CN103570720A - Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same - Google Patents

Meropenem raw medicine, preparation method thereof and pharmaceutical composition containing same Download PDF

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CN103570720A
CN103570720A CN201210276503.2A CN201210276503A CN103570720A CN 103570720 A CN103570720 A CN 103570720A CN 201210276503 A CN201210276503 A CN 201210276503A CN 103570720 A CN103570720 A CN 103570720A
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meropenem
impurity
preparation
subcrystalline
bulk drug
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CN103570720B (en
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任鹏
赵鹏
孙万鹏
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XINXIANG HAIBIN PHARMACEUTICAL CO Ltd
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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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    • 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
    • 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

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Abstract

The invention discloses a meropenem raw medicine which is characterized in that the content of meropenem in the raw medicine is 98.0-101.0% by weight based on anhydride; the content of the impurity A and impurity B in the related substances of the raw medicine is not greater than 0.25% respectively; the content of any unknown single impurity is not greater than 0.05%; the total content of other impurities except the A and B is not greater than 0.25%; the acetone residue is not greater than 300ppm. The invention also discloses a meropenem pharmaceutical composition for injection, and the pharmaceutical composition takes the meropenem raw medicine provided by the invention as an active ingredient and has excellent stability. The meropenem raw medicine provided by the invention has the advantages of high purity, clear impurity condition, low solvent residue, good solubility and good long-term storage stability, and can guarantee the effectiveness and safety of the medicine.

Description

A kind of meropenem bulk drug, its preparation method and the pharmaceutical composition that comprises it
Technical field
The invention belongs to pharmacy field, particularly, the pharmaceutical composition that the present invention relates to a kind of meropenem bulk drug, its preparation method and comprise 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 supply injection; be used for the treatment of multiple different infection; comprise meningitis and pneumonia; it is that form with trihydrate exists under normal conditions, and CAS registration number is [119478～56～7], and concrete structure formula as shown in the formula (I).
Figure BDA0000196349501
The English API (Active Pharmaceutical Ingredient) by name of bulk drug, refers to the material medicine for the production of all kinds of preparations, is the effective ingredient in preparation.Perfect be defined as of bulk drug in ICH Q7A: be intended to for any material of medicine manufacture or the mixture of material, and when for pharmacy, become a kind of activeconstituents of medicine.This kind of material has pharmacologically active or other direct effects in the prevention of diagnosis, treatment, remission, processing or the disease of disease, or can affect function or the structure of body.
Two 606 pages of standards about meropenem (Meropenem) of Chinese Pharmacopoeia version in 2010, wherein related substance is stipulated: 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, 2 times (1.0%) each impurity peak area and that must not be greater than contrast solution main peak area.Residual solvent regulation wherein: detect acetone, acetonitrile, methylene dichloride, ethyl acetate and tetrahydrofuran (THF) up to specification, stipulate in common residual solvent and limit in two appendix VIII P residual solvent assay method subordinate list 1 medicines of Chinese Pharmacopoeia version in 2010: 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 that open source literature is reported at present, as disclosed the preparation method of Meropenem trihydrate crystal in US4888344 embodiment 1, it is soluble in water in 30 ℃ by meropenem crude product, water-bath is cooling, 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 for two hours.This process for purification yield is higher, but the residual height of acetone, may be able to reach in two appendix residual solvent assay methods of Chinese Pharmacopoeia version in 2010 acetone in regulation medicine and be no more than 0.5% detection limit.But in American Pharmacopeia USP32-NF27, in Meropenem trihydrate standard, dissolvent residual is had and strict requirement, wherein acetone is residual must not be higher than 0.05%, and this process for purification is generally difficult to reach.And acetone belongs to easy system poison the 3rd class in public security organ's type of control, easily makes quick-fried class, 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 residual high injection of life-time service acetone is extremely unfavorable to patient's health 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, first acid for adjusting pH value, then uses the technique of tetrahydrofuran (THF) crystallization.This method is more loaded down with trivial details, and in two appendix residual solvent assay methods of Chinese Pharmacopoeia version in 2010 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: after high density sucks, can occur dizziness, headache, uncomfortable in chest, pectoralgia, cough, weak, stomachache, dry, feel sick, the symptom such as vomiting, can be with eye irritation, can there is hepatic insufficiency in some patients were., can there is liver fatty infiltration and cytolysis in high dosage or repeatedly contact; Long Term Contact can cause losing sexual function, Fertility, or kidney disease.So should avoid using in the final step of technique, not so THF is residual too high by the safety of serious threat meropenem injection.
CN201110218567.2 discloses a kind of preparation method of meropenem, and it comprises meropenem dissolving crude product in 10% sodium hydroxide water, filtration, crystallization after activated carbon treatment, then add ethyl acetate recovery meropenem.The method also needs minute two steps to carry out, and yield is not high; And filtrate adds ethyl acetate and reclaims meropenem also by greatly increasing the usage quantity of ethyl acetate, be unfavorable for environmental protection, be also unfavorable for reducing costs.In addition the people such as Yutaka Takeuchi in Chem. Pharm. Bull.43 (4) 689～692 (1995), to have recorded 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 ℃, with HPLC, monitor, can find that after 6 hours, HPLC peak area ratio is: meropenem 47%, degraded product A 11%, degraded product B 38%, compare the weak sodium bicarbonate of alkalescence, pH is approximately 14.3 10% sodium hydroxide solution can make the degraded of meropenem more serious undoubtedly.The people such as Yutaka Takeuchi have also recorded under acid (pH < 2) and alkalescence (pH > 13) environment in The Journal of Antibiotics Vol.46 No.5 P829, 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 is claimed the meropenem obtaining and is detected through two meropenem related substances of Chinese Pharmacopoeia version in 2010, single largest impurity 0.03%, total impurities 0.13%, its confidence level is worth suspecting, and two meropenem related substance examination criterias of contrast Chinese Pharmacopoeia version in 2010, it does not mention that " maximum contaminant of main peak front and rear " 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 cannot clearly know the wherein situation of meropenem impurity.
Impurity in meropenem or any active pharmaceutical ingredient (API) is unwanted, and under extreme case, even may align the patient who accepts to treat containing the formulation of API and be harmful to.For example official website of state food Drug Administration office issue < < adverse drug reaction in 2011 is monitored annual report > >, report shows, in pharmaceutical chemicals, all row is the first in total untoward reaction report and serious adverse reaction report for classes of anti-infective, and accounting is up to 51.2%.This and impurity, dissolvent residual are controlled not tight, there is not clear impurity in some microbiotic, in standing storage process, quality shakiness is established a capital certain relation, so in the urgent need to providing, a kind of foreign matter content is lower, impurity situation is clear, dissolvent residual is lower, steady quality, little meropenem raw material and the preparation compositions of untoward reaction.
Summary of the invention
Through great many of experiments, the applicant finds pleasantly surprisedly, by meropenem crude product through double crystallization can obtain that purity is high, impurity situation is clear, residual low, the meropenem bulk drug safely and effectively of solvent.
Therefore, an object of the present invention is by bulk drug effective constituent meropenem is carried out to assay, major impurity A and impurity B are carried out to material to be determined and content analysis, residual solvent is strictly controlled, a kind of meropenem bulk drug is provided, purity that this bulk drug is different from prior art is high, impurity situation is clear, solvent residual low, extended storage stability good, quality control index can guarantee, 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 of refining meropenem crude product by double crystallization.
A further object of the present invention is to provide a kind of meropenem pharmaceutical composition, and it is activeconstituents that this pharmaceutical composition be take meropenem bulk drug provided by the invention, has good stability.
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%, with anhydride, calculates; In described bulk drug, in the related substance of meropenem, impurity A, impurity B are 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%, the residual 300ppm that is not more than of acetone.
Wherein impurity A is:
Figure BDA0000196349502
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 of refining meropenem crude product by double crystallization.
Wherein, the crystallization for the first time in described double crystallization comprises the following steps:
1) meropenem crude product is added to the water, stirs and to make suspension post-heating and makes after described meropenem dissolving crude product, then make the temperature of the solution that obtains be down to 0 ~ 40 ℃, preferably 10 ~ 30 ℃;
2) in the solution obtaining 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) crystallizing system of step 3) is filtered and obtains crystal, then washing crystal dry, obtains refining meropenem for the first time.
It is pointed out that the meropenem crude product described in aforesaid method of the present invention refers to the have general formula compound of (I):
The not refining meropenem of this meropenem crude product for directly being prepared by protection meropenem;
Can prepare by preparing any method of meropenem in prior art, as prepared the method for meropenem in CN1960992A or CN200610083362.7.
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%, with anhydride, calculates; 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:
Figure BDA0000196349505
Described impurity B is:
Figure BDA0000196349506
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%, with anhydride, calculates; 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, the water using in described first subcrystalline step 1) is meropenem crude product 3 ~ 50 times, preferably 5 ~ 40 times, more preferably 10 ~ 20 times.
Preferably, in described first subcrystalline step 1) (and below second subcrystalline step 1) in) heats up suspension rapid heating to make its dissolving with interchanger.Temperature is not particularly limited herein, if can make solid dissolve completely all can, be generally 40 ~ 80 ℃, preferably 45 ~ 55 ℃.Described interchanger refers to the interchanger described in CN201120235961.2.
In described step 1), also can adopt anyly can reach rapidly-soluble mode and dissolve meropenem crude product, adopt any mode that can reach fast cooling that solution is lowered the temperature.
Preferably, described first subcrystalline step 2) comprise, the gac to adding meropenem crude product weight 1～20% in solution decolours 1～30 minute, preferably 1～10 minute at 15 ℃～25 ℃, then filters and obtains filtrate.Gac used is not particularly limited.
Preferably, in described first subcrystalline step 3), be with an organic solvent selected from the solvent miscible with water, preferably the mixed solvent of one or more in 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, in described first subcrystalline step 4), adopt organic solvent washing crystal; The solvent of washing crystal is selected from one or more the mixed solvent in can the organic solvent miscible with water such as water, acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, methyl-sulphoxide; Or be selected from one or more the mixed solvent in can not the organic solvent miscible with water such as ethyl acetate, propyl acetate, methylene dichloride.
Preferably, described crystallization for the second time comprises the following steps:
1) the refining meropenem for the first time obtaining is added to the water, stirs and make suspension post-heating to 35 ~ 95 ℃, preferably after 50 ~ 80 ℃, then be cooled to 0 ~ 30 ℃, preferably 0 ~ 5 ℃, then stir growing the grain; With
2) by step 2) crystallizing system filter and to obtain crystal, then washing crystal dry, obtains meropenem bulk drug.
Preferably, by weight, in described second subcrystalline step 1), the water that makes is to refine for the first time 5 ~ 30 times of 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, and more preferably 8 ~ 20 hours.
Preferably, described second subcrystalline step 2), adopt organic solvent washing crystal; The solvent of washing crystal is selected from one or more the mixed solvent in can the organic solvent miscible with water such as water, acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol; Or be selected from one or more the mixed solvent in can not the organic solvent miscible with water such as ethyl acetate, propyl acetate, methylene dichloride.
Of the present inventionly provide on the one hand more 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, preferably 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%, with anhydride, calculates; In described bulk drug, in the related substance of meropenem, impurity A, impurity B are 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%, the residual 300ppm that is not more than of acetone.
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, according to the weight ratio of meropenem bulk drug and sterile sodium carbonate, be 1000:195～1000:222, employing high efficient mixer mixes, and packaging vessel is carried out to aseptically process, filling, it is qualified according to method under American Pharmacopeia USP32-NF27 meropenem for injection item, to detect, packing 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 guarantee the safe, effective of medicine.
The words that are not specifically noted, assay item, related substance item, residual solvent item in detection method of the present invention, all according to the method under meropenem (Meropenem) item in American Pharmacopeia USP32-NF27, carry out, it is meropenem bulk drug provided by the invention, in described bulk drug, the content of meropenem is 98.0%～101.0%, with anhydride, calculates; 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%, by anhydride, calculate; Other impurity summations must not be greater than 0.25%.The residual 300ppm (0.03%) that is not more than of acetone.In standard, wantonly one or two major impurity refers to impurity A and impurity B, and the relative retention time of impurity A and the impurity B about 6min of retention time of meropenem (take be benchmark) is about respectively 0.5,2.2.
Wherein impurity A is:
Impurity B is:
Figure BDA0000196349508
Impurity A is the unit molecule ring-opening product (Mw:401) of meropenem, can be its isomer A 2:
Figure BDA0000196349509
Impurity B is the dimer (Mw:766) of a part meropenem and a part ring-opening product, can be also its isomer B 2:
Figure BDA00001963495010
Can quality control index to guaranteeing the effective, most important safely of product, impurity and residual solvent in meropenem or any active pharmaceutical ingredient (API) are unnecessary, only have impurity is clearly limited, to surpassing the impurity research of limit of identification, identify the chemical structure of this impurity, could be according to the character of impurity, work out targetedly limit of impurities, guarantee bulk drug and preparation safe, effective.In addition, the go wrong security, the validity that are also related to medicine of the stability of bulk drug and preparation can not be guaranteed, thus bulk drug and preparation have better stability be also safer, effectively guarantee.
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 residual low, solvability good, quality control index can guarantee product effectively, safety.
2) meropenem bulk drug provided by the invention, has better stability, and after standing storage, clarity and color still meet pharmacopeia requirement, causes that the possibility of side effect is less.
3) the present invention by meropenem crude product through double crystallization can obtain that foreign matter content is low, residual low, the high purity meropenem bulk drug safely and effectively of solvent, technique of the present invention is simple, operation is succinct, is applicable to the extensive aseptic meropenem production of raw medicine of industry.
Accompanying drawing explanation
In order to understand better essence of the present invention, below in conjunction with accompanying drawing, by the description to better embodiment of the present invention, describe in detail but do not limit 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 using in following embodiment, reagent, solvent and other test materials, being can be by commercially available.
Meropenem crude product can, with reference to the method preparation of embodiment 7, also can be prepared by preparing any method of meropenem in prior art, as prepared the method for meropenem in CN1960992A or CN200610083362.7.
By weight percentage, C in described meropenem crude product 17h 25n 3o 5the content of S is no less than 92%, with anhydride, calculates; 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 of the present invention, 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 (Varian 300); Infrared spectra (NICOLET 170SX FT～IR); Mass spectrum (API2000); UV spectrum (Thermo Spectronic 300); LC-MS (Agilent 1100 HPLC-AB API2000 mass spectrums); Preparative liquid chromatography (Waters 2535); Ultimate analysis: (the German ELEMENTAR vario EL of company elemental analyser).
embodiment 1
Meropenem crude product 12kg is joined in the water of 120kg, stir and make suspension, feed liquid is warming up to 50 ℃ it is dissolved, then cool to 10 ℃.
Add gac 100g decolouring, filter.
In filtrate, add recrystallisation solvent acetonitrile 480L, add rear stirring growing the grain 2 hours.
Filter, use acetonitrile washing crystal, dry, obtain refining meropenem 10.6kg for the first time.
Refine for the first time the quality condition of meropenem: total impurities 0.75%; Organic solvent residual 0.23%.
embodiment 2
The highly finished product of the meropenem for the first time 10kg that embodiment 1 is prepared joins in the water of 150kg, stirs, and with interchanger, feed liquid is warming up to 50 ℃, then cools to 0 ℃, stirs growing the grain 15 hours.
Filtration, acetonitrile washing crystal, dry, 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 is residual 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 KBr?cm -1:?1755,?1627,?1393,?1252,?1130.
1h-NMR (D 2o, δ/ppm):: 1.21 (3H, d, J=7.1 Hz), 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 is identified:
First utilize LC-MS system 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, adopt acetic acid to replace phosphoric acid preparation moving phase, the two collection of illustrative plates is very consistent, obtain the molecular weight of each impurity, tentatively determined structure; According to chromatograms, the relative retention time of impurity A and the impurity B about 6min of retention time of meropenem (take be benchmark) is respectively 0.5 and 2.2.
2, the liquid phase of impurity preparation:
In order to obtain further verifying compared with Multi-example, the moving phase condition in identifying with reference to initial gross separation, utilizes preparative liquid chromatography, removing foreign matter A, B, and repeated multiple times preparation, obtains the salts solution of all impurity, and impurity level reaches milligram level.
3, the chemosynthesis of impurity:
According to the character of impurity, impurity A and B have been carried out to chemosynthesis, obtain 1g impurity A, purity >95%; Approximately 50 milligrams of impurity Bs, purity >90%.
1) impurity A is synthetic:
According to method described in The Journal of Antibiotics Vol.46 No.5 P831～P832, prepare impurity A, through structural confirmation, be impurity A, and conform to document.
2) impurity B is synthetic:
According to the described method of Chem. Pharm. Bull. 43 (4) P690 (1995), prepare impurity B, through structural confirmation, be impurity B, and conform to document.
4, synthetic impurity A, B and product liquid phase separation impurity A, B contrast:
Utilize synthetic obtain impurity A, B and product liquid phase separation impurity A, B contrast, first uv-spectrogram is compared, result shows to correspond respectively to A, B impurity; For further checking, adopt application of sample method, the impurity A that our chemosynthesis is obtained and B test in the meropenem bulk drug obtaining respectively qualitative adding, according to the situation that in gained chromatograms, corresponding impurity peak area increases, further judge impurity A and the B in our product and synthesize the A, the B impurity that obtain in full accord.
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-NMR?δ/ppm?(D 2O)：1.03?(d,?J?=?7.2?Hz,?3H,?CH 3-CH);?1.23?(d,?J?=?12.3?Hz,?3H,?CH 3-CH);?1.26?(d,?J?=?7.5?Hz,?3H,?CH 3-CH);?1.31?(d,?J?=?6.3?Hz,?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-NMR?δ/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, stir and make suspension, feed liquid is warming up to 80 ℃ it is dissolved, then cool to 20 ℃.
Add gac 240g decolouring, filter.
In filtrate, add recrystallisation solvent acetone 360L, add rear continuation and stir growing the grain 3 hours.
Filter, use washing with acetone crystal, dry, obtain refining meropenem 10.44kg for the first time.
Refine for the first time the quality condition of meropenem: total impurities 0.62%; Organic solvent residual 0.25%.
embodiment 4
The highly finished product of the meropenem for the first time 10kg that embodiment 3 is prepared joins in the water of 100kg, stirs, and with interchanger, feed liquid is warming up to 60 ℃, then cools to 2 ℃, stirs growing the grain 20 hours.
Filtration, washing with acetone crystal, dry, 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 is residual 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, stir and make suspension, feed liquid is warming up to 70 ℃ it is dissolved, then cool to 30 ℃.
Add gac 120g decolouring, filter.
In filtrate, add recrystallisation solvent tetrahydrofuran (THF) 1920L, add rear continuation and stir growing the grain 2 hours.
Filter, use tetrahydrofuran (THF) washing crystal, dry, obtain refining meropenem 10.7kg for the first time.
Refine for the first time the quality condition of meropenem: total impurities 0.67%; Organic solvent residual 0.27%.
embodiment 6
The highly finished product of the meropenem for the first time 10kg that embodiment 5 is prepared joins in the water of 200kg, stirs, and with interchanger, feed liquid is warming up to 60 ℃, then cools to 5 ℃, stirs growing the grain 8 hours.
Filtration, washing with acetone crystal, dry, 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 is residual 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
Figure BDA00001963495011
To protect meropenem (I a) ?the concentrated solution that 33.0kg(or protection meropenem HLPC content are 33.0kg), THF 880L, water 700L, 3,5,-lutidine 14.5kg, 10% palladium carbon 5.28kg join in the autoclave of 2000L in the lump, remove air, pass into hydrogen, room temperature reaction 6 hours, reaction is finished, and filtration washing reclaims palladium carbon, adds 2625L tetrahydrofuran (THF) in filtrated stock, control 10-15 ℃ of temperature and stir 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%.
Wherein the tetrahydrofuran (THF) in 2625L tetrahydrofuran (THF) can change one or more of acetone, Virahol, methyl alcohol, ethanol, methyl ethyl ketone into, also can prepare up-to-standard meropenem crude product.
embodiment 8
The aseptic meropenem bulk drug of the 1kg preparing 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 to aseptically process, filling, it is qualified according to method under American Pharmacopeia USP32-NF27 meropenem for injection item, to detect, packing warehouse-in.
embodiment 9
The aseptic meropenem bulk drug of the 1kg preparing 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 to aseptically process, filling, it is qualified according to method under American Pharmacopeia USP32-NF27 meropenem for injection item, to detect, packing warehouse-in.
embodiment 10
The aseptic meropenem bulk drug of the 1kg preparing 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 to aseptically process, filling, it is qualified according to method under American Pharmacopeia USP32-NF27 meropenem for injection item, to detect, packing warehouse-in.
comparative example 1
5g meropenem crude product is dissolved in 50ml water in 30 ℃, and water-bath is cooling, 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 for 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 is residual is 599ppm.
According to method described in embodiment 8, prepare the pharmaceutical composition that the weight ratio of its meropenem bulk drug and sodium carbonate is 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
Packing: Aluminum Drum; Storage condition: 40 ° of C ± 2 ° C of temperature, humidity 75% RH ± 5% RH
1～6 month accelerated test study on the stability of meropenem bulk drug the results are shown in Table 1.
Table 1. meropenem bulk drug accelerated test stability result
Figure BDA00001963495012
From result, in comparative example 1, foreign matter content is high, the residual high meropenem bulk drug of acetone is placed 6 months under 40 ° of C ± 2 ° C of temperature, humidity 75% RH ± 5% RH accelerated test condition, related substance, solution colour are all undesirable, stability test is defective, cannot guarantee the drug safety after long-term storage; And bulk drug provided by the invention, with listing, be packaged under accelerated test condition impurity, solution colour still up to specification, stability is fine, can guarantee 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
Packing: Aluminum Drum; Storage condition: 25 ° of C ± 2 ° C of temperature, humidity 60% RH ± 5% RH
1～24 month test of long duration study on the stability of meropenem bulk drug the results are shown in Table 2.
Table 2. meropenem bulk drug test of long duration stability result
Figure BDA00001963495013
From result, with listing, be packaged under 25 ° of C ± 2 ° C of temperature, humidity 60% RH ± 5% RH test of long duration condition and place 24 months, impurity is still up to specification, 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 the isometric phase test of water-content stability result.
3. meropenem for injection pharmaceutical composition test of long duration study on the stability
Storage condition: 25 ° of C ± 2 ° C of temperature, humidity 60% RH ± 5% RH
1～36 month test of long duration study on the stability of meropenem for injection pharmaceutical composition 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 residual high meropenem bulk drug of acetone is placed 24 months and 36 months under 25 ° of C ± 2 ° C of temperature, humidity 60% RH ± 5% RH test of long duration condition, solution colour is undesirable, stability test is defective, cannot guarantee 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 is still up to specification, stability is fine, higher for Safety of intravenous medication as injection, better efficacy.
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 meet the requirements, thus can guarantee product effectively, safety.

Claims (11)

1. a meropenem bulk drug, is characterized in that, by weight percentage, in described bulk drug, the content of meropenem is 98.0%～101.0%, with anhydride, calculates; In described bulk drug, in the related substance of meropenem, 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%; The residual 300ppm that is not more than of acetone;
Wherein impurity A is:
Figure FDA0000196349491
Impurity B is:
。
2. the preparation method of meropenem bulk drug according to claim 1, described preparation method comprises the step of refining meropenem crude product by double crystallization.
3. preparation method according to claim 2, is characterized in that, the crystallization for the first time in described double crystallization comprises the following steps:
1) meropenem crude product is added to the water, stirs and to make suspension post-heating and makes described meropenem dissolving crude product, then make the temperature of the solution that obtains be down to 0 ~ 40 ℃, preferably 10 ~ 30 ℃;
2) in the solution obtaining 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) crystallizing system of step 3) is filtered and obtains crystal, then washing crystal dry, obtains refining meropenem for the first time.
4. preparation method according to claim 3, is characterized in that, in described first subcrystalline step 1), by weight percentage, C in described meropenem crude product 17h 25n 3o 5the content of S is no less than 92%, with anhydride, calculates; 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:
Figure FDA0000196349493
Described impurity B is:
Figure FDA0000196349494
；
Preferably, by weight percentage, C in described meropenem crude product 17h 25n 3o 5the content of S is no less than 95%, with anhydride, calculates; 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, the water using in described first subcrystalline step 1) is meropenem crude product 3 ~ 50 times, preferably 5 ~ 40 times, more preferably 10 ~ 20 times;
Preferably, in described first subcrystalline step 1) 40 ~ 80 ℃, preferably at the temperature of 45 ~ 55 ℃, make described meropenem dissolving crude product.
5. according to the preparation method described in claim 3 or 4, it is characterized in that, described first subcrystalline step 2) comprising: the gac to adding meropenem crude product weight 1～20% in solution, at 15 ℃～25 ℃, decolour 1～30 minute, preferably 1～10 minute, then filter and obtain filtrate.
6. according to the preparation method described in any one in claim 3 to 5, it is characterized in that, the organic solvent using in described first subcrystalline step 3) is selected from the solvent miscible with water, preferably one or more in acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol and methyl-sulphoxide;
Preferably, the organic solvent adding in described first subcrystalline step 3) and the volume ratio of filtrate are 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.
7. according to the preparation method described in any one in claim 3 to 6, it is characterized in that, in described first subcrystalline step 4), adopt organic solvent washing crystal;
Preferably, described organic solvent is selected from one or more in water, acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, methyl-sulphoxide, ethyl acetate, propyl acetate and methylene dichloride.
8. according to the preparation method described in claim 2 or 3, it is characterized in that, the crystallization for the second time in described double crystallization comprises the following steps:
1) the refining meropenem for the first time obtaining is added to the water, stirs and make suspension post-heating to 35 ~ 95 ℃, preferably 50 ~ 80 ℃, then be cooled to 0 ~ 30 ℃, preferably 0 ~ 5 ℃, then stir growing the grain; With
2) by step 2) crystallizing system filter and to obtain crystal, then washing crystal dry, obtains meropenem bulk drug.
9. preparation method according to claim 8, is characterized in that, by weight, the water using in described second subcrystalline step 1) is refining meropenem for the first time 5 ~ 30 times, preferably 10～20 times;
Preferably, the time of stirring growing the grain in second subcrystalline step 1) is 5 minutes ~ 48 hours, preferably 10 minutes ~ 24 hours, and more preferably 8 ~ 20 hours.
10. preparation method according to claim 8 or claim 9, is characterized in that described second subcrystalline step 2) in adopt organic solvent washing crystal;
Preferably, described organic solvent is selected from one or more in water, acetone, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, methyl-sulphoxide, ethyl acetate, propyl acetate and methylene dichloride.
11. 1 kinds of meropenem pharmaceutical compositions, it contains meropenem bulk drug according to claim 1 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 sodium carbonate is 1000:195～1000:222, preferably 1000:208;
Further preferably, described pharmaceutical composition is injection.
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