CN105395497B - A kind of stable alpha-crystal form perindopril tert-butylamine piece and preparation method - Google Patents
A kind of stable alpha-crystal form perindopril tert-butylamine piece and preparation method Download PDFInfo
- Publication number
- CN105395497B CN105395497B CN201510885002.8A CN201510885002A CN105395497B CN 105395497 B CN105395497 B CN 105395497B CN 201510885002 A CN201510885002 A CN 201510885002A CN 105395497 B CN105395497 B CN 105395497B
- Authority
- CN
- China
- Prior art keywords
- butylamine
- perindopril tert
- crystal form
- perindopril
- tert
- 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.)
- Active
Links
- IYNMDWMQHSMDDE-MHXJNQAMSA-N perindopril erbumine Chemical compound CC(C)(C)N.C1CCC[C@@H]2N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H](C(O)=O)C[C@@H]21 IYNMDWMQHSMDDE-MHXJNQAMSA-N 0.000 title claims abstract description 48
- 239000013078 crystal Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 26
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 19
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 19
- 239000008101 lactose Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 19
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 19
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 19
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 12
- 239000002274 desiccant Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 238000001514 detection method Methods 0.000 claims abstract description 6
- 239000012528 membrane Substances 0.000 claims abstract description 5
- 238000012856 packing Methods 0.000 claims abstract description 5
- 229920003023 plastic Polymers 0.000 claims abstract description 5
- 239000004033 plastic Substances 0.000 claims abstract description 5
- 229960001375 lactose Drugs 0.000 claims description 17
- 239000000463 material Substances 0.000 claims description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 7
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical group 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 4
- 239000005030 aluminium foil Substances 0.000 claims description 4
- 229960001021 lactose monohydrate Drugs 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 238000012549 training Methods 0.000 claims description 3
- 238000009826 distribution Methods 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims description 2
- 239000002808 molecular sieve Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- 238000010348 incorporation Methods 0.000 claims 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 claims 1
- 239000000194 fatty acid Substances 0.000 claims 1
- 229930195729 fatty acid Natural products 0.000 claims 1
- 150000004665 fatty acids Chemical class 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229960002582 perindopril Drugs 0.000 abstract description 14
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 abstract description 14
- 238000004090 dissolution Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000009702 powder compression Methods 0.000 abstract description 3
- 238000007873 sieving Methods 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 abstract 1
- 238000005260 corrosion Methods 0.000 abstract 1
- 230000007797 corrosion Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000000047 product Substances 0.000 description 56
- 239000000126 substance Substances 0.000 description 19
- 230000015556 catabolic process Effects 0.000 description 14
- 238000006731 degradation reaction Methods 0.000 description 14
- 239000012535 impurity Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000001133 acceleration Effects 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000945 filler Substances 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 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 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000002075 main ingredient Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 238000012356 Product development Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002416 angiotensin derivative Substances 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 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
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 150000003951 lactams Chemical group 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- RYCSJJXKEWBUTI-YDYAIEMNSA-N perindopril arginine Chemical class OC(=O)[C@@H](N)CCCNC(N)=N.C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 RYCSJJXKEWBUTI-YDYAIEMNSA-N 0.000 description 1
- ODAIHABQVKJNIY-PEDHHIEDSA-N perindoprilat Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(O)=O)[C@H]21 ODAIHABQVKJNIY-PEDHHIEDSA-N 0.000 description 1
- 229960005226 perindoprilat Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- BXRNXXXXHLBUKK-UHFFFAOYSA-N piperazine-2,5-dione Chemical compound O=C1CNC(=O)CN1 BXRNXXXXHLBUKK-UHFFFAOYSA-N 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of stable alpha-crystal form perindopril tert-butylamine piece, is made of perindopril tert-butylamine, lactose, microcrystalline cellulose, magnesium stearate.Preparation method of the present invention is technique of direct powder compression, first takes lactose and microcrystalline cellulose to be sieved and mixes, dry；It takes part to mix with perindopril tert-butylamine sieving respectively, is eventually adding magnesium stearate mixing, sample detection, tabletting, using aluminium-plastic bubble plate packing, built-in desiccant is cladded with compound membrane bag.The perindopril tert-butylamine piece prepared by the method for the invention, its character, dissolution rate, moisture, content, crystal form and in the medium of different pH dissolved corrosion and commercialized product without significant change, and its stability is more more stable than commercialized product in production and storage, ensure that Clinical efficacy and safety of the drug in taking.Perindopril piece preparation method provided by the invention is simple, reduces the cost of pharmaceutical production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of stable alpha-crystal form perindopril tert-butylamine piece and its system
Preparation Method.
Background technique
Perindopril and its esters belong to angiotensins, the treatment of cardiovascular disease are widely used in, especially in hypertension
There is good effect with fields such as heart failure.Although Perindopril is initially to be synthesized into the form of sodium salt, it is steady
Qualitative not good enough therefore more stable perindopril tert-butylamine and arginine salt is synthesized in succession, while also reducing safety wind
Danger.Perindopril arginine salt and perindopril tert-butylamine are developed to the folk prescription or compound preparation preparation of diversified forms, tradition
Perindopril tert-butylamine slice prescription in mostly use filler (such as lactose, microcrystalline cellulose), adhesive (such as hydroxy propyl cellulose
Element, povidone, hypromellose), disintegrating agent (sodium carboxymethyl starch), lubricant (magnesium stearate, talcum powder) etc. is through wet
Method granulating process preparation, specific preparation method be perindopril tert-butylamine successively with filler and appropriate disintegrating agent equal increments mistake
Sieve mixing adds adhesive softwood processed in right amount, and sieving granulation is dry, and whole grain mixes with remaining disintegrating agent, lubricant is then added
Total mix, tabletting to get.Commercialized product uses aluminium-plastic bubble plate packing, sets storage in the aluminium foil bag for adding desiccant, and require to store
Although result of study shows preparation at 30 DEG C hereinafter, the stability of product has been significantly greatly increased by starvation and moisture
Be not sufficient to guarantee the stabilization of perindopril tert-butylamine in this condition, i.e., its there is also high temperature degradations, while the packaging is also very big
Increase cost.
The related substance detection of perindopril tablets is carried out using liquid chromatography, degradation impurity is mainly B, D, F, K, knot
The weakness on analysis this body structure of Perindopril is closed, as the ethyl acetate base in structure makes it be easier to that hydrolysis generation carboxylic occurs
The Perindoprilat (impurity B, EP8.0) of based structures is main metabolites in perindopril tert-butylamine body；In addition, training diindyl
Carboxyl and peri position amino in Puli's structure increase and the Perindopril that acylation reaction cyclization generation has lactam structure occur
Diketopiperazine (impurity F, EP8.0), in addition to above-mentioned degradation impurity, perindopril tert-butylamine synthesis technology itself is complicated, is related to crowd
More process impurities and by-product, such as the hydrolysis of ester group impurity in products C and its epimer impurity D of impurity F, other if not with
The variation of time and increased process impurity E.The impurity degradation of perindopril tert-butylamine is shown in Fig. 1.
For perindopril tert-butylamine in addition to there is aforementioned stable, there is also polymorphous characteristics, open at present to report
There is a α in road, beta, gamma, the crystal forms such as δ, ε, and each crystal form has a corresponding Pharmaceutical composition patent, and domestic original grinds listing kind and brilliant using α
Type.It has been observed that since Perindopril is there are the unstability in structure, hydrothermal stability problem, but research shows that
When commercialized product is placed 10 and 30 days under the conditions of 40 DEG C, not only related substance is significantly increased even beyond limit as defined in standard
Degree, more seriously its crystal form can also change, thus it is speculated that its stability may be related with crystal form, and current research data is equal
The not yet explicitly different resulting stability problem of carry out.In conclusion the degradation of impurity is fast in the stability of Perindopril
Rate and crystal transfer are the difficult points of product development.
Summary of the invention
In view of the deficiencies of the prior art, it is an object of the present invention to provide a kind of stable alpha-crystal form perindopril tert-butylamine piece,
By weight by following component:
Alpha-crystal form perindopril tert-butylamine: 1-5 parts；
Lactose: 60-80 parts；
Microcrystalline cellulose: 20-33 parts；
Magnesium stearate: 0.8-1.5 parts.
Preferably, the alpha-crystal form perindopril tert-butylamine piece by following component by weight:
Alpha-crystal form perindopril tert-butylamine: 4 parts；
Lactose: 65 parts；
Microcrystalline cellulose: 20 parts；
Magnesium stearate: 1 part.
Above-mentioned perindopril tert-butylamine is alpha-crystal form, and lactose is lactose monohydrate, microcrystalline cellulose PH102.
It is a further object to provide a kind of preparation methods of stable alpha-crystal form perindopril tert-butylamine piece, lead to
Cross following steps realization:
(1) lactose and microcrystalline cellulose is taken to distinguish the sieving of -60 mesh of 30 mesh, mixing is dry to be lower than 5.0% to moisture, is divided into 3
Part；
(2) it takes portion to mix with the perindopril tert-butylamine for having been subjected to -80 mesh of 50 mesh, crosses -60 mesh of 30 mesh, mix；
The particle diameter distribution of perindopril tert-butylamine is that MEAN D (4,3) is 30-50um, and D90 is 70~90um.
(3) a auxiliary material, mixing in step (1) are continuously added；
(4) mixture of step (3) is mixed -30 minutes 10 minutes with auxiliary material remaining in step (1), preparation process environment
Humidity is lower than 40%RH；
(5) magnesium stearate is added to mix -10 minutes 1 minute, sample detection intermediates content, using 4mm*8mm tabletting, pressure
Sheet hardness is 40~70N；
(6) aluminium-plastic bubble plate packing is used, built-in desiccant is silica gel or molecular sieve.Overcoating compound membrane bag.
Alpha-crystal form perindopril tert-butylamine piece provided by the invention compared with commercialized product, appearance, dissolution rate, moisture,
Without significant change in content, and during stability experiment its impurity degradation rate be less than commercialized product, stability of crystal form with
Commercialized product no significant difference.
The present invention is to prepare the specific advantage in perindopril tert-butylamine piece method as follows:
There is preparation method of the present invention auxiliary material to use less varieties, simple process, advantage with short production cycle, at low cost.Place
It is avoided in side using disintegrating agent (sodium carboxymethyl starch etc.), glidant (silica), adhesive (HPC etc.) functional auxiliary material.
Perindopril tert-butylamine piece specification and slice weight are smaller, and itself is soluble easily in water, and lactose is soluble easily in water in the present invention, and crystallite is fine
Dimension element can also play the role of disintegration, therefore lactose and crystallite are applied in combination and serve as filler and can promote disintegration of tablet again.Training
Diindyl Puli's tert-butylamine piece is damp and hot unstable, and product of the present invention formula is avoided using adhesive, so as to effectively reduce wet granulation
The problem of the control of bring moisture and disintegration risk reduces it and is dissolved in water simultaneously because perindopril tert-butylamine is highly soluble in water
Turn brilliant problem afterwards, and it is now recognized that the stability of product can be reduced by turning crystalline substance.The use that silica is avoided in formula, there is patent
Show acidic excipient, as silica can accelerate the degradation of Perindopril.
The present invention to embodiment 1 be formulated in lactose model and crystallite model investigate.The result shows that using anhydrous lactitol
When sugar and microcrystalline cellulose PH112 tabletting, in stability experiment, impurity degradation rate and crystal transfer are compared with commercialized product
Fastly or even 0 day crystal form will change.Analyzing reason Lactis Anhydrous and microcrystalline cellulose PH112 is low water material, belongs to phase
To unstable state, in tablet stability, what moisture pick-up properties certainly will be faster than the lactose monohydrate and microcrystalline cellulose PH102 of stable state
It is more, lead to local moment high humidity, accelerates degradation under the high temperature conditions.
The present invention is provided that is, product moisture is lower than 4.5%, and process environments are wet to the humidity and moisture of process environments
Degree should be lower than 40%RH, and the content homogeneity question of perindopril tert-butylamine piece can be effectively solved using the present invention.
The present invention use direct powder compression, can to avoid conventional wet pelletize after tabletting production process in it is wet with it is hot
Influence, avoid a possibility that high temperature or high humidity influence, the content of impurity B and F substantially reduce, and are more advantageous to the steady of product
It is fixed, it is more advantageous to the safety of product.
The present invention uses direct powder compression, compared with the dry tablet forming technique of wet granulation, have auxiliary material using less varieties,
Simple process, advantage with short production cycle, at low cost.
Impurity degradation rate is obvious compared with commercialized product in its stability of alpha-crystal form perindopril tert-butylamine piece of the invention
It reduces, and stability of crystal form and variation are identical with commercialized product.
Preparation method design of the present invention is reasonable, Perindopril uncle safely, effectively, stable, quality controllable and simple, economic
The Recipe of butylamine realizes the principle for meeting imitation medicine Conformance Assessment when the industry of product is declared, by the meaningful of change.
Detailed description of the invention
Fig. 1 is the structural degradation schematic diagram of the process impurity of perindopril tert-butylamine.
Fig. 2 is the crystal form figure of commercialized product, made products, bulk pharmaceutical chemicals and blank auxiliary, deducts blank auxiliary as the result is shown
Peak, made products, bulk pharmaceutical chemicals are consistent with commercialized product crystal form, (PER-11-150309: bulk pharmaceutical chemicals；PER2007410: listing produces
Product；PER150901: made products；KBFL: blank auxiliary).
Fig. 3 be commercialized product, made products, bulk pharmaceutical chemicals respectively under influence factor illumination, high temperature, super-humid conditions 10 days and
30 days crystal form figures, made products, bulk pharmaceutical chemicals are consistent with commercialized product crystal form under illumination, super-humid conditions as the result is shown.And it is high
Commercialized product, made products, bulk pharmaceutical chemicals, which exist, under the conditions of temperature turns crystalline substance；PER-11-150309 in figure: bulk pharmaceutical chemicals,
PER2007410: commercialized product, PER150901: made products, PER-11-150309: bulk pharmaceutical chemicals；L10d:5000Lux illumination
10 days, H10d:75%RH was placed 10 days, and T10d:40 DEG C is placed 10 days.
Fig. 4 is that commercialized product, made products, bulk pharmaceutical chemicals wake up with a start figure in 30 days under acceleration conditions respectively, as the result is shown from
Product processed is consistent with commercialized product crystal form；PER-2007410 in figure: commercialized product；PER150706: made products；T90d:40
DEG C/75%RH under the conditions of 90 days (Acceleration study).
Specific embodiment
The present invention will be further explained below with reference to the attached drawings and specific examples.
Embodiment 1:
A kind of perindopril tablets, the perindopril tablets by following component by weight:
Alpha-crystal form perindopril tert-butylamine: 4 parts；
Lactose: 65 parts；
Microcrystalline cellulose: 20 parts；
Magnesium stearate: 1 part.
The piece finally made weighs about the tablet of 90mg, and preparation process includes the following steps:
(1) lactose and microcrystalline cellulose is taken to cross 50 meshes respectively, mixing is dry to be lower than 4.5% to moisture, is divided into 3 parts, control
Technical process humidity processed is lower than 40%RH.
(2) it takes portion to mix with the perindopril tert-butylamine Jing Guo 80 meshes, crosses 60 meshes and mix；
(3) mixed accessories in a (1), mixing are continuously added；
(4) (3) are mixed 20 minutes with auxiliary material remaining in (1)；
(5) it is eventually adding magnesium stearate to mix 5 minutes, sample detection content, using 4mm*8mm, tabletting, hardness 56N；
(6) it is packed using PVC and aluminium foil blister, built-in silica-gel desiccant, is cladded with compound membrane bag.
Compatibility experiments are carried out by the supplementary material to above-described embodiment.The biggish filler microcrystalline cellulose of dosage and cream
Sugar, in main ingredient: the mixing of auxiliary material=1:5 ratio, silica and magnesium stearate lubricant, by main ingredient: auxiliary material=20:1 ratio
Example mixing, by factors affecting stability test method, places 10 days, 30 days under conditions of strong light, high temperature, high humidity respectively, examines
Examine the variation that the related substance in placement front and back changes, while observing appearance character etc..Experimental result shows that degradation impurity B, F, K exist
Under the conditions of high temperature and humidity increase with time, this phenomenon and theoretically perindopril tert-butylamine it is damp and hot it is unstable be consistent, should exist
It is easy to moisture absorption under auxiliary material that high temperature and super-humid conditions is caused to generate degradation.And each auxiliary material mixing front and back, impurity, which has no, to be obviously increased, especially
To increase without apparent unknown impuritie, it can thus be assumed that supplementary material compatibility used in the present invention is good, in preparation production and
Storage should avoid the influence of high temperature and humidity.
1 supplementary material compatibility experiments of table
Embodiment 2: a kind of perindopril tablets, the perindopril tablets by following component by weight:
Alpha-crystal form perindopril tert-butylamine: 4 parts；
Lactose: 60 parts；
Microcrystalline cellulose: 25 parts；
Magnesium stearate: 1 part.
The piece finally made weighs about the tablet of 90mg, and preparation process includes the following steps:
(1) lactose and microcrystalline cellulose is taken to cross 50 meshes respectively, mixing is dry to be lower than 4.5% to moisture, is divided into 3 parts, control
Technical process humidity processed is lower than 40%RH；
(2) it takes portion to mix with the perindopril tert-butylamine Jing Guo 60 meshes, crosses 60 meshes and mix；
(3) mixed accessories in a (1), mixing are continuously added；
(4) (3) are mixed 20 minutes with auxiliary material remaining in (1)；
(5) it is eventually adding magnesium stearate to mix 5 minutes, sample detection content and uniformity of dosage units, using 4mm*8mm, pressure
Piece, hardness 50-60N；
(6) it is packed using PVC and aluminium foil blister, built-in silica-gel desiccant, is cladded with compound membrane bag.
3 batches are prepared in parallel using the formula of above-described embodiment, carry out quality versus.As a result, product prepared by the present invention
Consistent with commercialized product crystal form, the Key Qualities attribute such as character, related substance, dissolution rate, uniformity of dosage units, moisture, content is equal
Unanimously (table 2).
The quality versus of table 2 made products and commercialized product
Note: ND is to be not detected
Influence factor (40 DEG C of high temperature, illumination 5000lux/h, height are carried out simultaneously to above-described embodiment product and commercialized product
Wet RH75%) it places 10 days, 30 days and studies, character, the comparison in relation to substance, dissolution rate, content, crystal form.As a result made products
Character, dissolution rate, the content at each time point are consistent with commercialized product, and related substance change trend is better than commercialized product, crystal form
Variation is consistent with commercialized product, is shown in Table 3 and attached drawing 2 and Fig. 3.
The influence factor quality versus of 3 made products of table and commercialized product
Above-described embodiment product and commercialized product are carried out respectively under the conditions of influence factor and acceleration environment (40 DEG C/
RH75% placement January, 3) are carried out and carry out character, the comparison in relation to substance, dissolution rate, content, crystal form below the moon.As a result made products
Character, dissolution rate, the content at each time point are consistent with commercialized product, and the degradation rate in relation to substance is lower than commercialized product, brilliant
The change law of type is consistent with commercialized product.It is shown in Table 4 and attached drawing 4.
The Acceleration study quality versus of 4 made products of table and commercialized product
Claims (4)
1. a kind of stable alpha-crystal form perindopril tert-butylamine piece, which is characterized in that the perindopril tert-butylamine piece is by following
Component is by weight: perindopril tert-butylamine: 1-5 parts, lactose: and 60-80 parts, microcrystalline cellulose: 20-33 parts；Firmly
Fatty acid magnesium: 0.8-1.5 parts；The perindopril tert-butylamine is alpha-crystal form, and lactose is lactose monohydrate, and microcrystalline cellulose is
PH102；It is realized by following steps:
(1) it takes lactose and microcrystalline cellulose to cross -60 mesh of 30 mesh, is mixed into auxiliary material, it is dry to be lower than 5.0% to moisture, it is divided into 3 parts；
(2) it takes portion to mix with the perindopril tert-butylamine being sieved, crosses -60 mesh of 30 mesh, mix；
(3) auxiliary material in a step (1) is continuously added, is mixed；
(4) step (3) mixture is mixed with auxiliary material remaining in step (1)；
(5) magnesium stearate mixing, sample detection intermediates content, using 4mm*8mm tabletting are eventually adding；
(6) aluminium-plastic bubble plate packing is used, built-in desiccant is cladded with compound membrane bag；
The sieve mesh that wherein perindopril tert-butylamine is sieved in step (2) is -80 mesh of 50 mesh, the particle diameter distribution of perindopril tert-butylamine
It is 30-50um, D90 70-90um for MEAND；
The incorporation time of step (4) is -30 minutes 10 minutes, and preparation process ambient humidity is lower than 40%RH；
The incorporation time of step (5) is -10 minutes 1 minute, tabletting hardness are as follows: 40-70N.
2. a kind of stable alpha-crystal form perindopril tert-butylamine piece according to claim 1, which is characterized in that the training
Diindyl Puli's tert-butylamine piece by following component by weight: perindopril tert-butylamine: 4 parts；Lactose: 65 parts；Crystallite is fine
Dimension element: 20 parts；Magnesium stearate: 1 part；The perindopril tert-butylamine is alpha-crystal form, and lactose is lactose monohydrate, microcrystalline cellulose
For PH102.
3. a kind of stable alpha-crystal form perindopril tert-butylamine piece according to claim 1, which is characterized in that wherein prepare
The aluminium-plastic bubble plate packing of the step of method (6) is PVC+ aluminium foil.
4. a kind of stable alpha-crystal form perindopril tert-butylamine piece according to claim 1, which is characterized in that wherein prepare
Desiccant is silica gel or molecular sieve in the step of method (6).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510885002.8A CN105395497B (en) | 2015-12-04 | 2015-12-04 | A kind of stable alpha-crystal form perindopril tert-butylamine piece and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510885002.8A CN105395497B (en) | 2015-12-04 | 2015-12-04 | A kind of stable alpha-crystal form perindopril tert-butylamine piece and preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105395497A CN105395497A (en) | 2016-03-16 |
| CN105395497B true CN105395497B (en) | 2019-06-18 |
Family
ID=55461497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510885002.8A Active CN105395497B (en) | 2015-12-04 | 2015-12-04 | A kind of stable alpha-crystal form perindopril tert-butylamine piece and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105395497B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106620644B (en) * | 2016-12-13 | 2021-05-25 | 杭州新诺华医药有限公司 | Stable perindopril indapamide tablet and preparation process thereof |
| CN109700774A (en) * | 2019-03-05 | 2019-05-03 | 上药东英（江苏）药业有限公司 | A kind of perindopril tert-butylamine piece and its powder vertical compression technique |
| CN111419810B (en) * | 2020-04-29 | 2022-02-11 | 南京长澳医药科技有限公司 | High-stability perindopril tert-butylamine tablet and preparation method thereof |
| CN114917201B (en) * | 2022-06-14 | 2024-05-31 | 国药一心制药有限公司 | Troluridine pyrimidine tablet and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1440387A (en) * | 2000-07-06 | 2003-09-03 | 瑟维尔实验室 | Alpha crystalline form of perindopril tert-butyllamine salt |
| CN101766598A (en) * | 2008-12-31 | 2010-07-07 | 东英（江苏）药业有限公司 | Drug combination containing perindopril |
| CN103861080A (en) * | 2014-03-20 | 2014-06-18 | 东英（江苏）药业有限公司 | Efficient perindopril tablet and production process thereof |
| CN104177368A (en) * | 2014-05-27 | 2014-12-03 | 天津梅花医药有限公司 | Galanthamine hydrobromide compound as well as preparation method and medicine compositions thereof |
-
2015
- 2015-12-04 CN CN201510885002.8A patent/CN105395497B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1440387A (en) * | 2000-07-06 | 2003-09-03 | 瑟维尔实验室 | Alpha crystalline form of perindopril tert-butyllamine salt |
| CN101766598A (en) * | 2008-12-31 | 2010-07-07 | 东英（江苏）药业有限公司 | Drug combination containing perindopril |
| CN103861080A (en) * | 2014-03-20 | 2014-06-18 | 东英（江苏）药业有限公司 | Efficient perindopril tablet and production process thereof |
| CN104177368A (en) * | 2014-05-27 | 2014-12-03 | 天津梅花医药有限公司 | Galanthamine hydrobromide compound as well as preparation method and medicine compositions thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105395497A (en) | 2016-03-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105395497B (en) | A kind of stable alpha-crystal form perindopril tert-butylamine piece and preparation method | |
| TR201620462A2 (en) | PHARMACEUTICAL COMPOSITIONS CONTAINING POSACONAZOL AND PRODUCTION METHOD | |
| CN102764264A (en) | Celecoxib solid composition with high dissolution, preparation method and application | |
| CN105193752A (en) | Vildagliptin tablet and preparation method thereof | |
| CN102688206A (en) | Pitavastatin calcium tablet and preparation method thereof | |
| CN109718215A (en) | A kind of Ezetimibe piece | |
| CN107245054A (en) | A kind of amorphous bulleyaconitine A compound and preparation method thereof | |
| CN104055741B (en) | Montelukast sodium tablet and preparation method thereof | |
| CN107028912B (en) | A kind of preparation method of Irbesartan Capsules | |
| CN114272219B (en) | Donepezil hydrochloride Ji Pian and preparation method thereof | |
| CN104586800B (en) | A kind of direct tablet compressing technique of perindopril tablets and its powder | |
| EP4268821A1 (en) | Pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate compound, capsule, and preparation method therefor | |
| CN104173307A (en) | Preparation method of ezetimibe tablet | |
| CN110051639B (en) | Rapidly disintegrating nicergoline tablet and preparation method thereof | |
| CN107375938A (en) | A kind of adhesive of aminoglucose hydrochloride, tablet and preparation method thereof | |
| CN104739796B (en) | A kind of Oxiracetam tablet and preparation method thereof | |
| CN103127108A (en) | Telmisartan amlodipine tablet, and preparation method and use thereof | |
| CN106038523B (en) | A kind of potassium citrate sodium citrate piece and preparation method thereof | |
| CN107405342A (en) | A kind of solid composite medicament containing diamine derivative or its salt | |
| CN106620644A (en) | Stable perindopril indapamide tablet and preparation technology | |
| CN105435237B (en) | A kind of prasugrel hydrochloride pharmaceutical composition, tablet and preparation method thereof | |
| CN103284973A (en) | Adefovir dipivoxil composition and preparation method thereof | |
| CN111358795A (en) | Tofacitinib citrate preparation and preparation method thereof | |
| CN118903030A (en) | Preparation method of bemefibrate tablet | |
| CN106606485A (en) | Good taste levo S-oxiracetam particle and preparation method thereof |
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 | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20211209 Address after: 315700 No. 85, Binhai West Road, Daxie Development Zone, Ningbo, Zhejiang Patentee after: NINGBO MENOVO TIANKANG PHARMACEUTICAL Co.,Ltd. Address before: 310015 502-516, building C, No. 37, Xiangyuan Road, Gongshu District, Hangzhou City, Zhejiang Province Patentee before: HANGZHOU XINNUOHUA PHARMACEUTICAL Co.,Ltd. |