and preparation method thereof - Google Patents
Montelukast sodium tablet and preparation method thereof Download PDFInfo
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- CN116509810B CN116509810B CN202310561648.5A CN202310561648A CN116509810B CN 116509810 B CN116509810 B CN 116509810B CN 202310561648 A CN202310561648 A CN 202310561648A CN 116509810 B CN116509810 B CN 116509810B
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- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 title claims abstract description 105
- 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 92
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000013078 crystal Substances 0.000 claims abstract description 18
- 239000000945 filler Substances 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 7
- 239000000314 lubricant Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 239000000853 adhesive Substances 0.000 claims abstract description 5
- 230000001070 adhesive effect Effects 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 9
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 9
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 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 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- 229960001021 lactose monohydrate Drugs 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 7
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 7
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 7
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical group CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 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 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229960005127 montelukast Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000003086 colorant Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 102000010918 Cysteinyl leukotriene receptors Human genes 0.000 description 2
- 108050001116 Cysteinyl leukotriene receptors Proteins 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 239000000924 antiasthmatic agent Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 241000736199 Paeonia Species 0.000 description 1
- 235000006484 Paeonia officinalis Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000007885 bronchoconstriction Effects 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
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- -1 cysteine leukotriene Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 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 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 1
- OTZRAYGBFWZKMX-JUDRUQEKSA-N leukotriene E4 Chemical compound CCCCCC=CCC=C\C=C\C=C\[C@@H](SC[C@H](N)C(O)=O)[C@@H](O)CCCC(O)=O OTZRAYGBFWZKMX-JUDRUQEKSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000001782 photodegradation Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to a montelukast sodium tablet which comprises the following raw materials in parts by mass: 10-20 parts of montelukast sodium, 120-190 parts of filler, 70-120 parts of filler, 5-8 parts of disintegrating agent, 3-6 parts of adhesive and 1-2 parts of lubricant; the montelukast sodium at least comprises more than 80 weight percent of montelukast sodium crystal form D; the XRD pattern of montelukast sodium form D includes the following characteristic peaks of 2θ: 4.87+ -0.1 °, 11.63+ -0.1 °, 14.37 + -0.1 °, 16.94+ -0.1 °. The montelukast sodium tablet provided by the invention has excellent light stability, is more convenient to transport, store and clinically use, has a simple preparation process and low cost, and has obvious commercial and clinical significance.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a montelukast sodium tablet and a preparation method thereof.
Background
Montelukastsodium (Montelukastsodium) selectively binds to the cysteine leukotriene type 1 receptor (CysLT 1 receptor), thereby inhibiting the pathophysiological effects (bronchoconstriction, vascular permeability enhancement and mucous secretion promotion) produced by the binding of the inflammation inducing mediators LTD4 and LTE4 to the CysLT1 receptor. Based on the action mechanism, the montelukast can improve various factors of asthma inflammation and has an anti-asthma effect. Clinical data show that the montelukast sodium has good tolerance, light adverse reaction, high compliance and good clinical treatment effect, and becomes a star product of the current anti-asthma medicament.
But the montelukast sodium has poor stability, especially poor stability to light, and needs to be stored in a dark place. This places high demands on the preparation, transportation and storage of montelukast sodium tablets. The conventional montelukast sodium tablet at present cannot solve the defect of poor stability. The prior art improves the photostability of the montelukast sodium tablet by means of a light shielding agent, coating and the like, but often has the defects of influence on the dissolution rate, complex preparation process, high cost, strict requirements on the preparation process conditions and the like.
CN110721166a discloses a montelukast sodium tablet, which is prepared by adding high-substituted hydroxypropyl cellulose into organic solvents such as montelukast sodium honor methanol, ethanol, ethyl acetate, toluene and the like, dissolving, adding n-hexane, stirring, filtering, drying to obtain the montelukast sodium coated by the high-substituted hydroxypropyl cellulose, and tabletting with auxiliary materials. The obtained tablet has small increase of related substances after 3 months of illumination, which indicates that the light stability is obviously improved. But the dissolution rate is reduced, the bioavailability is lowered, and the therapeutic effect is affected.
CN101732268A discloses a montelukast sodium tablet, which improves the photostability of the montelukast sodium tablet through a colorant, the photostability is different according to different batches, such as the dispersion degree of the colorant, different preparation processes, and certain differences exist in the photostability of different batches of products, and adverse influence factors may be generated in consistency evaluation.
In the prior art, the montelukast sodium is prepared into a core-shell structure such as a microcapsule or is prepared into an inclusion compound with cyclodextrin, so that the montelukast sodium has a certain protection effect under the conditions of light and oxygen, but the defects of complex preparation process and high cost exist.
Polymorphism is a common phenomenon in pharmaceutical compounds, and compounds with different crystal forms may have different physicochemical properties, physiological activities and the like. Drug polymorphism is an important factor affecting the quality and clinical efficacy of a drug compound.
Clinical reports of the montelukast sodium polymorph are mainly form a, form B. The XRD characteristic peaks are as follows:
the aforementioned montelukast sodium form a, form B polymorphs have no significant difference in photostability and all tend to produce cis-isomer impurities under light.
The invention comprises the following steps:
in order to solve the problem that the stability and dissolution rate of the montelukast sodium tablet in the prior art are still to be improved, the invention provides the montelukast sodium tablet and the preparation method thereof, and the light stability of the montelukast sodium tablet can be obviously improved under the condition that the dissolution rate is not influenced.
The invention solves the technical problems by the following technical proposal:
the montelukast sodium tablet comprises the following raw materials in parts by mass: 10-20 parts of montelukast sodium, 120-190 parts of filler, 70-120 parts of filler, 5-8 parts of disintegrating agent, 3-6 parts of adhesive and 1-2 parts of lubricant; the montelukast sodium at least comprises more than 70 weight percent of montelukast sodium crystal form D; the XRD pattern of montelukast sodium form D includes the following characteristic peaks of 2θ: 4.87+ -0.1 °, 11.63+ -0.1 °, 14.37 + -0.1 °, 16.94+ -0.1 °.
Further, the montelukast sodium at least comprises more than 80wt% of montelukast sodium crystal form D, such as more than 90wt% and more than 95 wt%. In a more preferred embodiment of the present invention, the montelukast sodium comprises at least 99% by weight of montelukast sodium form D.
Further, the XRD pattern of montelukast sodium form D further includes the following characteristic peaks of 2θ: 4.02+ -0.1 °, 4.24+ -0.1 °, 5.13+ -0.1 °, 5.36+ -0.1 °, 19.58+ -0.1 °, 24.17+ -0.1 °, 24.85+ -0.1 °.
Preferably, the characteristic peak of 2θ of montelukast sodium form D of the present invention ranges between ±0.05°, such as between ±0.04°, between ±0.03°, between ±0.02°, between ±0.0°.
Further, the montelukast sodium crystal form D is worthy of preparation by a preparation method comprising the following steps: under the inert atmosphere and the light-shielding condition, the montelukast sodium is dissolved in an alcohol solvent, then the poor solvent of the montelukast sodium is added, stirred and crystallized at the temperature of 5-10 ℃, solid-liquid separated and dried, and the montelukast sodium crystal form D is obtained.
Further, the inert atmosphere is nitrogen or argon; the purity of the raw material montelukast sodium is more than 99.9%; the alcohol solvent is at least one selected from methanol, ethanol and isopropanol; the poor solvent is at least one selected from ethyl acetate, diethyl ether, n-butyl ether, benzene, toluene and cyclohexane; the solid-liquid separation is centrifugation, specifically centrifugation is carried out for 5-30min under the condition of 5000-10000 rpm; the drying is vacuum drying, specifically vacuum drying at 20-40deg.C and 0.01-0.1 MPa. During the whole preparation process of the montelukast sodium crystal form D, a light-shielding condition and an inert atmosphere as much as possible are maintained.
The inventors have unexpectedly found that crystalline form D of montelukast sodium prepared according to the above-described preparation method has significantly improved photostability. Montelukast sodium is unstable under light conditions, and can produce the cis-isomer of montelukast, impurity B in the pharmacopoeia. The pharmacopoeia has definite quality control requirements for impurity B. However, even if the quality control of the product reaches the standard when leaving the factory, if the product is stored in a dark place, new impurity B can still be generated in the process of transportation and storage. In order to improve the light stability of the current clinical montelukast sodium, components such as a colorant, a light shielding agent and the like are often added, so that on one hand, the cost is improved, and on the other hand, the process is complex. The invention takes a specific montelukast sodium crystal form D as an active ingredient, and has obviously improved light stability. Has obvious commercial and clinical significance.
Further, the filler is at least one selected from microcrystalline cellulose, lactose monohydrate and starch; preferably microcrystalline cellulose and lactose monohydrate according to the mass ratio of 1-2: 1-2.
Further, the disintegrating agent is at least one selected from the group consisting of croscarmellose sodium, crospovidone and cross-linked carboxymethyl starch.
Further, the adhesive is at least one selected from hydroxypropyl cellulose and polyvinylpyrrolidone.
Further, the lubricant is at least one selected from magnesium stearate, calcium stearate, zinc stearate, sodium stearate fumarate and talcum powder.
The second object of the present invention is to provide a preparation method of the montelukast sodium tablet, comprising the following steps:
(S1) weighing: accurately weighing raw materials and auxiliary materials according to a formula;
(S2) premixing: uniformly mixing montelukast sodium, a filling agent, a disintegrating agent and a binding agent to obtain a premix;
(S3) total mixing: uniformly mixing the lubricant and the premix;
(S4) tabletting: tabletting is carried out according to the photo weight, and the montelukast sodium tablet is obtained.
The invention has the excellent effect of providing a montelukast sodium tablet with a novel montelukast sodium crystal form D as a therapeutically active ingredient, and the montelukast sodium tablet has obviously improved photostability. The existing preparation process of the montelukast sodium tablet does not need to be changed, and the additive colorant or the microcapsule is not needed to be added, so that the stability of the montelukast is improved, and the method has important commercial value and clinical application significance.
Description of the drawings:
fig. 1 is an XRD pattern of crystalline form D of montelukast sodium of the present invention.
The specific embodiment is as follows:
in order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. The following examples facilitate a better understanding of the present invention, but are not intended to limit the same. The experimental methods in the following examples are conventional methods unless otherwise specified.
The invention adopts Montelukast sodium as raw material to be produced from peony Jiang Hengyuan pharmaceutical industry Co.Ltd.
The X-ray diffraction pattern was measured by using a CuK alpha radiation diffractometer from Bruker, and the 2 theta measurement range was 0-45 degrees (voltage 45kV, current 40 mA).
Preparation examplePreparation of Montelukast sodium Crystal form D
Taking 1g of solid montelukast sodium under the dark and nitrogen atmosphere, adding the solid montelukast sodium into 10mL of ethanol, stirring at room temperature for full dissolution, adding 25mL of n-butyl ether, stirring at 5 ℃ for 10h, centrifuging at 7000rpm, pouring out the supernatant, and vacuum drying the obtained solid at 30 ℃ under the condition of 0.1Mpa to obtain the montelukast sodium crystal form D.
The XRD derivative pattern and data table of montelukast sodium form D are shown in fig. 1 and table 1:
TABLE 1 XRD data for montelukast sodium form D
| 2θ (°) | Intensity (%) |
| 4.02 | 34.3 |
| 4.24 | 32.5 |
| 4.87 | 86.3 |
| 5.13 | 38.5 |
| 5.36 | 19.3 |
| 11.63 | 100 |
| 14.37 | 85.4 |
| 16.94 | 63.2 |
| 19.58 | 22.4 |
| 24.17 | 18.4 |
| 24.85 | 17.8 |
Example 1
(S1) weighing: 10g of montelukast sodium crystal form D,89g of microcrystalline cellulose, 85g of lactose monohydrate, 6g of croscarmellose sodium, 5.5g of hydroxypropyl cellulose and 1g of magnesium stearate prepared in the preparation example are accurately weighed according to a formula;
(S2) premixing: uniformly mixing montelukast sodium, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium and hydroxypropyl cellulose to obtain a premix;
(S3) total mixing: uniformly mixing 1 part of magnesium stearate and the premix;
(S4) tabletting: tabletting (each tablet contains montelukast sodium 10+/-0.1 and mg) according to the theoretical tablet weight to obtain the montelukast sodium tablet.
Example 2
Other conditions and operations are the same as in example 1, except that in step (S1), the formulation is: 10g portions of montelukast sodium crystal form D,105g microcrystalline cellulose, 75g lactose monohydrate, 7.1g croscarmellose sodium, 6.8g hydroxypropyl cellulose, 1.2g zinc stearate.
Example 3
Other conditions and operations are the same as in example 1, except that in step (S1), the formulation is: 10g portions of montelukast sodium crystal form D,174g of microcrystalline cellulose, 6g of croscarmellose sodium, 5.5g of hydroxypropyl cellulose and 1g of magnesium stearate.
Example 4
Other conditions and operations are the same as in example 1, except that in step (S1), the formulation is: 10g portions of montelukast sodium crystal form D,174 lactose monohydrate, 6g of croscarmellose sodium, 5.5g of hydroxypropyl cellulose, and 1g of magnesium stearate.
Comparative example 1
Other conditions and procedures were the same as in example 1 except that montelukast sodium form D was replaced with a commercially available montelukast sodium drug substance.
Effect example
The following quality tests were carried out on the montelukast sodium tablets obtained in the above examples and comparative examples.
Light stability test: the test is carried out by referring to the annex V D of the second edition of Chinese pharmacopoeia 2000. Each test set comprises taking at least 20 pieces of montelukast sodium tablet (each containing montelukast sodium 10 mg), irradiating with white fluorescent lamp at 60+ -5+ -RH% and 25+ -2deg.C with light intensity 4500+ -200 lx, respectively taking 10 pieces. On day 0 (i.e. without light), on day 5, and on day 12, 10 tablets were taken, respectively, and after grinding, they were weighed, and the equivalent of montelukast sodium powder having 10mg was subjected to content testing by HPLC (samples were dissolved in 20mL of a mixed solvent of methanol: water in a volume ratio of 3:1, sonicated, and filtered through a 0.45 μm filter, and subjected to HPLC testing). In addition, 10mg of Montelukast sodium reference substance is taken, and the mixture is diluted to a scale by a diluent (methanol: water volume ratio is 3:1) in a 20mL white measuring flask, shaken uniformly and placed under natural light for 30min to be used as a system applicability solution. And (3) 10 mu L of the system adaptive solution is injected into a high performance liquid chromatograph, the separation degree of an impurity B peak and a montelukast peak is not less than 1.5, and the theoretical plate number is not less than 2000 according to the montelukast. And calculating the content of the impurity B of the photodegradation product according to the peak area of the external standard method.
HPLC using high performance liquid chromatography (Agilent 1260); chromatographic column: agilent C8 is used; column temperature: 30 ℃; mobile phase: mobile phase a: acetonitrile: phosphate buffer solution volume ratio 60:40, a step of performing a; mobile phase B: acetonitrile; flow rate: 1.0 mL/min.
Dissolution test: reference is made to the second appendix X-C third Law of the Chinese pharmacopoeia 2000 edition. The specific method comprises the following steps: taking 0.5% sodium dodecyl sulfate as solvent, dissolving a piece of montelukast sodium tablet prepared in the above examples and comparative examples, and filtering. The montelukast sodium control was taken and dissolved in 0.5% sodium dodecyl sulfate. The absorbance was measured at 284nm according to spectrophotometry, and the elution amount of each tablet was calculated. The limit should be 85% of the nominal amountAnd is stipulated.
Table 1 montelukast sodium tablet quality test
Note that: all samples were tested for photostability on the 0 th day sample as HPLC basis, i.e. impurity B of the 0 th day sample, and total impurity content relative to 0%.
As can be seen from table 1, the present invention has significantly improved photostability with montelukast sodium form D as an active ingredient of the tablet, and has no adverse effect on dissolution. The invention solves the defect that the stability of the montelukast sodium tablet is improved by adding an opacifier or a complex preparation process in the prior art, and the montelukast sodium tablet provided by the invention is convenient to prepare, transport, store and clinically use.
Claims (7)
1. The montelukast sodium tablet is characterized by comprising the following raw materials in parts by mass: 10 parts of montelukast sodium, 120-190 parts of filler, 5-8 parts of disintegrating agent, 3-6 parts of adhesive and 1-2 parts of lubricant; the montelukast sodium comprises more than 80wt% of montelukast sodium crystal form D; the XRD pattern of montelukast sodium form D includes the following characteristic peaks of 2θ: 4.02+ -0.1 °, 4.24+ -0.1 °, 4.87+ -0.1 °, 5.13+ -0.1 °, 5.36+ -0.1 °, 11.63+ -0.1 °, 14.37 + -0.1 °, 16.94+ -0.1 °, 19.58+ -0.1 °, 24.17+ -0.1 °, 24.85+ -0.1 °;
the filler is at least one selected from microcrystalline cellulose and lactose monohydrate; the disintegrating agent is croscarmellose sodium; the adhesive is hydroxypropyl cellulose; the lubricant is at least one selected from magnesium stearate and zinc stearate.
2. The montelukast sodium tablet of claim 1, wherein the montelukast sodium comprises more than 90wt% of montelukast sodium form D.
3. The montelukast sodium tablet of claim 1, wherein the montelukast sodium comprises more than 95wt% of montelukast sodium form D.
4. The montelukast sodium tablet of claim 1, wherein the montelukast sodium crystal form D is prepared by a preparation process comprising: under inert atmosphere and light-shielding condition, dissolving montelukast sodium in an alcohol solvent, adding a poor solvent of the montelukast sodium, stirring and crystallizing at 5-10 ℃, carrying out solid-liquid separation, and drying to obtain a montelukast sodium crystal form D; the poor solvent is n-butyl ether; the alcohol solvent is ethanol.
5. The montelukast sodium tablet of claim 4, wherein the solid-liquid separation is a centrifugation at 5000-10000rpm for 5-30min; the drying is vacuum drying under the conditions of 20-40 ℃ and 0.01-0.1 MPa.
6. The montelukast sodium tablet of claim 1, wherein the filler is microcrystalline cellulose and lactose monohydrate in a mass ratio of 1-2: 1-2.
7. Process for the preparation of montelukast sodium tablet according to any one of claims 1 to 6, characterized in that it comprises the following steps:
(S1) weighing: accurately weighing raw materials and auxiliary materials according to a formula;
(S2) premixing: uniformly mixing montelukast sodium, a filling agent, a disintegrating agent and a binding agent to obtain a premix;
(S3) total mixing: uniformly mixing the lubricant and the premix;
(S4) tabletting: tabletting is carried out according to the photo weight, and the montelukast sodium tablet is obtained.
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