WO2014019282A1

WO2014019282A1 - Meropenem bulk drug, preparation method thereof and pharmaceutical composition containing same

Info

Publication number: WO2014019282A1
Application number: PCT/CN2012/082068
Authority: WO
Inventors: 任鹏; 管曙光; 谭汉梯; 唐南湘; 唐秋停; 向斌波
Original assignee: 深圳市海滨制药有限公司; 新乡海滨药业有限公司
Priority date: 2012-07-31
Filing date: 2012-09-26
Publication date: 2014-02-06
Also published as: CN103570718A; CN103570718B

Abstract

Disclosed in the present invention is a bulk drug of meropenem, characterized in that the meropenem content in the bulk drug is 98.5%~101.0% based on the anhydrous substances; the impurities A and B in the related substances of the bulk drug are both no more than 0.25%; any single unknown impurity is no more than 0.05%; the sum of the other impurities in addition to A and B is no more than 0.2%; the residue of acetone is no more than 400ppm, preferably no more than 100ppm. Also disclosed in the present invention is a meropenem pharmaceutical composition with very good stability for injection using the meropenem bulk drug provided by the present invention as the active ingredient. The meropenem bulk drug provided by the present invention has high purity, well-defined impurity levels, low residual solvent content, good solubility, and good stability for long-term storage, so it ensures that the drug is effective and safe. The present invention has a simple process, a very low cost, a compact process, and is easy to control, so it is suitable for the production of sterile meropenem bulk drug and pharmaceutical preparations on an industrial scale.

Description

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Meropenem raw material drug, preparation method thereof and pharmaceutical composition containing the same

The present invention relates to the field of pharmacy, and in particular, to a meropenem drug substance, a process for the preparation thereof, and a pharmaceutical composition comprising the meropenem drug substance. Background technique

Meropenem, chemical name (-)-(4R,5S,6S)-3-[(3S,5S)-5-(didecylamino)-3-pyrrolidine]sulfur-6-[ (lR)-l-hydroxyethyl]-4-mercapto-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylic acid trihydrate, is a carbon blue Amylin antibiotics, with broad-spectrum antibacterial properties and available for injection, for the treatment of a variety of different infections, including meningitis and pneumonia, which are normally in the form of trihydrates, CAS registration number [119478] ~ 56 ~ 7], the specific structural formula is shown in formula (I).

(I) The API (Active Pharmaceutical Ingredient) is the raw material used in the production of various preparations and is the active ingredient in the preparation. The perfect definition of APIs in ICH Q7A is: Any substance or mixture of substances intended for use in the manufacture of pharmaceuticals, and when used in pharmaceuticals, becomes an active ingredient of pharmaceuticals. This substance may have pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, treatment or prevention of the disease, or may affect the function or structure of the body.

The Pharmacopoeia of the Chinese Pharmacopoeia 2010 edition of 606 pages on Meropenem standard specifies the relevant substances: The maximum impurity peak area before and after the main peak should not be greater than 0.6 times (0.3%) of the main peak area of the control solution, other single The impurity peak area shall not be greater than 0.2 times (0.1%) of the main peak area of the control solution, and the sum of the impurity peak areas shall not be greater than 2 times (1.0%) of the main peak area of the control solution. Residual solvent regulations: Determination of acetone, acetonitrile, dichlorodecane, ethyl acetate and tetrahydrofuran in compliance with the regulations, Chinese Pharmacopoeia 2010 edition of the second appendix P residual solvent determination method Schedule 1 common solvents and limits specified in the drug: Acetone detection limit is 0.5% (5000 ppm); acetonitrile is 0.041% (410 ppm); dichlorodecane is 0.06% (600 ppm); ethyl acetate has a detection limit of 0.5% (5000 ppm); THF has a detection limit of 0.072% (720 ppm).

The refining method of meropenem reported in the open literature, as disclosed in US Pat. No. 4,888,344, Example 1, discloses a method for preparing meropenem trihydrate crystals, which comprises dissolving melopenem in water at 30 ° C, cooling in a water bath, and depositing a small amount of crystals. Acetone was added, stirred for 1 hour, and crystallized by filtration, washed with acetone, and dried under reduced pressure at room temperature for 2 hours to obtain crystals of meropenem trihydrate. The purification method has a high yield, but the acetone residue is high, which may reach the detection limit of the acetone in the drug specified in the Chinese Pharmacopoeia 2010 Appendix 2 residual solvent determination method. However, the United States Pharmacopoeia USP32-NF27 has a stringent requirement for solvent residues in the meropenem trihydrate standard, wherein the acetone residue should not be higher than 0.05%. This refining method is generally difficult to achieve. Moreover, acetone belongs to the third type of easy-to-manufacture type of the public security organs, and it is easy to make explosives. Although acetone belongs to three types of solvents, acute or short-term studies have shown that these solvents are less toxic and the results of genotoxicity studies are negative, but there is no The long-term toxicity or carcinogenicity of these solvents, and it is hepatotoxic to humans. Long-term use of high-injection of acetone residues is undoubtedly harmful to the health of patients. For example, some cancer patients have abnormally elevated levels of urine acetone.

US2009264643 discloses a process for the purification of meropenem trihydrate, which involves a process of adding aqueous ammonia, citric acid to adjust the pH, and then crystallizing with tetrahydrofuran. This method is rather cumbersome, and the Chinese Pharmacopoeia 2010 edition of the second appendix residual solvent determination method specifies that the detection limit of THF in the drug is 0.072%, and this purification method is generally difficult to achieve. And tetrahydrofuran belongs to the second class of solvents. It is a non-genotoxic but animal carcinogenic solvent. Its health hazards are: dizziness, headache, chest tightness, chest pain, cough, fatigue, stomach pain, dry mouth, nausea, vomiting after high concentration inhalation. Such symptoms may be accompanied by symptoms of eye irritation, and some patients may have liver dysfunction. High dose or repeated exposure may cause hepatic fat infiltration and cell lysis; prolonged exposure may result in loss of sexual function, fertility, or kidney disease. Therefore, it should be avoided in the last step of the process, otherwise the THF residue is too high will seriously threaten the safety of meropenem injection.

CN201010232062.7 discloses a preparation method of meropenem trihydrate crystals, which is completely crystallized in an aqueous solution, and the filtrate is added with an organic solvent to recover meropenem. The residual organic solvent in the meropenem trihydrate crystal prepared by this method is less than 0.05%, but it needs to be carried out in two steps, the yield is not high, and the recovery of the organic solvent by the organic solvent to remove the meropenem will greatly increase the organic solvent. The amount of use is not conducive to environmental protection, and is not conducive to reducing costs.

CN201110218567.2 discloses a preparation method of meropenem, which comprises dissolving crude meropenem in 10% sodium hydroxide water, filtering after activated carbon, crystallization, and adding acetic acid B. The ester is recovered from meropenem. The method also needs to be carried out in two steps, and the yield is not high; and the recovery of meropenem from the filtrate with ethyl acetate will greatly increase the amount of ethyl acetate used, which is not conducive to environmental protection and is not conducive to cost reduction. Furthermore, Yutaka Takeuchi et al., Chem. Pharm. Bull. 43 (4) 689-692 (1995), describe that meropenem is more unstable under acidic and basic conditions than the neutral environment, and the document P690 shows an equivalent amount. Sodium bicarbonate and meropenem aqueous solution were lyophilized to obtain meropenem sodium salt. 400 mg of meropenem sodium salt was dissolved in 1 ml of water and maintained at 30 ° C. It was found by HPLC that the HPLC peak area ratio after 6 hours was: meropenem 47%, Degradation product A 11%, degradation product B 38%, 10% sodium hydroxide solution with a pH of about 14.3 will undoubtedly make the degradation of meropenem more serious than the less alkaline sodium bicarbonate. Yutaka Takeuchi et al., The Journal of Antibiotics Vol. 46 No. 5 P829 also describes the immediate hydrolysis of meropenem in acidic (H < 2 ) and basic (H > 13) environments, the main degradation products (referring to ring-opening products). A) Generated. Therefore, this method of recrystallizing the crude product of meropenem in a strong alkaline 10% sodium hydroxide solution can not only achieve the purification purpose of meropenem but also increase the impurities of meropenem. Therefore, the example claimed that the meropenem has been tested by the Chinese Pharmacopoeia 2010 edition of the second meropenem-related substances, the single largest impurity is 0.03%, the total impurity is 0.13%, and its credibility is questionable, and the Chinese Pharmacopoeia 2010 edition two meropenem Regarding the substance testing standards, there is no mention of the "maximum impurities before and after the main peak". We cannot determine whether the "single maximum impurity" and "total impurities" include the "maximum impurities before and after the main peak", so that it is impossible to be clear. The situation of the impurities of meropenem is known.

Impurities in meropenem or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, may be harmful to patients undergoing treatment with API-containing dosage forms. For example, the 2011 Annual Report on Adverse Drug Reaction Monitoring released by the official website of the State Food and Drug Administration showed that anti-infectives in chemical products ranked first in total adverse reaction reports and serious adverse reactions reports, accounting for 51.2%. This is inconsistent with the control of impurities and solvent residues, some unclear impurities in some antibiotics, and unstable quality during long-term storage. Therefore, it is urgent to provide a lower impurity content, clear impurity conditions, and lower solvent residues. A meropenem raw material and a formulation composition having stable quality and low adverse reactions.

The thermal stability of meropenem is poor. The amount of mother liquor in the large production process is large, mainly water. If the mother liquor is directly heated, concentrated at high temperature and vacuum, the high temperature state will accelerate the degradation of meropenem, and the recovered mother liquor has a large mass. This recycling method has no practical value. If you use a new organic solvent for recycling, the amount of organic solvent that needs to be added is also large due to the large amount of water. It is also undesirable from environmental and cost considerations.

Nanofiltration membrane separation technology (English name is Nanofiltration, referred to as NF, Chinese translation for "Nano Filtration is a functional filtration technique that allows solvent molecules or certain low molecular weight solutes or low-cost ions to pass through. Nanofiltration membranes are semi-permeable membranes with nanoscale pores and a rejection of greater than 95%. The minimum molecular weight is about 1 nm, the molecular weight of the retained organic matter is about 150 ~ 500, the ability to retain the soluble salt is between 2 and 98%, and the desalting of the monovalent anion salt solution is lower than that of the high-priced anionic salt solution, mainly for removal. The organic matter and color of surface water, remove the hardness of groundwater, partially remove dissolved salts, concentrate juice, etc.

At present, the application of the reaction liquid produced by the preparation of the drug substance of meropenem into the next batch of crude meropenem has not been reported. If the meropenem crystals are directly concentrated by nanofiltration, whether the nanofiltration process will affect the stability of the crystallization solution containing a large amount of meropenem is still to be investigated. Moreover, since the concentration of meropenem is large, the volume cannot be concentrated to a small extent, otherwise the crystals will precipitate and cause the nanofiltration membrane to clog, so that a large amount of organic solvent is required to be crystallized, and it is difficult to obtain a meropenem drug substance having a low residual organic solvent. Summary of the invention

After a large number of experiments, the applicant was pleasantly surprised to find that the crude product of meropenem is purified by pure water. In addition to the meropenem raw material, a filter mother liquor can also be obtained, which is an aqueous solution containing meropenem 1-2%, and the solution is subjected to nanofiltration. After the membrane is concentrated, the water volume is greatly reduced. The weight ratio before and after the nanofiltration concentration is 5:1 - 15:1, and the concentration of meropenem after concentration is 5-20%, and the concentration is greatly increased.

At the same time, since the crude product of meropenem needs to be added to the crystallization system to precipitate the crude meropenem, the mother liquor after the removal of the crude meropenem contains a large amount of organic solvent, wherein the ratio of the volume of the organic solvent to the volume of water Approximately 3:1 to 6:1, these organic solvents are mainly one or more of acetone, tetrahydrofuran, isopropanol, decyl alcohol, ethanol, and mercaptoethyl ketone. This mother liquor is too wasteful to waste as a waste liquid. For recycling, the cost is also high. If the concentrate concentrated by the nanofiltration membrane is added to the crude mother liquor which is mainly an organic solvent, the next batch of crude meropenem can be directly crystallized, so that the organic solvent can be fully utilized.

Alternatively, the concentrated liquid obtained by concentrating the nanofiltration membrane may be added to the mother liquor in which the crude product is not precipitated after the hydrogenation filtration in the subsequent crude product preparation, and the organic solvent such as acetone, tetrahydrofuran, isopropanol, decyl alcohol, ethanol, hydrazine is added dropwise according to a conventional method. One or more of the ethyl ethyl ketones, the ratio of the volume of the adjusted organic solvent to the volume of the water is about 3:1 to 6:1, and the same can be crystallized to obtain the crude product of meropenem.

Based on the above findings, an object of the present invention is to determine the content of the main impurity A and the impurity B by quantitatively controlling the content of the main ingredient A and the impurity B, and to strictly control the residual solvent to provide a meropenem drug substance. The raw material drug is different from the prior art, and has high purity, clear impurity condition, low solvent residue, long-term storage stability, and quality control index. Ensuring that the product is effective and safe.

Another object of the present invention is to provide a method for preparing a meropenem drug, which comprises refining a crude meropenem drug to obtain a meropenem drug substance and a solution containing a low concentration of meropenem, and the resulting solution is concentrated by a nanofiltration membrane. Enter the preparation of the subsequent crude meropenem. The method is simple, compact and controllable, and has high yield and low cost, and has great economic advantages.

Still another object of the present invention is to provide a pharmaceutical composition of meropenem which has excellent stability as the active ingredient of the meropenem drug of the present invention.

The object of the present invention is achieved by the following technical solutions.

In one aspect, the present invention provides a meropenem drug substance, wherein the content of meropenem in the drug substance is 98.5%-101.0%, calculated as an anhydrate; the impurity A in the related substance of the drug substance , impurity B is not more than 0.25%; any unknown single impurity is not more than 0.05%; the sum of other impurities except A and B is not more than 0.2%; acetone residue is not more than 400ppm, preferably not more than 100ppm.

Among them, impurity A is:

In another aspect, the present invention provides a method for preparing a meropenem drug, the method comprising: purifying and filtering the crude meropenem to obtain a mother liquor 3 and a meropenem drug substance, and the mother liquor 3 is concentrated by a nanofiltration membrane, The obtained concentrate is added to a mother liquid (mother liquid 2) which has been subjected to hydrogenation in the subsequent crude product preparation, and which has been precipitated after filtration or a mother liquid (mother liquor 1) in which no crude product is precipitated, and crystallized to obtain a crude product of meropenem.

It should be noted that the crude meropenem according to the present invention and the meropenem seed crystal referred to below refer to a compound having the general formula (I):

(I) In the preparation of meropenem, the crude meropenem is generally prepared by hydrogenation of meropenem (la), which is unrefined meropenem (compound I). The reaction formula is as follows:

The reaction process is generally: adding meropenem (or protecting meropenem concentrate), a reaction solvent, a catalyst (such as palladium carbon) to a high pressure hydrogenation reactor, removing air, introducing a hydrogen reaction, and completing the reaction, and recovering palladium carbon by filtration. Obtaining a mother liquor which is not precipitated as a crude product; the mother liquor is the mother liquor of the unprecipitated crude product of the present invention, referred to as mother liquor 1;

The mother liquor 1 is added with an organic solvent, controlled to stir and crystallize at a temperature, and filtered to obtain a mother liquor 2 and a crude product of meropenem; this mother liquor 2 is a mother liquor of the precipitated crude product of the present invention, which is referred to as a mother liquor 2 .

The crude product of meropenem is refined and filtered to obtain mother liquor 3 and meropenem bulk drug; mother liquor 3 is concentrated by nanofiltration to obtain nanofiltration concentrated solution, which is added to mother liquor 1 or mother liquor 2 in the subsequent crude product preparation, and then crystallized to obtain meropenem Crude.

The process flow of the preparation method is shown in Fig. 10.

This process can be recycled and controlled under the conditions of controlling the quality of meropenem crude and meropenem. It can not only greatly reduce the amount of organic solvent used, but also maximize the recovery of meropenem in mother liquor 3. Greatly improve product yield and reduce production costs.

The meropenem crude and seed crystals are preferably prepared according to the method described below in the present invention, or may be prepared by any of the methods of preparing meropenem in the prior art, such as the method of preparing meropenem in CN1960992A or CN200610083362.7.

Preferably, in the method, a pressure of 5 X 10 ⁵ Pa to 20 X 10 ⁵ Pa, preferably 15 x 10 ⁵ Pa to 20 χ 10 ⁵ Pa, and a temperature of 5 to 35 ° C, preferably 10 to 25 ° C The nanofiltration of the mother liquor was concentrated.

Moreover, the weight ratio of the mother liquor to the obtained concentrate is 5:1 to 15:1, preferably 7:1 to 10:1; The content of meropenem in the obtained concentrate is 5 to 20%, preferably 7 to 15%.

In addition, the total volume of the organic solvent in the system for obtaining the crude meropenem is 3:1 ~ 6:1; the organic solvent is selected from the group consisting of acetone, tetrahydrofuran, isopropanol, decyl alcohol, ethanol and sulfhydryl. One or more of ethyl ketones.

The nanofiltration concentration described herein is preferably carried out in accordance with the methods of the present invention, and can be carried out by any of the methods of the prior art. The membrane concentration can be concentrated by a polytetrafluoroethylene nanofiltration membrane, a polystyrene nanofiltration membrane, a polyethersulfone resin nanofiltration membrane, a composite membrane, a cellulose acetate membrane, a polyamide membrane, etc., and the nanofiltration concentrated separation device can be buy. The molecular weight of the organic membrane retained by the nanofiltration membrane is about 150 to 500. The molecular weight of meropenem trihydrate is 437.5, and the molecular weight of meropenem anhydrous is 383.5. Therefore, solvent molecules and water molecules can pass, and meropenem is trapped, and a nanofiltration membrane that satisfies this condition can be applied.

The mother liquor after concentration by nanofiltration is preferably added to the mother liquor (mother liquor 2) which has been subjected to hydrogenation after the subsequent crude product preparation by the method of the present invention, or the mother liquor (mother liquor 1) in which the crude product is not precipitated, and crystallized to obtain a crude product of meropenem. It can also be directly added to the reaction liquid, the crystallization liquid and the filtered mother liquid for preparing the crude meropenem in any method of the prior art, and simultaneously crystallized to obtain crude meropenem. For example, the nanofiltration concentrate is directly added to the aqueous solution after hydrogenation filtration in CN1960992A, and the mixed solution is added to tetrahydrofuran to obtain the crude meropenem; or the nanofiltration concentrate is directly added to the sample 2 of CN200610083362.7 to filter the perfect roperan. In the mother liquor of (5.1g), direct crystallization of meropenem is obtained; or the nanofiltration concentrate is directly added to the organic solvent to be separately crystallized and recovered as the next batch of crude meropenem.

In another aspect, the present invention provides a method for preparing a meropenem drug, the method comprising the steps of:

1) Dissolving the crude meropenem in water at a temperature of 50 ° C ~ 80 ° C, and then reducing the temperature of the resulting solution to 10 ° C ~ 30 ° C to obtain a solution I;

2) The solution I obtained in the step 1) is decolorized by activated carbon and filtered to obtain a filtrate II;

3) The temperature of the filtrate II obtained in the step 2) is lowered to 0 ° C ~ 20 ° C to crystallize, and after filtration, the mother liquid 3 and the filter cake are obtained, and the filter cake is washed and dried to obtain a meropenem raw material drug; as well as

4) The mother liquor 3 obtained in the step 3) is concentrated by nanofiltration, and then added to the next batch of the crude product to be hydrogenated, and the mother liquor which has been precipitated or not precipitated after filtration is crystallized to obtain a crude product of meropenem.

In the step 1) of the above preparation method of the present invention, the content of C ₁₇ H ₂₅ N ₃ _{5 5} S in the crude product of meropenem is not less than 92% by weight percentage, calculated as anhydrate; impurity A and impurity B are both Not more than 0.8%; any unknown single impurity is not more than 0.3%; the sum of other impurities except A and B is not more than 3.0%. Wherein the impurity A is:

The impurity B is:

Preferably, in the step 1) of the above preparation method of the present invention, the content of C ₁₇ H ₂₅ N ₃ _{5 5} S in the crude meropenem is not less than 95% by weight, calculated as anhydrate; A, impurity B is not more than 0.6%; any unknown single impurity is not more than 0.3%; the sum of other impurities except A and B is not more than 2.0%.

Preferably, the step of dissolving the crude meropenem in water at a temperature of 50 ° C to 80 ° C in the step 1) comprises: adding the crude meropenem to 10 to 20 times by weight, preferably 15 to 20 times by weight of 5 ~ 20 ° C in water for injection, stir and mix evenly, and then the resulting suspension is heated to 50 ° C ~ 80 ° C, preferably 60 ° C ~ 80 ° C dissolved; wherein the dissolution time is less than 4 minutes, preferably Less than 1 minute.

After dissolution, preferably, the temperature of the resulting solution is lowered to 10 ° C to 25 ° C; wherein the time for cooling is less than 4 minutes, preferably less than 1 minute.

The temperature rise and fall in step 1) can be carried out by means of a heat exchanger, for example the heat exchanger described in the Chinese patent application CN201120235961.2. Preferably, the method of the present invention utilizes the heat exchange of the heat exchanger to rapidly dissolve and rapidly cool the temperature; the crude meropenem can be dissolved by any means which can achieve rapid dissolution, and the solution can be cooled by any means which can achieve rapid cooling.

In the step 2) of the method of the present invention, the solution I can be decolorized by using 1 to 20% of the activated carbon of the meropenem weight of 1 to 20% at 15 ° C to 25 ° C for 1 to 30 minutes, preferably 1 to 10 minutes, and then filtered. The filtrate II was obtained.

Alternatively, in step 2), the solution is decolorized by in-line filtration through an activated carbon filter. Preferably, the activated carbon treatment is carried out by the method of the invention, and the solution can also be activated by any known means. The activated carbon used is not particularly limited.

In the step 3) of the method of the present invention, the temperature of the filtrate II is lowered to 0 ° C ~ 5 ° C for crystallization, and crystallized for 2 ~ 20 hours, preferably 5 ~ 10 hours; filtered to obtain the mother liquid 3 and the filter cake The filter cake is washed with acetone to wash the crystal, and dried under vacuum at 20 ° C to 40 ° C, preferably 25 ° C to 30 ° C for 3 to 10 hours, preferably 5 to 6 hours, thereby obtaining a meropenem drug substance. . Wherein, the crystal is preferably stirred and crystallized, and the stirring speed is 100 to 200 rpm, preferably 110 to 130 rpm. The crystal growth time of the present invention refers to the crystal growth time, and the step 3) the crystal growth time is the time during which the crystal growth between the seed crystals and the filtration is added.

In the crystallization process of step 3), seed crystals may or may not be added, and seed crystals are preferably added. Preferably, the step 3) further comprises: adding seed crystals to the filtrate II obtained in the step 2) before crystallization; wherein the temperature of the seed crystal is 0 ° C ~ 20 ° C, preferably 0 ° C ~ 5 ° C; The mass ratio of the seed crystal to the crude product of meropenem is 1%: 1 ~ 10%: 1, preferably 1%: 1 ~ 2%: 1.

More preferably, in step 3), 1% to 10% by weight of the filtrate II is taken before crystallization, crystallized by adding an organic solvent thereto, and the obtained seed crystal is added to the remaining filtrate II for crystallization. (in the crystallization tank); wherein the organic solvent is selected from one or more of acetone, tetrahydrofuran, isopropanol, decyl alcohol, ethanol and mercaptoethyl ketone, preferably acetone and/or tetrahydrofuran; The weight (kg) of the partial filtrate II and the organic solvent is 1:2 to 1:6, and the seed crystal preparation temperature is 5 ° C to 20 ° C, preferably 10 ° C to 15 ° C.

In step 4) of the method of the invention, at a pressure of 5 X 10 ⁵ Pa~20 X 10 ⁵ Pa, preferably 15 x 10 ⁵ Pa ~ 20 χ 10 ⁵ Pa and 5 to 35 ° C, preferably 10 to 25 ° C The nanofiltration concentration of the mother liquor 3 is carried out at a temperature such that the weight ratio of the mother liquor 3 to the obtained concentrate is 5:1 to 15:1, preferably 7:1 to 10:1; and the meropenem content in the obtained concentrate is 5 ~ 20% by weight, preferably 7 to 15% by weight.

Preferably, the crystallization of the crude meropenem in the step 4) gives a volume ratio of the total volume of the organic solvent to the water of 3:1 to 6:1; the organic solvent is selected from the group consisting of acetone, tetrahydrofuran, isopropanol, and decyl alcohol. One or more of ethanol and mercaptoethyl ketone; preferably, the crystallization temperature is from 5 ° C to 15 ° C.

Further preferably, the mother liquor (mother liquor 2) in which the crude product has been precipitated after hydrogenation or filtration or the mother liquor (mother liquor 1) in which the crude product is not precipitated is the mother liquor 1 and the mother liquor 2 in the process of preparing the crude meropenem by the following method;

Add meropenem (or protect meropenem concentrate), THF, water, 3,5,-dimercaptopyridine, 10% palladium carbon to the autoclave, remove the air, pass hydrogen, and react at room temperature. , washing and recovering palladium carbon to obtain a mother liquid without precipitation of crude product, the mother liquid can be used as a mother liquid without precipitation of crude product, referred to as mother liquor 1; The mother liquor is added with an organic solvent, the temperature is controlled at 10-15 ° C, the mixture is filtered, washed, and the product is dried to obtain a crude product of meropenem (Compound I); the mother liquor is a mother liquor which has been precipitated as a crude liquid, and the mother liquor can be used as a mother liquor for which a crude product has been precipitated. , referred to as mother liquor 2.

The organic solvent is selected from one or more of tetrahydrofuran, acetone, isopropanol, decyl alcohol, ethanol, mercaptoethyl ketone; preferably tetrahydrofuran, acetone; preferably, the sum of the volume of the organic solvent in the mother liquor 2 and water The volume ratio is 3: 1 ~ 6: 1.

According to the above method, the content of meropenem is 98.5% ~ 101.0%, calculated as anhydrate; the impurity A and the impurity B in the related substances of the raw material drug are not more than 0.25%; a single impurity is not more than 0.05%; the sum of other impurities except A and B is not more than 0.2%; the acetone residue is not more than 400ppm, preferably not more than 100ppm;

Among them, impurity A is:

Impurity B is:

In a further aspect, the present invention provides a meropenem pharmaceutical composition comprising the meropenem drug of the present invention and a pharmaceutically acceptable excipient; preferably, the excipient is sterile sodium carbonate, wherein the The weight ratio of the drug substance to the sterile sodium carbonate is 1000: 195 to 1000: 222, preferably 1000: 208; preferably, the pharmaceutical composition is an injection.

In the meropenem pharmaceutical composition, the content of meropenem in the drug substance is 98.5% ~ 101.0%, calculated as an anhydrate; the impurity A and the impurity B in the related substances of the drug substance are not more than 0.25%. Any unknown single impurity is not more than 0.05%; the sum of other impurities except A and B is not more than 0.2%; the acetone residue is not more than 400ppm, preferably not more than 100ppm.

The invention also provides a preparation method of the meropenem pharmaceutical composition for injection, the method comprising: pulverizing the sterile meropenem drug substance and the sterile sodium carbonate, and detecting the sterility and the particle size requirement, according to the meropenem drug substance and The weight ratio of sterile sodium carbonate is 1000: 195 ~ 1000: 222, and the mixture is mixed with a high-efficiency mixer. The packaging container is aseptically processed and filled according to the US medicine. The USP32-NF27 injection was tested by meropenem and packaged into the warehouse.

The meropenem pharmaceutical composition for injection provided by the invention has better stability, and the clarity and color after long-term storage still meet the requirements, and the medicine can be ensured to be safe and effective.

It is within the scope of the present invention to make any possible variations or substitutions of the present invention without departing from the spirit and scope of the invention.

Unless otherwise specified, the content determination item, the related substance item, and the residual solvent item in the detection method of the present invention are all carried out according to the method of Meropenem in the United States Pharmacopoeia USP32-NF27, that is, the meropenem raw material provided by the present invention. Medicine, the content of meropenem in the raw material medicine is 98.5% ~ 101.0%, calculated as anhydrate; in the related substances of the raw material medicine: any two main impurities (impurity A and impurity B) shall not be greater than 0.25%, Calculated as anhydrate; other individual impurities shall not be greater than 0.05%, calculated as anhydrate; the sum of other impurities shall not be greater than 0.2%. The acetone residue is not more than 400 ppm (0.04%), preferably not more than 100 ppm. The two main impurities in the standard refer to the relative retention times of impurity A and impurity B, impurity A and impurity B (based on the retention time of meropenem for about 6 minutes) of about 0.5 and 2.2, respectively.

Among them, impurity A is:

Single molecule ring-opening (Mw: 401), which can be its isomer A ₂ :

A ₂

Impurity B is a dimer of one molecule of meropenem and one molecule of ring-opening (Mw: 766), or it can be its isomer B ₂ :

Quality control indicators are essential for ensuring the effectiveness and safety of the product. Impurities and residual solvents in meropenem or any active pharmaceutical ingredient (API) are superfluous, only the impurities are clearly defined, and the limits of identification are exceeded. Impurity studies identify the chemical structure of the impurity, in order to determine the impurity limit according to the nature of the impurity, in order to ensure the safety and effectiveness of the drug substance and preparation. In addition, the problem of the stability of the drug substance and the preparation is also related to the safety and effectiveness of the drug, so that the stability of the drug substance and the preparation is safer and more effective.

Compared with the prior art, the beneficial effects of the invention are:

1) The meropenem raw material provided by the invention has high purity, clear impurity condition, low solvent residue, good solubility, and quality control index can ensure the product is effective and safe.

2) The meropenem drug substance provided by the invention has better stability, and the clarity and color after long-term storage still meet the requirements of the pharmacopoeia, and the possibility of causing side effects is smaller.

3) In the present invention, the crude product of meropenem is purified by purified water to obtain a high-quality meropenem drug substance, and the mother liquid 3 obtained is concentrated by a nanofiltration membrane, and then added to a crude liquid preparation (hydrogen mother 2) after being subjected to hydrogenation after filtration and filtration. In the mother liquor (mother liquor 1) in which no crude product was precipitated, the crude product of meropenem was obtained by crystallization. The separate recovery step of the mother liquor is eliminated, the working hours are shortened, the amount of organic solvent used can be greatly reduced, and the meropenem in the mother liquor 3 can be recovered as much as possible, the product yield is greatly improved, and the production cost is remarkably reduced.

4) The invention can concentrate the heat-labile meropenem solution in a relatively short time at a relatively low temperature, greatly reducing the decomposition of meropenem, the nanofiltration concentration process is easy to control, and the temperature rise is low, which ensures that the product is in the material. The liquid does not deteriorate.

5) It can be seen from the concentration results that the decomposition of meropenem is not detected; the residue of meropenem in the wastewater is not detected, and the concentrated yield is 100%, indicating that the operating conditions are appropriate, and the nanofiltration membrane has good separation and separation effect, which is suitable for existing Separation of the product.

6) The invention has the advantages of simple process, low cost, compact process and simple control, and the obtained meropenem raw material has high purity, low solvent residue, good solubility and good long-term storage stability, and is suitable for industrial large-scale sterile meropenem raw materials. Production of pharmaceuticals and pharmaceutical preparations. DRAWINGS

The invention will be described in detail, but not by way of limitation, the description of the preferred embodiments of the invention. among them:

Figure 1 shows the nuclear magnetic carbon spectrum of impurity A;

Figure 2 is the nuclear magnetic resonance spectrum of impurity A;

Figure 3 is an infrared analysis spectrum of impurity A;

Figure 4 is a mass spectrum of impurity A;

Figure 5 is an ultraviolet absorption spectrum of impurity A;

Figure 6 is the nuclear magnetic resonance spectrum of impurity B;

Figure 7 is an infrared analysis spectrum of impurity B;

Figure 8 is a mass spectrum of impurity B;

Figure 9 shows the ultraviolet absorption spectrum of impurity B.

Figure 10 is a flow chart of the preparation method of the present invention. The best mode for carrying out the invention

The materials, reagents, solvents, and other test materials and membrane concentration separation equipment used in the following examples are all commercially available.

The concentrate protecting meropenem (formula) or protecting meropenem can be prepared by any method known in the art, such as the method shown in CN200610083362.7.

The crude meropenem can be prepared by the method of Example 13, or by any method of preparing meropenem in the prior art, such as the method of preparing meropenem in CN1960992A or CN200610083362.7.

The content of C ₁₇ H ₂₅ N ₃ _{5 5} S in the crude meropenem is not less than 92%, calculated as anhydrate; the impurity A and the impurity B are not more than 0.8%; any unknown single impurity is not More than 0.3%; the sum of other impurities except A and B is not more than 3.0%.

Unless otherwise specified, the content determination item, the related substance item, and the residual solvent item in the detection method of the present invention are carried out in accordance with the method of Meropenem in the United States Pharmacopoeia USP32-NF27. The stability test was conducted in accordance with the United States Pharmacopoeia USP32-NF27 method.

Apparatus used: nuclear magnetic resonance (Varian 300); infrared light language (NICOLET 170SX FT ~ IR); mass spectrometry (API2000); ultraviolet light ( Thermo Spectronic 300); LC/MS (Agilent 1100 HPLC-AB API2000 mass spectrometry); preparation Liquid chromatography (Waters 2535); Elemental analysis (Germany ELEMENTAR vario EL elemental analyzer). Example 1

Add 1kg of meropenem to 20kg of water for injection at a temperature of 10 °C, stir and mix, and then suspend the suspension through a heat exchanger to 80 ° C for dissolution, and quickly drop to 25 °C through a heat exchanger. C, solution I is obtained.

The decolorizing solution I was filtered in-line through an activated carbon filter to obtain a filtrate II.

210 g of the filtrate II was discharged, the temperature was set to 10 ° C, 1050 ml of acetone was added, and the mixture was stirred for 15 minutes, and then filtered to obtain a seed crystal. The temperature was lowered to 2 ° C, and the obtained seed crystals were added to the remaining 20.8 kg of the filtrate II, the stirring speed was maintained at 130 rpm, the crystal was maintained for 8 hours, and filtered to obtain a mother liquid 3, and the mother liquid 3 was subjected to the next nanofiltration concentration.

The filter cake was rinsed with acetone, and the filter cake was dried under vacuum at 30 ° C for 5 hours, and pulverized to obtain meragene saponin 680 g, yield 68%.

The content of meropenem is 99.6% (based on anhydrous matter); the impurity A in the relevant substance is 0.06%; the impurity B is 0.11%; any unknown single impurity is 0.02%; the sum of other impurities except A and B is 0.05% The acetone residue is 80 ppm.

First, the structure of meropenem is determined:

The physical properties of the meropenem drug substance are as follows:

Elemental analysis: C ₁₇ H ₂₅ N ₃ 0 ₅ S'3H ₂ 0

Calculated: C, 46.67%; H, 7.14%; N, 9.60%; S, 7.33%;

Found: C, 46.38%; H, 7.40%; N, 9.68%; S, 7.26%.

UV solid ² . Dear: 296

IR^^cm" ¹ : 1755, 1627, 1393, 1252, 1130.

Ifi-NMR (D ₂ 0, δ/ppm): : 1.21 (3H, d, J = 7.1 Hz), 1.29 ( 3H, d, J = 6.3 Hz ) 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 (lH).

Conclusion: The results of physical properties are consistent with the structure of meropenem.

Second, the impurity research process

1. Initial separation and identification:

First, the impurities were separated and mass spectrometrically determined by the LC/MS system. Refer to the mobile phase under Meropenem in USP32-NF27, and use acetic acid instead of phosphoric acid to prepare the mobile phase. The spectra are very consistent. The molecular weight of each impurity was obtained, and the structure was initially determined. According to the liquid phase spectrum, the relative retention times of impurity A and impurity B (based on the retention time of meropenem for about 6 min) were 0.5 and 2.2, respectively.

2. Liquid phase preparation of impurities: In order to obtain more samples for further verification, referring to the mobile phase conditions in the preliminary separation and identification, the preparative liquid chromatography is used to separate the impurity AB, and the preparation is repeated several times to obtain a salt solution of all the impurities, and the impurity amount reaches the milligram level.

3. Chemical synthesis of impurities:

According to the nature of the impurities, the impurities A and B are chemically synthesized to obtain lg impurity A, purity >95%; impurity B is about 50 mg, purity >90%

1) Synthesis of impurity A:

The impurity A was prepared according to the method described in The Journal of Antibiotics Vol. 46 No. 5 P831 to P832, and confirmed to be an impurity A by the structure, and was in conformity with the literature.

2) Synthesis of impurity B:

Impurity B was prepared according to the method described in Chem. Pharm. Bull. 43(4) P690 (1995), confirmed by structure as impurity B, and in accordance with the literature.

4, synthetic impurities VIII, B and product liquid phase separation impurities A B comparison:

The impurity AB obtained by synthesis is compared with the impurity AB in the liquid phase of the product. First, the UV spectra are compared, and the results indicate that they correspond to AB impurities respectively. For further verification, the impurities A and B obtained by chemical synthesis are respectively added by the addition method. Qualitatively adding the meropenem drug substance obtained by the experiment, according to the increase of the corresponding impurity peak area in the obtained liquid phase spectrum, it is further determined that the impurities A and B in the product are completely consistent with the synthesized AB impurity.

5, impurities A B structure confirmation

1) Impurity A Physical property determination results are:

UV (λ ^mo ): ~ 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+l), 802.6 (2xM+l).

Ifi-NMR (D ₂ 0, δ/ppm): 1.26 (t, J = 7.2, 1.5H, CH ₃ -CH-OH, A); 1.33 (t, J = 6.9, 3H, 1- -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).

¹³ C-NMR (D ₂ 0, 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: The physical property determination results are in agreement with the impurity A structure. The correlation spectrum is shown in Figure 1-5. 2) Impurity B Physical property determination results are:

Υν (λ ^H20 ) _: 297

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+l) ₀

Ifi-NMR δ/ppm (D ₂ 0): 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).

¹³ C-NMR δ/ppm (D ₂ 0): 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: The physical property determination results are in agreement with the impurity B structure, and the correlation spectrum is shown in Figure 6-9. Example 2

3 21.0 kg of the meropenem refined mother liquor obtained in Example 1 was added to the solution tank of the nanofiltration equipment; the outlet pressure of the nanofiltration equipment was controlled to start concentration at 18 X 10 ⁵ Pa, and the temperature of the liquid in the concentration process was controlled to be 10 ° C to 25 ° C. It took 98 minutes to reduce the concentrate from 21.0kg to 2.70kg, and obtained 18.30kg of concentrated wastewater. The sampled concentrated wastewater was used to detect the meropenem content, and the result was not detected. The concentration of meropenem was 10%.

2.70 kg of the concentrate was added to 152 L of the filtered crude mother liquor (mother liquor 2), and the temperature was controlled at 10-15 ° C for 30 min; after filtration, washing and drying, 186 g of crude meropenem was obtained; The crude impurities and content, of which the content of meropenem is 97.8%; the impurity A in the relevant substance is 0.11%; the impurity B is 0.38%; any unknown single impurity is 0.12%; the sum of other impurities except A and B is 1.0%

The mother liquor 2 contains about 16% water and 84% THF. For the preparation method, refer to Example 13. Example 3

Add 20kg of meropenem to 300kg of water for injection at a temperature of 20 °C, stir and mix evenly. The suspension is instantly heated to 70 °C through a heat exchanger and dissolved rapidly to 20 °C through a heat exchanger. Solution I

The decolorization solution I was filtered through an activated carbon filter to obtain a filtrate II.

6.4 kg of filtrate II was discharged, the temperature was set to 5 ° C, 25.6 L of tetrahydrofuran was added, and after stirring for 20 minutes, it was filtered to obtain a seed crystal. The temperature was lowered to 0 ° C, and the obtained seed crystals were added to the remaining 288 kg of the filtrate II, the stirring speed was maintained at 120 rpm, the crystal was maintained for 10 hours, and filtered to obtain a mother liquid 3 , and the mother liquid 3 was subjected to the next nanofiltration concentration.

The filter cake was rinsed with acetone, and the filter cake was dried at 25 ° C for 6 hours, and pulverized to obtain 14 kg of meropenem raw material, yield 70%.

The content of meropenem is 99.7% (based on anhydrous matter); the impurity A in the relevant substance is 0.04%; the impurity B is 0.09%; any unknown single impurity is 0.03%; the sum of other impurities except A and B is 0.05% ; acetone residue is 20ppm

The physical properties of the meropenem drug substance are as follows:

Elemental analysis: C ₁₇ H ₂₅ N ₃ 0 ₅ S'3H ₂ 0

Calculated: C, 46.67%; H, 7.14%; N, 9.60%; S, 7.33%;

Found: C, 46.40%; H, 7.38%; N, 9.66%; S, 7.28%

UV ² . Dear: 296

IR^^cm" ¹ : 1755, 1627, 1393, 1252, 1130.

Ifi-NMR (D ₂ 0, δ/ppm): : 1.21 (3H, d, J = 7.1 Hz), 1.29 ( 3H, d, J = 6.3 Hz ) 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 (lH)

The impurity A B was analyzed and measured in accordance with the method described in Example 1, and the results were in agreement. Example 4

3 340 kg of the meropenem refined mother liquor obtained in Example 3 was added to the nanofiltration equipment solution tank; the outlet pressure of the nanofiltration equipment was controlled to start concentration at 20 X 10 ⁵ Pa, and the temperature of the concentrated liquid was controlled to be 5 ° C ~ 35.0 ° C, concentrated. The liquid was reduced from 340kg to 42kg, and 298kg of concentrated wastewater was obtained. The sampled concentrated wastewater was used to detect the meropenem content, and the result was not detected. The concentration of meropenem was 9%.

42 kg of the concentrate was added to 398 L of the filtered mother liquor (mother liquor 2) from which the crude product had been precipitated. The temperature was controlled at 5 °C for 60 min; filtered, washed and dried to obtain 3.06 kg of crude meropenem; the impurities and content of meropenem were sampled and tested, wherein the content of meropenem was 98.0%; the impurity A in the related substance was 0.20. %; impurity B is 0.18%; any unknown single impurity is 0.13%; the sum of other impurities except A and B is 1.0%

The mother liquor 2 contains about 14% water and THF+ acetone is 86%; Preparation method refers to Example 13 Example 5

1 kg of the crude meropenem obtained in Example 4 was added to 17 kg of water for injection at a temperature of 5 ° C, stirred and mixed, and the suspension was instantaneously heated to 60 ° C by a heat exchanger to dissolve, and quickly passed through a heat exchanger. Drop to 10 ° C, get solution I

1.8 kg of the filtrate II was discharged, the temperature was set to 20 ° C, 10.8 L of acetone was added, and the mixture was stirred for 15 minutes, and then filtered to obtain a seed crystal. The temperature was lowered to 5 ° C, and the obtained seed crystals were added to the remaining 16.2 kg of the filtrate II, the stirring speed was maintained at 110 rpm, the crystals were maintained for 5 hours, and filtered to obtain a mother liquor 3, and the mother liquor 3 was subjected to the next nanofiltration concentration.

The filter cake was rinsed with acetone, and the filter cake was dried at 20 ° C for 10 hours, and pulverized to obtain merapene 6.2 g, a yield of 69%.

The content of meropenem is 99.8% (calculated as anhydrate); the impurity A in the relevant substance is 0.05%; the impurity B is 0.07%; any unknown single impurity is 0.03%; the sum of other impurities except A and B is 0.08% ; Acetone residue was not detected.

The physical properties of the meropenem drug substance are as follows:

Elemental analysis: C ₁₇ H ₂₅ N ₃ 0 ₅ S'3H ₂ 0

Calculated: C, 46.67%; H, 7.14%; N, 9.60%; S, 7.33%;

Found: C, 46.43%; H, 7.32%; N, 9.56%; S, 7.38%

UV ² . Dear: 296

IR^^cm" ¹ : 1755, 1627, 1393, 1252, 1130.

The impurity A B was analyzed and measured in accordance with the method described in Example 1, and the results were in agreement. Example 6

The 18.5 kg of the meropenem refined mother liquor obtained in Example 5 was added to the nanofiltration equipment solution tank. Control the outlet pressure of the nanofiltration equipment 5 X 10 ⁵ Pa to start concentration, control the concentration of the liquid in the concentration process to 10 °C ~ 30 °C, reduce the concentrate from 18.8kg to 3.76kg, obtain 15kg of concentrated wastewater, and sample the concentrated wastewater to detect meropenem The content was not detected; the concentration of meropenem was 5%.

3.76kg of concentrated liquid was added to 30L of the filtered crude mother liquor (mother liquor 2), and the temperature was controlled at 5 ~ 10 °C for 30min; after filtration, washing and drying, 148.6g of crude meropenem was obtained; The crude impurities and content of Luo Peinan were qualified.

The mother liquor 2 contains about 15% water and THF + mercaptoethyl ketone is 85%; Preparation method refers to Example 13 Example 7

Add 30kg of meropenem to 600kg of water for injection at a temperature of 10 °C, stir and mix evenly. The suspension is heated to 65 °C through a heat exchanger and dissolved rapidly to 15 °C through a heat exchanger. Solution I

9.5 kg of the filtrate II was discharged, the temperature was set to 5 ° C, 28.5 L of tetrahydrofuran was added, and the mixture was stirred for 20 minutes, and then filtered to obtain a seed crystal. The temperature was lowered to 0 ° C, and the prepared seed crystals were added to the remaining 620.5 kg of filtrate I, maintained at a stirring speed of 120 rpm, crystallized for 10 hours, filtered to obtain a mother liquor 3, and the mother liquor 3 was subjected to a next nanofiltration concentration.

The filter cake was rinsed with acetone, and the filter cake was dried at 25 ° C for 6 hours, and pulverized to obtain 21 kg of meropenem raw material, yield 70%.

The content of meropenem is 99.7% (calculated as anhydrous matter); the impurity A in the relevant substance is 0.05%; the impurity B is 0.06%; any unknown single impurity is 0.02%; the sum of other impurities except A and B is 0.06% ; acetone residue is 60ppm

The physical properties of the meropenem drug substance are as follows:

Elemental analysis: C ₁₇ H ₂₅ N ₃ 0 ₅ S'3H ₂ 0

Calculated: C, 46.67%; H, 7.14%; N, 9.60%; S, 7.33%;

Found: C, 46.45%; H, 7.22%; N, 9.54%; S, 7.39%

UV ² . Dear: 296

IR^^cm" ¹ : 1755, 1627, 1393, 1252, 1130.

Ifi-NMR (D ₂ 0, δ/ppm): : 1.21 (3H, d, J = 7.1 Hz), 1.29 ( 3H, d, J = 6.3 Hz ) 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 (lH). The impurities A and B were analyzed and measured in accordance with the method described in Example 1, and the results were in agreement. Example 8

3 600 kg of the meropenem refined mother liquor obtained in Example 7 was added to the nanofiltration equipment solution tank, and the outlet pressure of the nanofiltration equipment was controlled to start concentration at 20 X 10 ⁵ Pa, and the temperature of the concentrated liquid was controlled to be 10 ° C ~ 25 ° C, concentrated. At 51 kg, 542 L of concentrated wastewater was obtained, and the content of meropenem was detected by sampling and concentrating wastewater, and the result was not detected; the concentration of meropenem was 15%.

51 kg of the concentrate was added to a crude crystallizing tank containing 1700 L of the filtered mother liquor (mother liquor 1) which was not precipitated, and the crude product was continuously produced. 2120 L of tetrahydrofuran crystals were added, and the temperature was controlled at 5 to 10 ° C for 30 min; filtered and washed. After crystal and drying, 24.05kg of meropenem crude product was obtained; the impurities and content of meropenem crude were sampled and tested, wherein the content of meropenem was 98.4%; the impurity A in the related substance was 0.24%; the impurity B was 0.14%; any unknown single impurity was 0.10. %; The sum of other impurities except A and B is 0.58%.

The preparation method of the mother liquid 1 is as described in Example 13. Example 9

60 kg of meropenem crude was added to 600 kg of water for injection at a temperature of 20 ° C, stirred and mixed uniformly, and the suspension was instantaneously heated to 50 ° C through a heat exchanger to dissolve, and rapidly lowered to 10 ° C through a heat exchanger. Solution I was obtained.

The temperature was lowered to 5 °C, 3 kg of seed crystals were added, the stirring speed was maintained at 110 rpm, the crystals were maintained for 20 hours, and filtered to obtain a mother liquor 3, and the mother liquor 3 was subjected to the next nanofiltration concentration.

The filter cake was rinsed with acetone, and the filter cake was dried at 25 ° C for 6 hours, and pulverized to obtain 41.4 kg of meropenem raw material, yield 69%.

The content of meropenem is 99.5% (based on anhydrous matter); the impurity A in the relevant substance is 0.07%; the impurity B is 0.09%; any unknown single impurity is 0.02%; the sum of other impurities except A and B is 0.06% The acetone residue is 50 ppm.

The physical properties of the meropenem drug substance showed that it was consistent with the meropenem structure.

The impurities A and B were analyzed and measured in accordance with the method described in Example 1, and the results were in agreement. Example 10

3 600 kg of the meropenem refined mother liquor obtained in Example 9 was added to the nanofiltration equipment solution tank, and the outlet pressure of the nanofiltration equipment was controlled to start concentration at 20 X 10 ⁵ Pa, and the temperature of the liquid in the concentration process was controlled to be 10 °C ~ 25 °C, concentrated to 40kg, 560L of concentrated wastewater was obtained, and the content of meropenem was detected by sampling and concentrating wastewater. The result was not detected; the concentration of meropenem was 20%.

Add 40kg of concentrated liquid to the crude crystallizing tank containing 1700L of the filtered mother liquor (mother liquor 1) without precipitation, carry out the crude product production together, add 3560L acetone crystal, control the temperature 5 ~ 10 °C and stir for 30min; After crystallizing and drying, 29.6 kg of crude meropenem was obtained. The impurities and content of meropenem were determined by sampling. The content of meropenem was 98.2%; the impurity A in the related substance was 0.28%; the impurity B was 0.30%; any unknown single impurity was 0.11. %; The sum of other impurities except A and B is 0.64%.

The preparation method of the mother liquid 1 is as described in Example 13. Example 11

1 kg of the crude meropenem obtained in Example 10 was added to 13 kg of water for injection at 70 ° C, dissolved by stirring for 2 minutes, and rapidly lowered to 25 ° C in 4 minutes.

10 g of medical activated carbon was added for decolorization for 5 minutes, and filtered to obtain a filtrate II.

Cool down to 2 ° C, add 20 g of seed crystals, keep stirring at 100 rpm, crystallize for 7 hours, filter, and the mother liquor is concentrated in the next nanofiltration.

The filter cake was rinsed with acetone, and the cake was dried under vacuum at 25 ° C for 6 hours, and pulverized to obtain 670 g of meropenem prodrug, and the yield was 67%.

The content of meropenem is 99.4% (based on anhydrous matter); the impurity A in the relevant substance is 0.08%; the impurity B is 0.13%; any unknown single impurity is 0.03%; the sum of other impurities except A and B is 0.07% The acetone residue is 10 ppm.

The impurities A and B were analyzed and measured in accordance with the method described in Example 1, and the results were in agreement. Example 12

3 13 kg of the meropenem refined mother liquor obtained in Example 11 was added to the nanofiltration equipment solution tank, and the outlet pressure of the nanofiltration equipment was controlled to be 15 x 10 ⁵ Pa; the concentration was started, and the temperature of the concentrated liquid was controlled to be 10 ° C to 25 ° C. Concentrated to 1.85 kg, 11.15 kg of concentrated wastewater was obtained, and the content of meropenem was detected by sampling and concentrating wastewater, and the result was not detected; the concentration of meropenem was 7%.

1.85 kg of the concentrate was added to a crude crystallization tank containing 1700 L of the filtered mother liquor (mother liquor 1) without precipitation, and the crude product was continuously produced, and 2,625 L of sterol crystals were added thereto, and the temperature was controlled at 5 to 10 ° C for 30 minutes; After washing and drying, 19.7 kg of crude meropenem was obtained; the impurities and content of crude meropenem were sampled and tested, and the results were satisfactory. The mother liquor 1 was prepared from Example 13 to obtain Example 13

It will protect 33.0kg of meropenem (I _a ) (or a concentrate with a merocene HLPC content of 33.0kg), THF 880L, water 700L, 3,5,-dimercaptopyridine 14.5kg, 10% palladium carbon 5.28kg And added to a 2000L high pressure reaction vessel, the air is removed, hydrogen is introduced, and the reaction is carried out for 6 hours at room temperature. After the reaction is completed, the palladium carbon is recovered by filtration and washing to obtain 1700 L of the filtered mother liquid without precipitation of crude product, wherein the THF is about 880 L and the water is about 700 L. Other about 120L; this mother liquor can be used as the filtered mother liquor without precipitation of crude product, referred to as mother liquor 1;

The mother liquor was added with 2625 L of tetrahydrofuran, the temperature was controlled at 10-15 ° C for 30 min, filtered, washed, and the product was dried to obtain 19.5 kg of crude meropenem (Compound I), the mass yield was 59%; wherein the content of meropenem was 97.8%; The impurity A in the relevant substance was 0.20%; the impurity B was 0.40%; any unknown single impurity was 0.13%; the sum of the other impurities except A and B was 1.2%.

4300 L of the filtered mother liquor having a precipitated crude product was obtained, wherein the water content was about 700 L and the THF was about 3600 L; that is, about 16% of water and 84% of THF. This mother liquor can be used as a filtered mother liquor which has been precipitated as a crude product, referred to as mother liquor 2 .

The tetrahydrofuran in 2625L tetrahydrofuran can be replaced by one or more of acetone, isopropanol, decyl alcohol, ethanol, mercaptoethyl ketone; the volume ratio of the volume of the organic solvent in the mother liquor 2 to water is 3: 1 ~ 6: 1 can be.

Among them, the tetrahydrofuran in 2625L of tetrahydrofuran can be replaced by one or more of acetone, isopropanol, decyl alcohol, ethanol and mercaptoethyl ketone, and the crude meropenem can be prepared. Example 14

The 500 g of sterile meropenem drug substance prepared by the method described in Example 1 and 104 g of sterile sodium carbonate were pulverized, and the test was carried out according to the requirements of sterility and particle size, and the mixture was uniformly mixed with a high-efficiency mixer, and the packaging container was aseptically processed. Filling, according to the United States Pharmacopoeia USP32-NF27 injection with meropenem under the test method qualified, packaged into the warehouse. Example 15

1000g of sterile meropenem drug substance prepared by the method described in Example 、, 222g of sterile sodium carbonate pulverized, tested to meet the requirements of sterility and particle size, and uniformly mixed with a high-efficiency mixer, and the packaging container is aseptically processed. Filling, according to the United States Pharmacopoeia USP32-NF27 injection with meropenem under the test method qualified, packaged into the warehouse. Example 16

The 2000 g of sterile meropenem drug substance prepared by the method described in Example 9 and 390 g of sterile sodium carbonate were pulverized, and the test was carried out according to the requirements of sterility and particle size, and the mixture was uniformly mixed with a high-efficiency mixer, and the packaging container was aseptically processed. Filling, according to the United States Pharmacopoeia USP32-NF27 injection with meropenem under the test method qualified, packaged into the warehouse. Comparative Example 1

5 g of meropenem was dissolved in 50 ml of water at 30 ° C, cooled in a water bath, a small amount of crystals were precipitated, and 250 ml of acetone was added. When stirred, the crystals were obtained by filtration, washed with 90 ml of acetone, and dried under reduced pressure at room temperature for two hours to obtain about 4.7 g. Robinan trihydrate crystals.

The content of meropenem is 98.4% (based on anhydrous matter); the impurity A in the relevant substance is 0.19%; the impurity B is 0.27%; any unknown single impurity is 0.10%; the sum of other impurities except A and B is 0.26% The acetone residue was 599 ppm.

The weight ratio of the meropenem drug substance to sodium carbonate prepared according to the method described in Example 14 was

1000:208 pharmaceutical composition. Comparative Example 2

200 g of crude meropenem was dissolved in 20 L of water at 20 ° C to form a solution, 10 g of activated charcoal was added to the solution, and the solution was stirred for about one hour. After removing the activated carbon by filtration, the filtrate was washed with water to form an aqueous solution, and the aqueous solution was concentrated by a reverse osmosis concentration apparatus operating at a pressure of 120 psig and an operating temperature of 10 ° C to 20 ° C to obtain 6.7 L of a concentrate. The concentrate is cooled to 0 ° C to 10 ° C, 1 g of seed crystals is added to the concentrate, and 20.1 L of tetrahydrofuran at a temperature of 0 ° C to 10 ° C is added as a solvent for the concentrate, followed by stirring for 6 hours, and stirring. The temperature was from 0 ° C to 5 ° C, and the precipitated crystals were collected, washed with acetone and dried at 30 ° C for 3 hours to obtain 165 g of meropenem.

According to the Chinese Pharmacopoeia 2010 edition of the second test, the content of meropenem is 98.9% (in terms of anhydrous matter); the maximum impurities before and after the main peak in the relevant substances are 0.13%, 0.23%, respectively. He has a single impurity of 0.08%; the sum of each impurity is 0.52%, and the organic residue of THF is 998 ppm. The weight ratio of the meropenem drug substance to sodium carbonate prepared according to the method described in Example 14 was

1000:208 pharmaceutical composition. Stability test

Next, the beneficial effects of the drug substance and the preparation provided by the present invention will be explained by the results of the stability investigation.

1. Investigation on the stability of melopenem drug substance accelerated test

Packing: Aluminum drum; Storage conditions: Temperature 40. C±2. C, Humidity 75% RH±5% RH Meropenem drug substance 1 ~ 6 months Accelerated test stability test results are shown in Table 1.

Table 1. Stability results of melopenem drug substance accelerated test

Item Indicator 0-Month 1-Month 2-Month 3-Month 4-Month 6-Month Example 1 Sample related substances

Impurity A < 0.25% 0.06% 0.12% 0.12% 0.14% 0.14% 0.15% 0.15% Impurity B < 0.25% 0.11% 0.08% 0.05% 0.06% 0.06% 0.06% 0.04% Any unknown single impurity: < 0.05% 0.02% 0.03% 0.04% 0.02% 0.03% 0.03% 0.02% Except for the sum of other impurities except A and B: < 0.2% 0.05% 0.05% 0.10% 0.09% 0.08% 0.11% 0.06% Example 1 sample and No. 5 standard

Solution color colorimetric liquid comparison < Y5 < Υ5 < Υ5 < Υ5 < Υ5 < Υ5 = Υ4 Not deeper

Example 3 Sample related substances

Impurity A < 0.25% 0.04% 0.13% 0.15% 0.14% 0.14% 0.16% 0.15% Impurity B < 0.25% 0.09% 0.08% 0.08% 0.06% 0.06% 0.06% 0.04% Any unknown single impurity: < 0.05% 0.03% 0.03% 0.02% 0.02% 0.03% 0.03% 0.02% Except for the sum of other impurities except A and B: < 0.2% 0.05% 0.05% 0.08% 0.09% 0.08% 0.11% 0.07% Example 3 sample and No. 5 standard

Solution color colorimetric liquid comparison < Υ5 < Υ5 < Υ5 < Υ5 < Υ5 < Υ5 = Υ4 Not deeper

Example 7 Sample related substances

Impurity A < 0.25% 0.05% 0.12% 0.13% 0.11% 0.13% 0.16% 0.15% Impurity B < 0.25% 0.06% 0.08% 0.08% 0.05% 0.05% 0.06% 0.04% Any unknown single impurity: < 0.05% 0.02% 0.03% 0.02% 0.01% 0.02% 0.02% 0.02% The sum of other impurities except A and B: < 0.2% 0.06% 0.06% 0.07% 0.07% 0.08% 0.11% 0.06% Example 7 sample and No. 5 standard

Solution color colorimetric liquid comparison < Υ5 < Υ5 < Υ5 < Υ5 < Υ5 < Υ5 Υ4-Υ5 Not deeper

Comparative Example 1 Related Substances USP32-NF2

Impurity A 7 0.19%

0.19% 0.20% 0.21% 0.21% 0.21% 0.23% Impurity B < 0.3% 0.27%

0.27% 0.28% 0.29% 0.29% 0.30% 0.32% Any unknown single impurity: < 0.3% 0.10%

0.12% 0.12% 0.14% 0.15% 0.14% 0.15% The sum of other impurities except A and B: < 0.1% 0.26%

0.27% 0.26% 0.28% 0.29% 0.31% 0.33%

< 0.3% Comparative Example 1 sample and No. 5 standard

Solution color Comparison of colorimetric liquid Y2-Y3 Y4-Y5 Y4-Y5 Y4-Y5 = Y5 = Y5 >Y5 Must not be deeper

Comparative Example 2 related substances (Chinese Pharmacopoeia)

The largest impurity before the main peak 2010 edition)

0.13% 0.15% 0.16% 0.16% 0.17% 0.18% 0.18% Maximum impurity after main peak <0.3%

0.23% 0.23% 0.24% 0.26% 0.27% 0.28% 0.31% Other single impurities <0.3%

0.08% 0.12% 0.15% 0.13% 0.15% 0.14% 0.16% The sum of each impurity <0.1%

0.52% 0.55% 0.61% 0.64% 0.68% 0.71% 0.80%

<1.0%

Comparative Example 2 Sample and Standard 5

Solution color colorimetric liquid comparison = Y3 = Y5 Y4-Y5 Y4-Y5 = Y5 = Y5 >Υ5 Not deeper

From the results, it was found that the meropenem drug substance having a high impurity content in Comparative Examples 1 and 2 and having a high organic residue of acetone or tetrahydrofuran was at a temperature of 40. C±2. C, humidity 75% RH ± 5% RH accelerated test conditions for 6 months, the relevant substances, the color of the solution does not meet the requirements, the stability test is unqualified, can not guarantee the safety of medication after long-term storage; and the raw materials provided by the present invention The medicine, in the packaged packaging under the accelerated test conditions, the impurities and the color of the solution still meet the requirements, the stability is very good, and the product can be ensured to be effective and safe. Therefore, the preparation of the injection as a raw material medicine for intravenous administration has higher safety and better curative effect.

Other detection items of the meropenem drug substance provided by the present invention, such as specific rotation, acidity, clarity, bacterial endotoxin, sterility, moisture, visible foreign matter, insoluble particles, organic residues, pyrophoric residues, heavy metals, crystal water, Accelerated test stability results such as anhydrous content also meet the requirements.

The results of the accelerated test stability of the above-mentioned various indicators of the meropenem drug substance provided by other embodiments of the present invention also meet the requirements.

2. Stability study of long-term test of meropenem drug substance

Packing: Aluminum drum; Storage conditions: Temperature 25. C±2. C, Humidity 60% RH±5% RH Meropenem drug substance 1 ~ 24 months long-term test stability test results are shown in Table 2.

Table 2. Stability results of long-term trials of meropenem drug substance

Item Indicator 0-Month 3-Month 6-Month 9-Month 12-Month 18-Month 24-Month Example 1 Sample related substances

Impurity A < 0.25% 0.06% 0.08% 0.12% 0.13% 0.14% 0.14% 0.15% Impurity B < 0.25% 0.11% 0.06% 0.07% 0.06% 0.06% 0.07% 0.08% Any unknown single impurity: < 0.05% 0.02% 0.03% 0.02% 0.02% 0.03% 0.03% 0.04% The sum of other impurities except A and B: < 0.2% 0.05% 0.07% 0.08% 0.08% 0.08% 0.10% 0.11% Example 3 Sample related substances

Impurity A < 0.25% 0.04% 0.08% 0.11% 0.12% 0.13% 0.14% 0.15% Impurity B < 0.25% 0.09% 0.08% 0.08% 0.06% 0.06% 0.08% 0.09% Any unknown single impurity: < 0.05% 0.03% 0.03% 0.02% 0.02% 0.03% 0.03% 0.02% The sum of other impurities except A and B: < 0.2% 0.05% 0.07% 0.07% 0.09% 0.08% 0.11% 0.07% Example 7 sample related substances

Impurity A < 0.25% 0.05% 0.09% 0.11% 0.11% 0.12% 0.14% 0.14% Impurity B < 0.25% 0.06% 0.08% 0.08% 0.05% 0.05% 0.06% 0.04% Any unknown single impurity: < 0.05% 0.02% 0.03% 0.02% 0.01% 0.02% 0.02% 0.03% Sum of other impurities except A and B: < 0.2% 0.06% 0.09% 0.07% 0.07% 0.08% 0.09% 0.06% It can be seen that the package is packaged at a temperature of 25. C±2. C. Humidity 60% RH±5% RH is placed under long-term test conditions for 24 months. The impurities are still in compliance with the regulations and the stability is very good. Therefore, the preparation of injection as a raw material medicine is safer and more effective for intravenous administration.

Other detection items of the meropenem drug substance provided by the present invention, such as specific rotation, acidity, clarity, color, bacterial endotoxin, sterility, moisture, visible foreign matter, insoluble particles, organic residue, ignition residue, heavy metal, crystallization Long-term test stability results such as water and anhydrous content also meet the requirements.

The long-term test stability results of the above-mentioned various indicators of the meropenem drug substance provided by other embodiments of the present invention also meet the requirements.

3. Long-term stability study of meropenem pharmaceutical composition for injection

Storage conditions: Temperature 25. C±2. C, humidity 60% RH 5% RH

The results of the long-term stability study of the meropenem pharmaceutical composition for injection for 1 to 36 months are shown in Table 3. The long-term stability of the pharmaceutical composition for injection of meropenem

From the results, it was found that the compositions prepared in the comparative examples 1 and 2 having a high impurity content and having a high residual organic residue of acetone or tetrahydrofuran were at a temperature of 25. C±2. C, humidity 60% RH ± 5% RH placed under long-term test conditions for 24 months and 36 months, the color of the solution does not meet the requirements, the stability test is unqualified, can not guarantee the safety of medication after long-term storage; and the injection provided by the present invention The long-term test conditions of the meropenem pharmaceutical composition are still in compliance with the regulations, and the stability is very good. The use as an injection for intravenous administration is safer and more effective.

Other detection items of the meropenem pharmaceutical composition for injection provided by the present invention, such as traits, identification, alkalinity, clarity, related substances, loss on drying, content uniformity, bacterial endotoxin, sterility, visible foreign matter, insoluble particles, Long-term test stability results such as content determination also meet the requirements, so the product can be guaranteed to be effective and safe.

Claims

Rights request

A meropenem drug substance, characterized in that, in weight percentage, the content of meropenem in the drug substance is 98.5% to 101.0%, calculated as an anhydrate; the impurity A in the related substance of the drug substance , impurity B is not more than 0.25%; any unknown single impurity is not more than 0.05%; the sum of other impurities except A and B is not more than 0.2%; acetone residue is not more than 400ppm, preferably not more than lOOppm;

Wherein the impurity A is:

The impurity B is

2. A method for preparing a meropenem bulk drug, the preparation method comprising: purifying and filtering a crude meropenem to obtain a mother liquor 3 and a meropenem drug substance, and the mother liquor 3 is concentrated through a nanofiltration membrane, and the obtained concentrate is added to The crude mother liquor is precipitated after hydrogenation in the subsequent crude preparation and filtration.

In the mother liquor (mother liquor 2) or the mother liquor (mother liquor 1) in which no crude product was precipitated, the crude product of meropenem was obtained by crystallization.

3. The production method according to claim 2, characterized in ^{5x l0 5 Pa ~ 20 X 10} 5 Pa, ύ selected pressure ^{15χ 10 5 Pa ~ 20 x 10} 5 Pa and 5 ~ 35 ° C, preferably The nanofiltration of mother liquor 3 was concentrated at a temperature of 10 to 25 °C.

The preparation method according to claim 2 or 3, wherein the weight ratio of the mother liquid 3 to the obtained concentrate is 5:1 to 15:1, preferably 7:1 to 10:1; The content of Sino-American ropamine is 5-20%, preferably 7-15%.

The preparation method according to claim 2, wherein the total volume of the organic solvent in the system for obtaining the crude meropenem is 3:1 to 6:1; the organic solvent is selected from the group consisting of acetone One or more of tetrahydrofuran, isopropanol, decyl alcohol, ethanol, and mercaptoethyl ketone.

6. The method of claim 2, the method of preparation comprising the steps of:

4) The mother liquor 3 obtained in the step 3) is concentrated by nanofiltration, and then added to the mother liquor (mother liquor 2) which has been subjected to hydrogenation in the next batch of crude product preparation, and which has been precipitated after filtration, or the mother liquor (mother liquor 1) in which the crude product is not precipitated. Crystallization gives crude meropenem.

The method according to claim 6, wherein in step 1), the content of C ₁₇ H ₂₅ N ₃ _{5 5} S in the crude product of meropenem is not less than 92% by weight percentage, calculated according to the anhydrous substance. ; impurity A, impurity B are not more than 0.8%; any unknown single impurity is not more than 0.3%; the sum of other impurities except A and B is not more than 3.0%;

Wherein the impurity A is:

The impurity B is

Preferably, the content of C ₁₇ H ₂₅ N ₃ _{5 5} S in the crude meropenem is not less than 95%, calculated as an anhydrate; the impurity A and the impurity B are not more than 0.6%; any unknown a single impurity is not more than 0.3%; the sum of other impurities except A and B is not more than 2.0%;

Dissolving the crude meropenem in water at a temperature of 50 ° C to 80 ° C in the step 1) includes: adding the crude meropenem to 10 to 20 times by weight, preferably 15 to 20 times by weight of 5 to 20 ° Mix well with water for injection, and then heat the resulting suspension to 50 ° C ~ 80 ° C, Preferably, it dissolves at 60 ° C to 80 ° C; wherein the dissolution time is less than 4 minutes, preferably less than 1 minute; preferably, the temperature of the resulting solution is lowered to 10 ° C to 25 ° C; wherein the cooling time is less than 4 minutes , preferably less than 1 minute.

The preparation method according to claim 6 or 7, wherein the step 2) comprises: dissolving the solution I at a temperature of 15 ° C to 25 ° C with a weight of 1 to 20% of the crude product of meropenem 1 ~ 30 minutes, preferably 1 ~ 10 minutes after filtration, to obtain filtrate II;

Alternatively, in step 2), the solution is decolorized by in-line filtration through an activated carbon filter.

The preparation method according to any one of claims 6 to 8, wherein the step 3) comprises: lowering the temperature of the filtrate II to 0 ° C to 5 ° C for crystallization, and maintaining the crystal 2 to 20 Hour, preferably 5~10 hours; after filtration, the mother liquor 3 and the filter cake are obtained, and the filter cake is washed with acetone to wash the crystal, and vacuum dried at 20 ° C ~ 40 ° C, preferably 25 ° C ~ 30 ° C 3 ~ 10 hours, preferably 5 to 6 hours, thereby obtaining a meropenem drug substance;

Preferably, the crystal is a stirred crystal, wherein the stirring speed is 100 to 200 rpm, preferably 110 to 130 rpm.

The preparation method according to any one of claims 6 to 9, wherein the step 3) further comprises: adding a seed crystal to the filtrate II obtained in the step 2) before crystallization;

The temperature at which the seed crystal is added is 0 ° C ~ 20 ° C, preferably 0 ° C ~ 5 ° C; the mass ratio of the added seed crystal to the crude product of meropenem is 1%: 1 ~ 10%: 1, preferably 1%: 1 ~ 2%: 1.

The preparation method according to any one of claims 6 to 10, wherein in step 3), 1% to 10% by weight of the filtrate II is taken before crystallization, and an organic solvent is added thereto. Forming a seed crystal, adding the obtained seed crystal to the remaining filtrate II for crystallization;

Wherein the organic solvent is selected from one or more of acetone, tetrahydrofuran, isopropanol, decyl alcohol, ethanol and mercaptoethyl ketone, preferably acetone and/or tetrahydrofuran; the weight of the partial filtrate II and the organic solvent (kg): The volume (L) ratio is 1:2 to 1:6, and the seed crystal preparation temperature is 5 ° C to 20 ° C, preferably 10 ° C to 15 ° C.

The preparation method according to any one of claims 6 to 11, wherein in step 4), at 5 X 10 ⁵ Pa ~ 20 X 10 ⁵ Pa, preferably 15 10 ⁵ Pa ~ 20 χ 10 ⁵ The pressure of Pa and the nanofiltration concentration of the mother liquor 3 are carried out at a temperature of 5 to 35 ° C, preferably 10 to 25 ° C, so that the weight ratio of the mother liquor 3 to the obtained concentrate is 5:1 to 15:1, preferably 7 : 1 to 10:1; The meropenem content in the obtained concentrate is 5 to 20% by weight, preferably 7 to 15% by weight.

The preparation method according to any one of claims 6 to 12, wherein the volume ratio of the total volume of the organic solvent to the water in the system for obtaining the crude product of meropenem in the step 4) is 3: 1~6:1; organic solvent is selected from acetone, tetrahydrofuran, isopropanol, decyl alcohol, ethanol And one or more of mercaptoethyl ketone; preferably, the crystallization temperature is from 5 ° C to 15 ° C ;

Further preferably, the mother liquor 1 and the mother liquor 2 in the crude meropenem process are prepared by the following method:

Add meropenem (or protect meropenem concentrate), THF, water, 3,5,-dimercaptopyridine, 10% palladium carbon to the autoclave, remove the air, pass hydrogen, and react at room temperature. , washing and recovering palladium carbon to obtain mother liquor 1;

The organic solvent is added to the mother liquor, the temperature is controlled at 10-15 ° C, the mixture is filtered, washed, and the product is dried to obtain a crude product of meropenem (Compound I) and a mother liquor 2 .

The preparation method according to any one of claims 2 to 13, wherein the content of meropenem in the raw material prepared by the method is 98.5% ~ 101.0%, calculated as an anhydrate; The impurities and impurities B in the relevant substances of the raw material drug are not more than 0.25%; any unknown single impurity is not more than 0.05%; the sum of other impurities except A and B is not more than 0.2%; the acetone residue is not more than 400 ppm, preferably not more than 100 ppm.

A pharmaceutical composition of meropenem comprising the meropenem bulk drug according to claim 1 and a pharmaceutically acceptable excipient;

Preferably, the pharmaceutically acceptable excipient is sterile sodium carbonate, wherein the weight ratio of meropenem to sterile sodium carbonate is 1000: 195 ~ 1000: 222;

Further preferably, the pharmaceutical composition is an injection.