CN103570720B - A kind of meropenem bulk drug, its preparation method and comprise its pharmaceutical composition - Google Patents
A kind of meropenem bulk drug, its preparation method and comprise its pharmaceutical composition Download PDFInfo
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- CN103570720B CN103570720B CN201210276503.2A CN201210276503A CN103570720B CN 103570720 B CN103570720 B CN 103570720B CN 201210276503 A CN201210276503 A CN 201210276503A CN 103570720 B CN103570720 B CN 103570720B
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- DMJNNHOOLUXYBV-PQTSNVLCSA-N C[C@H]([C@H]([C@@H]([C@H]1C)N2C(C(O)=O)=C1S[C@@H](C1)CN[C@@H]1C(N(C)C)=O)C2=O)O Chemical compound C[C@H]([C@H]([C@@H]([C@H]1C)N2C(C(O)=O)=C1S[C@@H](C1)CN[C@@H]1C(N(C)C)=O)C2=O)O DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
Abstract
The invention discloses a kind of meropenem bulk drug, it is characterized in that, by weight percentage, in described bulk drug, the content of meropenem is 98.0% ~ 101.0%, calculates with anhydride; In the related substance of described bulk drug, impurity A, impurity B are all not more than 0.25%; The single impurity of any the unknown is not more than 0.05%; Except A and B, other impurity summation is not more than 0.25%; Acetone residue is not more than 300ppm.The invention also discloses a kind of meropenem pharmaceutical composition of injection, this pharmaceutical composition for activeconstituents, has good stability with meropenem bulk drug provided by the invention.Meropenem bulk drug purity provided by the invention is high, impurity situation is clear, solvent remain low, solvability good, extended storage stability good, can ensure medicine effectively, safety.<!--1-->
Description
Technical field
The invention belongs to pharmacy field, specifically, the present invention relates to a kind of meropenem bulk drug, its preparation method and comprise the pharmaceutical composition of this meropenem bulk drug.
Background technology
Meropenem (Meropenem), chemical name is (-)-(4R, 5S, 6S)-3-[(3S, 5S)-5-(dimethyl amine acyl group)-3-tetramethyleneimine] sulphur-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxygen-1-azabicyclo [3.2.0]-hept-2-ene"-2-carboxylic acid trihydrate, it is a kind of carbapenem antibiotic, there is broad spectrum antibacterial and can injection be supplied, be used for the treatment of multiple different infection, comprise meningitis and pneumonia, it is exist with the form of trihydrate under normal conditions, CAS registration number is [119478 ~ 56 ~ 7], concrete structure formula as shown in the formula (I).
Bulk drug English API (ActivePharmaceuticalIngredient) by name, referring to the material medicine for the production of all kinds of preparation, is the effective ingredient in preparation.Perfect in ICHQ7A of bulk drug is defined as: the mixture being intended to any one material or the material manufactured for medicine, and when for pharmacy, becomes a kind of activeconstituents of medicine.This kind of material has pharmacologically active or other direct effects in the prevention of the diagnosis of disease, treatment, remission, process or disease, or can affect function or the structure of body.
Chinese Pharmacopoeia version in 2010 two 606 pages of standards about meropenem (Meropenem), wherein related substance specifies: the maximum contaminant peak area of main peak front and rear all must not be greater than 0.6 times (0.3%) of contrast solution main peak area, other single impurity peak area must not be greater than 0.2 times (0.1%) of contrast solution main peak area, each impurity peak area and 2 times (1.0%) of contrast solution main peak area must not be greater than.Wherein residual solvent regulation: detect acetone, acetonitrile, methylene dichloride, ethyl acetate and tetrahydrofuran (THF) and conform with the regulations, specify in common residual solvent and limit in Chinese Pharmacopoeia version in 2010 two annex VIII P residual solvent assay method subordinate list 1 medicines: acetone detection limit is 0.5%(5000ppm); Acetonitrile is 0.041%(410ppm); Methylene dichloride is 0.06%(600ppm); The detection limit of ethyl acetate is 0.5%(5000ppm); The detection limit of THF is 0.072%(720ppm).
The process for purification of the meropenem of current open source literature report, as disclosed the preparation method of meropenem trihydrate crystal in US4888344 embodiment 1, it is soluble in water in 30 DEG C by meropenem crude product, water-bath cools, and separates out a small amount of crystal, adds acetone, stir one hour, filtration obtains crystal, and with washing with acetone, decompression drying at room temperature obtains meropenem trihydrate crystal in two hours.This process for purification yield is higher, but acetone residue is high, may can to reach in Chinese Pharmacopoeia version in 2010 two annex residual solvent assay methods acetone in regulation medicine and be no more than the detection limit of 0.5%.But have dissolvent residual and strict requirement in Meropenem trihydrate standard in American Pharmacopeia USP32-NF27, wherein acetone residue must not higher than 0.05%, and this process for purification is generally difficult to reach.And acetone belongs to easy system poison the 3rd class, the easily quick-fried class of system in public security organ's type of control, although acetone belongs to three kind solvents, acute or short-term research shows, these solvent toxicity are lower, genotoxicity result of study is negative, but there is no the long term toxicity of these solvents or the data of carinogenicity, and it has liver toxicity to human body, the injection that life-time service acetone residue is high is extremely unfavorable to the health of patient undoubtedly, as some cancer patients's urine sample acetone level can raise extremely.
US2009264643 discloses a kind of process for purification of Meropenem trihydrate, wherein relates to and successively adds ammoniacal liquor, formic acid adjust ph, then use the technique of tetrahydrofuran (THF) crystallization.This method is more loaded down with trivial details, and in Chinese Pharmacopoeia version in 2010 two annex residual solvent assay methods in regulation medicine the detection limit of THF be 0.072%, this process for purification is generally difficult to reach.And tetrahydrofuran (THF) belongs to two kind solvents, belong to without genotoxicity but have the solvent of animal carinogenicity, its Health hazard has: the symptoms such as dizziness, headache, uncomfortable in chest, pectoralgia, cough, weak, stomachache, dry, Nausea and vomiting can appear in high density after sucking, can with Eye irritation symptom, can hepatic insufficiency be there is in some patients., liver fatty infiltration and cytolysis can be there is in high dosage or repeatedly contact; Long Term Contact can cause losing sexual function, Fertility, or kidney diaseases.So should avoid using in the final step of technique, not so THF remains too high by the safety of serious threat meropenem injection.
CN201110218567.2 discloses a kind of preparation method of meropenem, and it comprises by meropenem dissolving crude product in 10% sodium hydroxide water, filtration, crystallization after activated carbon treatment, then adds ethyl acetate recovery meropenem.The method also needs point two steps to carry out, and yield is not high; And filtrate adds ethyl acetate recovery meropenem also by greatly increasing the usage quantity of ethyl acetate, is unfavorable for environmental protection, is also unfavorable for reducing costs.In addition the people such as YutakaTakeuchi in Chem.Pharm.Bull.43 (4) 689 ~ 692 (1995), describe meropenem more unstable than neutral environment under acid and alkaline condition, and document P690 shows the sodium bicarbonate of equivalent, the freeze-drying of the meropenem aqueous solution obtains meropenem sodium salt, 400mg meropenem sodium salt is dissolved in 1ml water and maintains 30 DEG C, monitor with HPLC, can find that after 6 hours, HPLC peak area ratio is: meropenem 47%, degraded product A11%, degraded product B38%, compare the sodium bicarbonate that alkalescence is more weak, 10% sodium hydroxide solution that pH is approximately 14.3 can make the degraded of meropenem more serious undoubtedly.The people such as YutakaTakeuchi also describe under acid (pH < 2) and alkalescence (pH > 13) environment in TheJournalofAntibioticsVol.46No.5P829, meropenem is hydrolyzed immediately, and main degradation products (referring to open-loop products A) generates.Therefore this by the method for meropenem dissolving crude product recrystallization in alkaline 10% sodium hydroxide water, not only the purification object of meropenem can not be realized and the impurity of meropenem can be increased.So embodiment claims that the meropenem obtained detects through Chinese Pharmacopoeia version in 2010 two meropenem related substances, single largest impurity 0.03%, total impurities 0.13%, its confidence level is doubtful, and contrast Chinese Pharmacopoeia version in 2010 two meropenem related substance examination criterias, it is not mentioned " maximum contaminant of main peak front and rear ", and content is how many, we cannot determine whether " single largest impurity " and " total impurities " comprise " maximum contaminant of main peak front and rear ", to such an extent as to clearly cannot know the situation of wherein meropenem impurity.
Impurity in meropenem or any active pharmaceutical ingredient (API) is unwanted, and in extreme circumstances, even may align the patient accepting to treat containing the formulation of API and be harmful to.Such as official website of state food Drug Administration office issues " Adverse reaction monitoring annual report in 2011 ", report display, and in pharmaceutical chemicals, classes of anti-infective all arranges first place in total untoward reaction report and serious adverse reaction report, and accounting is up to 51.2%.This and impurity, dissolvent residual control not tight, there is not clear impurity in some microbiotic, in prolonged storage, quality shakiness establishes a capital certain relation, so the meropenem raw material that a kind of foreign matter content is lower in the urgent need to providing, impurity situation is clear, dissolvent residual is lower, steady quality, untoward reaction are little and preparation compositions.
Summary of the invention
Through great many of experiments, the applicant surprisingly finds, through double crystallization, meropenem crude product can be obtained that purity is high, impurity situation is clear, solvent remains low, meropenem bulk drug safely and effectively.
Therefore, an object of the present invention is by carrying out assay to bulk drug effective constituent meropenem, carry out material to major impurity A and impurity B to determine and content analysis, residual solvent is strictly controlled, a kind of meropenem bulk drug is provided, this bulk drug is different from that the purity of prior art is high, impurity situation is clear, solvent remain low, extended storage stability good, quality control index can ensure, product effective and safe.
Another object of the present invention is to provide the preparation method of described meropenem bulk drug, and described method comprises the step being carried out refining meropenem crude product by double crystallization.
Another object of the present invention is to provide a kind of meropenem pharmaceutical composition, and this pharmaceutical composition for activeconstituents, has good stability with meropenem bulk drug provided by the invention.
The object of the invention is to be achieved through the following technical solutions.
On the one hand, the invention provides a kind of meropenem bulk drug, by weight percentage, in described bulk drug, the content of meropenem is 98.0% ~ 101.0%, calculates with anhydride; In described bulk drug meropenem related substance in impurity A, impurity B be not more than 0.25%; The single impurity of any the unknown is not more than 0.05%; Except A and B, other impurity summation is not more than 0.25%, and acetone residue is not more than 300ppm.
Wherein impurity A is:
Impurity B is:
On the other hand, the present invention also provides the preparation method of described meropenem bulk drug, and described method comprises the step being carried out refining meropenem crude product by double crystallization.
Wherein, the first time crystallization in described double crystallization comprises the following steps:
1) meropenem crude product is added to the water, stirs and make after suspension post-heating makes described meropenem dissolving crude product, then make the temperature of the solution obtained be down to 0 ~ 40 DEG C, preferably 10 ~ 30 DEG C;
2) in the solution obtained through step 1), add activated carbon decolorizing, then filter and obtain filtrate;
3) to through step 2) add organic solvent with crystallization in the filtrate that obtains, and stir growing the grain; With
4) filtration of the crystallizing system of step 3) is obtained crystal, then washing crystal is also dry, obtains first time refining meropenem.
It is pointed out that the meropenem crude product described in aforesaid method of the present invention refers to the compound with general formula (I):
This meropenem crude product is the not refining meropenem directly prepared by protection meropenem;
Can be prepared, as prepared the method for meropenem in CN1960992A or CN200610083362.7 by any method preparing meropenem in prior art.
In the subcrystalline step 1) of preparation method first of the present invention, by weight percentage, C in described meropenem crude product
17h
25n
3o
5the content of S is no less than 92%, calculates with anhydride; Impurity A, impurity B are all not more than 0.8%; The single impurity of any the unknown is not more than 0.3%; Except A and B, other impurity summation is not more than 3.0%;
Wherein said impurity A is:
Described impurity B is:
Preferably, in the subcrystalline step 1) of preparation method first of the present invention, by weight percentage, C in described meropenem crude product
17h
25n
3o
5the content of S is no less than 95%, calculates with anhydride; Impurity A, impurity B are all not more than 0.6%; The single impurity of any the unknown is not more than 0.3%; Except A and B, other impurity summation is not more than 2.0%;
Preferably, by weight, 3 ~ 50 times that the water used in described first subcrystalline step 1) is meropenem crude product, preferably 5 ~ 40 times, 10 ~ 20 times are more preferably.
Preferably, in described first subcrystalline step 1) suspension rapid heating to heat up with interchanger and makes it dissolve by (and hereafter second subcrystalline step 1) in).Temperature is not particularly limited herein, if can make solid dissolve completely all can, be generally 40 ~ 80 DEG C, preferably 45 ~ 55 DEG C.Described interchanger refers to the interchanger described in CN201120235961.2.
In described step 1), also can adopt and anyly can reach rapidly-soluble mode and dissolve meropenem crude product, adopt any mode that can reach fast cooling to be lowered the temperature by solution.
Preferably, described first subcrystalline step 2) comprise, in solution, add the gac of meropenem crude product weight 1 ~ 20%, decolour 1 ~ 30 minute, preferably 1 ~ 10 minute at 15 DEG C ~ 25 DEG C, then filter and obtain filtrate.Gac used is not particularly limited.
Preferably, the solvent miscible with water is with an organic solvent selected from described first subcrystalline step 3), one or more the mixed solvent in preferred acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, methyl-sulphoxide; Preferably, the volume ratio of described organic solvent and water is 2:1 ~ 8:1.
Preferably, the time of stirring growing the grain in described first subcrystalline step 3) is 0 ~ 24 hour, preferably 1 ~ 5 hour.
Preferably, organic solvent washing crystal is adopted in described first subcrystalline step 4); The solvent of washing crystal is selected from water, acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, methyl-sulphoxide etc. can one or more mixed solvent in the organic solvent miscible with water; Or being selected from ethyl acetate, propyl acetate, methylene dichloride etc. can not one or more mixed solvent in the organic solvent miscible with water.
Preferably, described second time crystallization comprises the following steps:
1) first time of acquisition refined meropenem to be added to the water, stir and make suspension post-heating to 35 ~ 95 DEG C, preferably after 50 ~ 80 DEG C, then be cooled to 0 ~ 30 DEG C, preferably 0 ~ 5 DEG C, then stir growing the grain; With
2) by step 2) crystallizing system filter and obtain crystal, then washing crystal dry, obtains meropenem bulk drug.
Preferably, by weight, in described second subcrystalline step 1) use water for first time 5 ~ 30 times of refining meropenem, preferably 10 ~ 20 times.
Preferably, the time of stirring growing the grain in described second subcrystalline step 1) is 5 minutes ~ 48 hours, preferably 10 minutes ~ 24 hours, more preferably 8 ~ 20 hours.
Preferably, described second subcrystalline step 2) middle employing organic solvent washing crystal; The solvent of washing crystal is selected from water, acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol etc. can one or more mixed solvent in the organic solvent miscible with water; Or being selected from ethyl acetate, propyl acetate, methylene dichloride etc. can not one or more mixed solvent in the organic solvent miscible with water.
Another aspect of the invention provides a kind of meropenem pharmaceutical composition, this pharmaceutical composition consist of meropenem bulk drug provided by the invention and pharmaceutically acceptable auxiliary material;
Preferably, described pharmaceutically acceptable auxiliary material is sterile sodium carbonate, and wherein the weight ratio of meropenem bulk drug and sterile sodium carbonate is 1000:195 ~ 1000:222, preferred 1000:208.Further preferably, described pharmaceutical composition is injection.
In described meropenem pharmaceutical composition, in described bulk drug, the content of meropenem is 98.0% ~ 101.0%, calculates with anhydride; In described bulk drug meropenem related substance in impurity A, impurity B be not more than 0.25%; The single impurity of any the unknown is not more than 0.05%; Except A and B, other impurity summation is not more than 0.25%, and acetone residue is not more than 300ppm.
The present invention also provides a kind of preparation method of meropenem pharmaceutical composition of injection, aseptic meropenem bulk drug, sterile sodium carbonate are pulverized, detection meets aseptic and granularity requirements, be 1000:195 ~ 1000:222 according to the weight ratio of meropenem bulk drug and sterile sodium carbonate, employing high efficient mixer mixes, and packaging vessel is carried out aseptically process, filling, it is qualified to detect according to method under American Pharmacopeia USP32-NF27 meropenem for injection item, packaging warehouse-in.
The meropenem pharmaceutical composition of injection provided by the invention, has better stability, and after standing storage, clarity and color still meet the requirements, and can ensure the safe, effective of medicine.
The words be not specifically noted, assay item, related substance item, residual solvent item in detection method, all carry out according to the method under meropenem (Meropenem) item in American Pharmacopeia USP32-NF27, i.e. meropenem bulk drug provided by the invention, in described bulk drug, the content of meropenem is 98.0% ~ 101.0%, calculates with anhydride; In described bulk drug related substance: wantonly one or two major impurity (impurity A and impurity B) must not be greater than 0.25%, calculates by anhydride; Other single impurity must not be greater than 0.05%, calculate by anhydride; Other impurity summations must not be greater than 0.25%.Acetone residue is not more than 300ppm (0.03%).In standard, wantonly one or two major impurity refers to impurity A and impurity B, and the relative retention time (being about 6min for benchmark with the retention time of meropenem) of impurity A and impurity B is about 0.5,2.2 respectively.
Wherein impurity A is:
Impurity B is:
Impurity A is the unit molecule ring-opening product (Mw:401) of meropenem, can be its isomer A
2:
Impurity B is the dimer (Mw:766) of a part meropenem and a part ring-opening product, also can be its isomer B
2:
Can quality control index to ensure the effective, most important safely of product, impurity in meropenem or any active pharmaceutical ingredient (API) and residual solvent are unnecessary, only have and impurity is clearly limited, the impurity research exceeding limit of identification is identified to the chemical structure of this impurity, could according to the character of impurity, work out limit of impurities targetedly, guarantee bulk drug and preparation safe, effective.In addition, the stability of bulk drug and preparation go wrong also be related to Drug safety, validity can not be guaranteed, so bulk drug and preparation have better stability be also safer, effectively ensure.
The present invention compared with prior art beneficial effect is:
1) meropenem bulk drug purity provided by the invention is high, impurity situation is clear, solvent remain low, solvability good, quality control index can ensure product effectively, safety.
2) meropenem bulk drug provided by the invention, has better stability, and after standing storage, clarity and color still meet pharmacopoeial requirements, causes the possibility of side effect less.
3) through double crystallization, meropenem crude product can be obtained that foreign matter content is low by the present invention, solvent remains low, high purity meropenem bulk drug safely and effectively, present invention process is simple, operation is succinct, is applicable to the meropenem production of raw medicine that industrial-scale is aseptic.
Accompanying drawing explanation
In order to understand essence of the present invention better, below in conjunction with accompanying drawing, by the description to better embodiment of the present invention, describing in detail but not limiting the present invention.Wherein:
Fig. 1 is the nuclear-magnetism carbon spectrum of impurity A;
Fig. 2 is the nucleus magnetic hydrogen spectrum of impurity A;
Fig. 3 is the infrared analysis collection of illustrative plates of impurity A;
Fig. 4 is the mass spectrum of impurity A;
Fig. 5 is the ultraviolet absorpting spectrum of impurity A;
Fig. 6 is the nucleus magnetic hydrogen spectrum of impurity B;
Fig. 7 is the infrared analysis collection of illustrative plates of impurity B;
Fig. 8 is the mass spectrum of impurity B;
Fig. 9 is the ultraviolet absorpting spectrum of impurity B.
Embodiment
The raw material used in following embodiment, reagent, solvent and other test materials, being can by commercially available.
Meropenem crude product can be prepared with reference to the method for embodiment 7, also can be prepared, as prepared the method for meropenem in CN1960992A or CN200610083362.7 by any method preparing meropenem in prior art.
By weight percentage, C in described meropenem crude product
17h
25n
3o
5the content of S is no less than 92%, calculates with anhydride; Impurity A, impurity B are all not more than 0.8%; The single impurity of any the unknown is not more than 0.3%; Except A and B, other impurity summation is not more than 3.0%.
Be not specifically noted, in detection method, assay item, related substance item, residual solvent Xiang Jun carry out according to the method under meropenem (Meropenem) item in American Pharmacopeia USP32-NF27.Study on the stability test is carried out according to American Pharmacopeia USP32-NF27 method.
Instrument: nucleus magnetic resonance (Varian300); Infrared spectra (NICOLET170SXFT ~ IR); Mass spectrum (API2000); UV spectrum (ThermoSpectronic300); LC-MS (Agilent1100HPLC-ABAPI2000 mass spectrum); Preparative liquid chromatography (Waters2535); Ultimate analysis: (German ELEMENTAR company varioEL elemental analyser).
embodiment 1
Meropenem crude product 12kg is joined in the water of 120kg, stirs and make suspension, feed liquid is warming up to 50 DEG C and makes it dissolve, then cool to 10 DEG C.
Add gac 100g to decolour, filter.
In filtrate, add recrystallisation solvent acetonitrile 480L, add rear stirring growing the grain 2 hours.
Filter, with acetonitrile wash crystal, drying, obtain first time refining meropenem 10.6kg.
The quality condition of refining meropenem for the first time: total impurities 0.75%; Organic solvent residual 0.23%.
embodiment 2
First time meropenem highly finished product 10kg embodiment 1 prepared joins in the water of 150kg, stirs, with interchanger, feed liquid is warming up to 50 DEG C, then cools to 0 DEG C, stirs growing the grain 15 hours.
Filtration, acetonitrile wash crystal, drying, obtain high-purity meropenem bulk drug 8.1kg.
Wherein the content of meropenem is that 99.6%(is in anhydride); In related substance, impurity A is 0.04%; Impurity B is 0.03%; The single impurity of any the unknown is 0.01%; Except A and B, other impurity summation is 0.02%; Acetone residue is 100ppm, and acetonitrile does not detect.
One, meropenem structure is determined:
Meropenem bulk drug physical properties measurement result is:
Ultimate analysis: C
17h
25n
3o
5s3H
2o
Calculated value: C, 46.67%; H, 7.14%; N, 9.60%; S, 7.33%;
Measured value: C, 46.46%; H, 7.29%; N, 9.70%; S, 7.27%.
UV
max H2Onm:296
IR
max KBrcm
-1:1755,1627,1393,1252,1130.
1h-NMR (D
2o, δ/ppm):: 1.21 (3H, d, J=7.1Hz), 1.29(3H, d, J=6.3Hz) 1.97 (1H, m), 2.99 (3H, s), 3.06 (3H, s), 3.09 (1H, m), 3.38 (1H, m), 3.46 (2H, m), 3.77 (1H, dd, J=11.9 and 6.2Hz), 4.05 (1H, m), 4.23 (2H, m), 4.82 (1H).
Conclusion: determination of physical appearance result and meropenem structure are coincide.
Two, impurity research process
1, initial gross separation qualification:
First LC-MS system is utilized to carry out separation and mass spectroscopy to each impurity, with reference to the moving phase under meropenem (Meropenem) item in American Pharmacopeia USP32-NF27, acetic acid is adopted to replace phosphoric acid to prepare moving phase, the two collection of illustrative plates is very consistent, obtain the molecular weight of each impurity, tentatively determine structure; According to chromatograms, the relative retention time (being about 6min for benchmark with the retention time of meropenem) of impurity A and impurity B is respectively 0.5 and 2.2.
2, the liquid phase preparation of impurity:
Verify further to obtain comparatively Multi-example, with reference to the moving phase condition in initial gross separation qualification, utilize preparative liquid chromatography, removing foreign matter A, B, repeated multiple times preparation, obtain the salts solution of all impurity, impurity level reaches milligram level.
3, the chemosynthesis of impurity:
According to the character of impurity, chemosynthesis is carried out to impurity A and B, has obtained 1g impurity A, purity >95%; Impurity B about 50 milligrams, purity >90%.
1) synthesis of impurity A:
Prepare impurity A according to method described in TheJournalofAntibioticsVol.46No.5P831 ~ P832, be impurity A through structural confirmation, and conform to document.
2) synthesis of impurity B:
Prepare impurity B according to Chem.Pharm.Bull.43 (4) P690 (1995) described method, be impurity B through structural confirmation, and conform to document.
4, synthesize impurity A, B and product liquid phase separation impurity A, B to contrast:
Utilize synthesis to obtain impurity A, B and product liquid phase separation impurity A, B to contrast, first compare uv-spectrogram, result shows to correspond respectively to A, B impurity; In order to further checking, adopt application of sample method, the impurity A obtain our chemosynthesis and B are qualitative respectively to add in the meropenem bulk drug of testing and obtaining, according to the situation that impurity peak area corresponding in gained chromatograms increases, further A, B impurity judging that the impurity A in our product and B and synthesis obtain is completely the same.
5, impurity A, B structural confirmation
1) impurity A determination of physical appearance result is:
UV(λ
max H2O)：～275nm.
IR(KBr,cm
-1)：3438.8,2889.2,2599.9,1750.5,1654.8,1595.0,1386.7,1336.6,1155.3,781.1.
MS(m/z)：401.9(M+1)，802.6(2×M+1).
1H-NMR(D
2O,δ/ppm)：1.26(t,J=7.2,~1.5H,CH
3-CH-OH,A);1.33(t,J=6.9,3H,1-β-CH
3,A+A2);1.49(d,J=6.6,~1.5H,CH
3-CH-OH,A2);1.85～2.15(m,CH-CH
2-CH,A2);2.3～2.41(m,CH
3-CH-CH,A2);2.6～2.7(m,S-CH-CH
2,A2);2.8～3.1(m,N-CH
2-CH,CH-CH-NH,A2);3.03(s,3H,N-CH
3,A+A2);3.1(s,3H,N-CH
3,A+A2);3.35-3.45(m,CH-CH
2-CH,A);3.65～3.78(m,CH
3-CH-CH,A);3.8～4.0(m,N-CH
2-CH,A,CH
2-CH-NH,A+A2);4.1～4.3(m,CH-CH-COOH,A+A2);4.3～4.36(dd,CH-CH-NH,A);4.47～4.6(m,CH
3-CH-OH,A+A2).
13C-NMR(D
2O,δ/ppm)：12.88,15.55,17.25,18.21,22.3,23.0,23.74,37.76,38.94,39.77,41.74,44.21,45.11,45.6,46.05,49.36,52.0,54.16,54.62,55.15,57.37,60.23,61.02,62.57,67.0,71.73,93.9,100.48,124.56,170.43,172.84,174.25,177.39,180.82,182.1.
Conclusion: determination of physical appearance result and impurity A structure are coincide, and relevant spectrogram is shown in Fig. 1-5.
2) impurity B determination of physical appearance result is:
UV(λ
max H2O)：297nm。
IR(KBr,cm
-1)：3398.3,2966.3,2871.8,1751.2,1627.8,1396.4,1263.3,1145.6,781.1。
MS(m/z)：767(M+1)。
1H-NMRδ/ppm(D
2O)：1.03(d,J=7.2Hz,3H,CH
3-CH);1.23(d,J=12.3Hz,3H,CH
3-CH);1.26(d,J=7.5Hz,3H,CH
3-CH);1.31(d,J=6.3Hz,3H,CH
3-CH);1.68～1.82(m,2H,CH-CH
2-CH);2.6～3.0(m,3H,CH-CH-CH);2.95(s,6H,N-CH
3);3.04(s,3H,N-CH
3);3.18(s,3H,N-CH
3);3.05～3.3(m,2H,S-CH-CH
2);3.44(d,1H,S-CH-CH);3.48～3.8(m,3H,CH
2,CH-CH-CH);3.9～4.5(m,8H,HO-CH-CH
3,CH2);4.7～4.85(m,1H,CO-CH-N);5.05(m,1H,CO-CH-N)。
13C-NMRδ/ppm(D
2O)：176.9,173.9,173.6,173.3,169.4,168.2,140.4,132.3,115.5,74.7,73.7,69.7,65.9,59.2,58.4,58.1,57.7,56.7,52.8,51.6,50.7,45.3,43.4,40.4,38.0,37.9,37.5,36.8,34.8,34.4,20.9,16.9,15.6,11.0。
Conclusion: determination of physical appearance result and impurity B structure are coincide, and relevant spectrogram is shown in Fig. 6-9.
embodiment 3
Meropenem crude product 12kg is joined in the water of 180kg, stirs and make suspension, feed liquid is warming up to 80 DEG C and makes it dissolve, then cool to 20 DEG C.
Add gac 240g to decolour, filter.
In filtrate, add recrystallisation solvent acetone 360L, add rear continuation and stir growing the grain 3 hours.
Filter, with washing with acetone crystal, drying, obtain first time refining meropenem 10.44kg.
The quality condition of refining meropenem for the first time: total impurities 0.62%; Organic solvent residual 0.25%.
embodiment 4
First time meropenem highly finished product 10kg embodiment 3 prepared joins in the water of 100kg, stirs, with interchanger, feed liquid is warming up to 60 DEG C, then cools to 2 DEG C, stirs growing the grain 20 hours.
Filtration, washing with acetone crystal, drying, obtain high-purity meropenem bulk drug 8.3kg.
Wherein the content of meropenem is that 99.8%(is in anhydride); In related substance, impurity A is 0.05%; Impurity B is 0.04%; The single impurity of any the unknown is 0.01%; Except A and B, other impurity summation is 0.01%; Acetone residue is 200ppm.
Products obtained therefrom determination of physical appearance result and meropenem structure are coincide.
Impurity A, B are according to methods analyst, mensuration described in embodiment 2, and result meets.
embodiment 5
Meropenem crude product 12kg is joined in 240kg water, stirs and make suspension, feed liquid is warming up to 70 DEG C and makes it dissolve, then cool to 30 DEG C.
Add gac 120g to decolour, filter.
In filtrate, add recrystallisation solvent tetrahydrofuran (THF) 1920L, add rear continuation and stir growing the grain 2 hours.
Filter, with tetrahydrofuran (THF) washing crystal, drying, obtain first time refining meropenem 10.7kg.
The quality condition of refining meropenem for the first time: total impurities 0.67%; Organic solvent residual 0.27%.
embodiment 6
First time meropenem highly finished product 10kg embodiment 5 prepared joins in the water of 200kg, stirs, with interchanger, feed liquid is warming up to 60 DEG C, then cools to 5 DEG C, stirs growing the grain 8 hours.
Filtration, washing with acetone crystal, drying, obtain high-purity meropenem bulk drug 8.0kg.
Wherein the content of meropenem is that 99.8%(is in anhydride); In related substance, impurity A is 0.03%; Impurity B is 0.02%; The single impurity of any the unknown is 0.01%; Except A and B, other impurity summation is 0.01%; Acetone residue is 120ppm, and tetrahydrofuran (THF) does not detect.
Products obtained therefrom determination of physical appearance result and meropenem structure are coincide.
Impurity A, B are according to methods analyst, mensuration described in embodiment 2, and result meets.
embodiment 7
The preparation of meropenem (Compound I) crude product
Meropenem (I will be protected
a) 33.0kg(or protection meropenem HLPC content is the concentrated solution of 33.0kg), THF880L, water 700L, 3,5,-lutidine 14.5kg, 10% palladium carbon 5.28kg join in the autoclave of 2000L in the lump, removing air, pass into hydrogen, room temperature reaction 6 hours, reaction is finished, and filtration washing Recover palladium carbon, adds 2625L tetrahydrofuran (THF) in filtrated stock, control temperature 10-15 DEG C is stirred 30min, filter, washing, product drying, obtain meropenem (Compound I) crude product 19.5kg, mass yield 59%; Wherein the content of meropenem is 97.8%; In related substance, impurity A is 0.20%; Impurity B is 0.40%; The single impurity of any the unknown is 0.13%; Except A and B, other impurity summation is 1.2%.
Tetrahydrofuran (THF) wherein in 2625L tetrahydrofuran (THF) can change into acetone, Virahol, methyl alcohol, ethanol, methyl ethyl ketone one or more, also can prepare up-to-standard meropenem crude product.
embodiment 8
The aseptic meropenem bulk drug of 1kg prepared according to method described in embodiment 2,208g sterile sodium carbonate are pulverized, detection meets aseptic and granularity requirements, employing high efficient mixer mixes, packaging vessel is carried out aseptically process, filling, it is qualified to detect according to method under American Pharmacopeia USP32-NF27 meropenem for injection item, packaging warehouse-in.
embodiment 9
The aseptic meropenem bulk drug of 1kg prepared according to method described in embodiment 4,222g sterile sodium carbonate are pulverized, detection meets aseptic and granularity requirements, employing high efficient mixer mixes, packaging vessel is carried out aseptically process, filling, it is qualified to detect according to method under American Pharmacopeia USP32-NF27 meropenem for injection item, packaging warehouse-in.
embodiment 10
The aseptic meropenem bulk drug of 1kg prepared according to method described in embodiment 6,195g sterile sodium carbonate are pulverized, detection meets aseptic and granularity requirements, employing high efficient mixer mixes, packaging vessel is carried out aseptically process, filling, it is qualified to detect according to method under American Pharmacopeia USP32-NF27 meropenem for injection item, packaging warehouse-in.
comparative example 1
Be dissolved in 50ml water by 5g meropenem crude product in 30 DEG C, water-bath cools, and separates out a small amount of crystal, add 250ml acetone, stir one hour, filter and obtain crystal, use 90ml washing with acetone, decompression drying at room temperature obtains about 4.7g meropenem trihydrate crystal in two hours.
Wherein the content of meropenem is 98.4%; In related substance, impurity A is 0.19%; Impurity B is 0.27%; The single impurity of any the unknown is 0.10%; Except A and B, other impurity summation is 0.26%; Acetone residue is 599ppm.
The weight ratio preparing its meropenem bulk drug and sodium carbonate according to method described in embodiment 8 is the pharmaceutical composition of 1000:208.
stability test
The beneficial effect of bulk drug provided by the present invention and preparation is described below by study on the stability result.
1. meropenem bulk drug accelerated test study on the stability
Packaging: Aluminum Drum; Storage condition: temperature 40 ° of C ± 2 ° C, humidity 75%RH ± 5%RH
Meropenem bulk drug 1 ~ 6 month accelerated test study on the stability the results are shown in Table 1.
Table 1. meropenem bulk drug accelerated test stability result
From result, in comparative example 1, foreign matter content is high, the meropenem bulk drug that acetone residue is high is placed 6 months under temperature 40 ° of C ± 2 ° C, humidity 75%RH ± 5%RH accelerated test condition, related substance, solution colour are all undesirable, stability test is defective, cannot ensure the drug safety after long-term storage; And bulk drug provided by the invention, be packaged in impurity under accelerated test condition with listing, solution colour still conforms with the regulations, stability is fine, can ensure product effectively, safety, so it is higher for Safety of intravenous medication to prepare injection as bulk drug, better efficacy.
Other detections of meropenem bulk drug provided by the invention, as specific optical rotation, acidity, clarity, bacterial endotoxin, aseptic, moisture, visible foreign matters, particulate matter, organic residue, residue on ignition, heavy metal, crystal water, also meet the requirements without accelerated test stability result such as water-contents.
2. meropenem bulk drug test of long duration study on the stability
Packaging: Aluminum Drum; Storage condition: temperature 25 ° of C ± 2 ° C, humidity 60%RH ± 5%RH
Meropenem bulk drug 1 ~ 24 month test of long duration study on the stability the results are shown in Table 2.
Table 2. meropenem bulk drug test of long duration stability result
From result, place 24 months under being packaged in temperature 25 ° of C ± 2 ° C, humidity 60%RH ± 5%RH test of long duration condition with listing, impurity still conforms with the regulations, and stability is fine, so it is higher for Safety of intravenous medication to prepare injection as bulk drug, better efficacy.
Other detections of meropenem bulk drug provided by the invention, as specific optical rotation, acidity, clarity, color, bacterial endotoxin, aseptic, moisture, visible foreign matters, particulate matter, organic residue, residue on ignition, heavy metal, crystal water, also meet the requirements without water-content isometric phase test stability result.
3. meropenem for injection pharmaceutical composition test of long duration study on the stability
Storage condition: temperature 25 ° of C ± 2 ° C, humidity 60%RH ± 5%RH
Meropenem for injection pharmaceutical composition 1 ~ 36 month test of long duration study on the stability the results are shown in Table 3.
Table 3. meropenem for injection pharmaceutical composition test of long duration stability result
From result, in comparative example 1, foreign matter content is high, composition prepared by the meropenem bulk drug that acetone residue is high is placed 24 months and 36 months under temperature 25 ° of C ± 2 ° C, humidity 60%RH ± 5%RH test of long duration condition, solution colour is undesirable, stability test is defective, cannot ensure the drug safety after long-term storage; And meropenem for injection pharmaceutical composition provided by the invention solution colour under test of long duration condition still conforms with the regulations, stability is fine, is used for Safety of intravenous medication higher, better efficacy as injection.
Other detections of meropenem for injection pharmaceutical composition provided by the invention, as the test of long duration stability result such as proterties, discriminating, basicity, clarity, related substance, weight loss on drying, uniformity of dosage units, bacterial endotoxin, aseptic, visible foreign matters, particulate matter, assay also meets the requirements, thus can ensure product effectively, safety.
Claims (15)
1. a preparation method for meropenem bulk drug, described preparation method comprises the step being carried out refining meropenem crude product by double crystallization;
First time crystallization in wherein said double crystallization comprises the following steps:
1) meropenem crude product is added to the water, wherein by weight, described water is 3 ~ 50 times of meropenem crude product, and then stirring is made suspension post-heating to 40 ~ 80 DEG C and made described meropenem dissolving crude product, then makes the temperature of the solution obtained be down to 0 ~ 40 DEG C;
2) to through step 1) add the gac of meropenem crude product weight 1 ~ 20% in the solution that obtains, decolour 1 ~ 30 minute at 15 DEG C ~ 25 DEG C, then filter and obtain filtrate;
3) to through step 2) add organic solvent with crystallization in the filtrate that obtains, wherein said organic solvent is selected from the solvent miscible with water, is 2:1 ~ 8:1 with the volume ratio of filtrate, then stirs growing the grain 0 ~ 24 hour; With
4) by step 3) crystallizing system filter and obtain crystal, then adopt organic solvent washing crystal and dry, obtain first time refining meropenem;
Second time crystallization in described double crystallization comprises the following steps:
1) first time of acquisition is refined meropenem to be added to the water, by weight, described water is 5 ~ 30 times that first time refine meropenem, stirs and makes suspension post-heating to 35 ~ 95 DEG C, be cooled to 0 ~ 30 DEG C again, then stir growing the grain 5 minutes ~ 48 hours; With
2) by step 1) crystallizing system filter and obtain crystal, then adopt organic solvent washing crystal and dry, obtain meropenem bulk drug.
2. preparation method according to claim 1, is characterized in that, described first subcrystalline step 1) in, by weight percentage, C in described meropenem crude product
17h
25n
3o
5the content of S is no less than 92%, calculates with anhydride; Impurity A, impurity B are all not more than 0.8%; The single impurity of any the unknown is not more than 0.3%; Except A and B, other impurity summation is not more than 3.0%;
Wherein said impurity A is:
Described impurity B is:
3. preparation method according to claim 1 and 2, is characterized in that, by weight percentage, and C in described meropenem crude product
17h
25n
3o
5the content of S is no less than 95%, calculates with anhydride; Impurity A, impurity B are all not more than 0.6%; The single impurity of any the unknown is not more than 0.3%; Except A and B, other impurity summation is not more than 2.0%.
4. preparation method according to claim 1, is characterized in that, by weight, described first subcrystalline step 1) described in water be 5 ~ 40 times of meropenem crude product.
5. the preparation method according to claim 1 or 4, is characterized in that, by weight, described first subcrystalline step 1) described in water be 10 ~ 20 times of meropenem crude product.
6. preparation method according to claim 1, is characterized in that, described first subcrystalline step 1) at the temperature of 45 ~ 55 DEG C, make described meropenem dissolving crude product.
7. preparation method according to claim 1, is characterized in that, described first subcrystalline step 1) in make the temperature of the solution obtained be down to 10 ~ 30 DEG C.
8. preparation method according to claim 1, is characterized in that, described first subcrystalline step 2) at 15 DEG C ~ 25 DEG C decolour 1 ~ 10 minute.
9. preparation method according to claim 1, is characterized in that, described first subcrystalline step 3) described in organic solvent be selected from acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol and methyl-sulphoxide one or more.
10. preparation method according to claim 1, is characterized in that, described first subcrystalline step 3) in stir time of growing the grain be 1 ~ 5 hour.
11. preparation methods according to claim 1, it is characterized in that, described first subcrystalline step 4) described in organic solvent be selected from acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, methyl-sulphoxide, ethyl acetate, propyl acetate and methylene dichloride one or more.
12. preparation methods according to claim 1, is characterized in that, by weight, described second subcrystalline step 1) described in water be first time 10 ~ 20 times of refining meropenem.
13. preparation methods according to claim 1, is characterized in that, second subcrystalline step 1) in stir time of growing the grain be 10 minutes ~ 24 hours.
14. preparation methods according to claim 1 or 13, it is characterized in that, the time of described stirring growing the grain is 8 ~ 20 hours.
15. preparation methods according to claim 1, it is characterized in that, described second subcrystalline step 2) described in organic solvent be selected from acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, methyl-sulphoxide, ethyl acetate, propyl acetate and methylene dichloride one or more.
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| EP0256377B1 (en) * | 1986-07-30 | 1992-09-30 | Sumitomo Pharmaceuticals Company, Limited | Carbapenem compound in crystalline form, and its production and use |
| CN101914098A (en) * | 2010-07-20 | 2010-12-15 | 深圳市海滨制药有限公司 | Preparation method of Meropenem trihydrate crystals |
| CN101921276A (en) * | 2010-09-07 | 2010-12-22 | 江苏天禾迪赛诺制药有限公司 | Crystallization refining method of Meropenem |
| CN102336757A (en) * | 2011-08-02 | 2012-02-01 | 天津市嵩锐医药科技有限公司 | Meropenem compound in stable crystal form |
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| EP0256377B1 (en) * | 1986-07-30 | 1992-09-30 | Sumitomo Pharmaceuticals Company, Limited | Carbapenem compound in crystalline form, and its production and use |
| CN101914098A (en) * | 2010-07-20 | 2010-12-15 | 深圳市海滨制药有限公司 | Preparation method of Meropenem trihydrate crystals |
| CN101921276A (en) * | 2010-09-07 | 2010-12-22 | 江苏天禾迪赛诺制药有限公司 | Crystallization refining method of Meropenem |
| CN102336757A (en) * | 2011-08-02 | 2012-02-01 | 天津市嵩锐医药科技有限公司 | Meropenem compound in stable crystal form |
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