CN113968874B - Refining method of cefixime - Google Patents
Refining method of cefixime Download PDFInfo
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- CN113968874B CN113968874B CN202111271010.5A CN202111271010A CN113968874B CN 113968874 B CN113968874 B CN 113968874B CN 202111271010 A CN202111271010 A CN 202111271010A CN 113968874 B CN113968874 B CN 113968874B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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Abstract
The invention belongs to the technical field of pharmacy, and relates to a method for refining cefixime. The refining method of cefixime comprises the following steps: (1) dissolving and decoloring cefixime crude product; and (2) crystallizing the cefixime, and then filtering, washing and drying to obtain cefixime crystals. The cefixime product prepared by the invention has good quality, namely high purity, almost no genotoxic impurity M, narrow crystal particle size distribution, namely good particle size uniformity, good fluidity, high crystallinity and good stability.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a refining method of cefixime.
Background
Cefixime is also called as cefotaxime cephalosporin, provenance and provenance, belongs to the third generation oral cephalosporin antibiotics, has wide antibacterial spectrum, and has certain antibacterial effect on some gram-negative bacteria and gram-positive bacteria. The mechanism is mainly that the bactericidal effect can be played by inhibiting the synthesis of bacterial cell walls. The preparation is clinically used for treating bacterial infectious diseases caused by streptococcus (except enterococcus), streptococcus pneumoniae, gonococcus, escherichia coli, catablain hansenula, serratia, citrobacter, enterobacter cloacae, enterobacter aerogenes, haemophilus influenzae, klebsiella, serratia, proteus, influenza bacillus and the like.
The chemical name of cefixime is: (6R, 7R) -7[ [ (Z) -2- (2-amino-4-thiazolyl) -2- [ (carboxymethoxy) imino group]Acetyl group]Amino group]-3-vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0]An oct-2-ene-2-carboxylic acid trihydrate having the molecular formula C 16 H 15 N 5 O 7 S 2 ·3H 2 O, molecular weight 507.49, structural formula:
chinese patent document CN103980292B discloses a crystallization method of cefixime trihydrate, comprising the following steps: (1) Suspending cefixime in water to form suspension, and then adding alkali to completely dissolve the cefixime to form alkali solution; (2) Preparing a mixed solvent of water and an organic solvent, wherein the volume of the mixed solvent is 10-18 times of the weight of the cefixime in the step (1), and the volume ratio of the water to the organic solvent is 1:1, heating the mixed solvent to 20-45 ℃, preferably 30-40 ℃, and adjusting the pH of the mixed solvent to 2-4, preferably 2.5-3.2 by using 2-15 wt%, preferably 8-15 wt% of acid; (3) Dropwise adding the alkali solution into the mixed solvent, and controlling the pH of the solution to be 2-4, preferably 2.5-3.2 by using 2-15 wt%, preferably 8-15 wt% of acid during dropwise adding; and (4) cooling and crystallizing after the dropwise addition is finished. The patent literature indicates that the obtained product has good fluidity, high product quality, generally purity of about 99.4-99.5%, and good stability. However, the present inventors repeated example 1 of CN103980292B and obtained cefixime with a purity of about 99.5%, but the obtained crystal had too high crystal water activity, poor stability, poor particle size uniformity, poor fluidity, and high genotoxic impurity (2-mercaptobenzothiazole). The invention adopts a 'pair-dropping' crystallization mode, namely, cefixime alkali solution and acid are dropped into a mixed solvent together, and the method has the advantages of high crystallization speed, poor crystal crystallinity and high water activity, so that the stability of the product is not good enough. Further, since the crystallization end point pH is controlled to 2 to 4 (the isoelectric point of cefixime is pH =2, the solubility is lowest near the isoelectric point, and the amount of crystallization is large), for example, in example 1, the crystallization end point is controlled to 2.70 to 2.90, so that the amount of crystallization of the crystal is insufficient, the yield is affected, and industrialization is not facilitated.
After the outbreak of nelfinavir mesylate (vilaset troche) in 2006, the European Medicines Agency (EMA) immediately issued "genotoxic impurity limit guidelines", the international harmonization conference (ICH) for registration of human medicines and the united states Food and Drug Administration (FDA) issued corresponding regulations, the national food and drug administration of china also closely tracked the technical requirements for international quality control of medicines, and continuously perfected the current pharmacopoeia regulatory technical guidelines. 2-mercaptobenzothiazole (hereinafter referred to as M) is a byproduct generated in the synthesis process of cefixime, belongs to genotoxic impurities from the structural point of view, has a certain amount of residues in a cefixime crude product, and has lower and lower requirements on the residual amount of the genotoxic impurities at home and abroad at present.
Therefore, the present inventors have made an effort to research and improve a method for refining cefixime, and have sought to obtain cefixime which is excellent in product quality, i.e., high in purity, low in the content of genotoxic impurity M, narrow in crystal size distribution (good in uniformity of particle size), excellent in fluidity, high in crystallinity, and excellent in stability.
Disclosure of Invention
Technical problem
Therefore, the invention aims to provide a cefixime refining method with reasonable process design, and the prepared cefixime product has good quality, namely high purity, almost no genotoxic impurity M, narrow crystal particle size distribution (good particle size uniformity), good fluidity, high crystallinity and good stability.
Technical scheme
According to the invention, the method for refining cefixime provided by the invention comprises the following steps:
(1) Dissolving and decoloring cefixime crude product
Mixing the cefixime crude product with water at 0-10 ℃, and then adding alkali to dissolve the cefixime crude product to obtain a clear solution; adjusting the pH value of the solution to 4.5-6.5 by acid, and then carrying out activated carbon decoloration treatment;
(2) Three-step crystallization of cefixime
First crystallization: adding water and acetone into the cefixime solution decolored by the active carbon at the temperature of between 25 and 35 ℃, gradually adding acid while stirring to separate out the cefixime until the solution is in a fog shape, and growing the crystal for 30 to 240 minutes; then, acetone is added into the mixture, and crystal growth is continued for 30 to 60 minutes;
second crystallization: after crystal growth at 25-35 ℃, acid is gradually added into the first crystallization liquid under stirring until the pH value is 2.5-3.0, and then crystal growth is carried out for 30-240 minutes; then, acetone is added into the mixture, and crystal growth is continued for 30 to 60 minutes;
and (3) third crystallization: after crystal growth at 25-35 ℃, acid is gradually added into the second crystallization liquid under stirring until the pH value is 1.8-2.2, and then crystal growth is carried out for 30-240 minutes; then, adding acetone into the mixture, and continuing growing the crystals for 30 to 60 minutes;
and then, filtering, washing and drying the third crystallization liquid to obtain the cefixime crystal.
Advantageous effects
Compared with the prior art, the invention has the advantages that:
(1) The cefixime adopts a low temperature condition of 0-10 ℃ in the dissolving process, thereby greatly reducing the risk of impurity rise caused by using alkali liquor in the dissolving process;
(2) After the cefixime solution is obtained, adjusting the pH value of the solution to 4.5-6.5 by adopting acid, performing activated carbon decoloration treatment, and decoloring the activated carbon at the pH value of 4.5-6.5, so that the cefixime is effectively prevented from decomposing at high pH to generate impurities, and the decolored activated carbon has the best pigment and impurity adsorption effect under the weak acid condition;
(3) Three-stage gradient crystallization is adopted in the cefixime crystallization process, the crystal yield rate is uniform, the crystal growth is complete, and in the three-stage gradient crystallization, after the pH is adjusted by acid, a certain amount of acetone is added, so that the crystal particles can be effectively improved, the crystal particle size distribution of the system is narrow, the fluidity is good, the bulk density is high, and meanwhile, product impurities and genotoxic impurities M can be effectively reduced;
(4) Cefixime is a crystal containing three crystal waters, the activity of different crystal waters shows the degree of crystallinity of the crystal, the lower the water activity measurement value is, the tighter the combination of water and cefixime crystal is, the crystal lattice formation participates in the crystallization process, the better the crystallinity is, and the cefixime with good crystallinity has good stability.
Drawings
Fig. 1 to 7 show the results of particle size analysis of the cefixime crystals purified in examples 1 to 5 and comparative examples 1 to 2 using a malvern laser particle sizer.
Detailed Description
The method for purifying cefixime of the present invention is described in more detail below.
In the step (1), in the dissolving and decoloring of the cefixime crude product, mixing the cefixime crude product with water at 0-10 ℃, and then adding alkali to dissolve the cefixime crude product to obtain a clear solution; adjusting the pH of the solution to 4.5-6.5 by acid, and then carrying out activated carbon decolorization treatment.
Wherein the cefixime crude product is a cefixime crude product which is conventional in industrial production, for example, a cefixime crude product which is prepared in a synthesis reaction and is not purified, and the purity is generally lower than 99% (HPLC area normalization method).
Firstly, putting water into a reaction kettle, and then putting a cefixime crude product, wherein the ratio of the cefixime crude product to the water is 1: 15-20, starting stirring, controlling the temperature at 0-10 ℃, and putting alkali into the reaction kettle in batches to completely dissolve cefixime, wherein the alkali used can be one or a mixture of more than two of sodium carbonate, sodium bicarbonate, sodium acetate, disodium hydrogen phosphate, sodium isooctanoate, ammonia water and the like, and is preferably one or a mixture of more than two of sodium carbonate, sodium bicarbonate and sodium acetate. Wherein the amount of the base can be such that the cefixime crude product is completely dissolved, and preferably when the base is monobasic, the molar ratio of the cefixime crude product to the monobasic base is 1:1 to 1.2; when the base is a binary base, the molar ratio of the cefixime crude product to the binary base is 1:0.5 to 0.6.
Cefixime is a quaternary lactam antibiotic, and the structural characteristics of cefixime cause cefixime to be easily destroyed and opened when encountering alkaline substances, so that low temperature and low pH value play an important role in stabilizing the structure of cefixime. The method adopts the low-temperature condition of 0-10 ℃ in the dissolving process of the cefixime crude product, and uses weak base, thereby effectively reducing the risk of impurity rise in the dissolving process.
After the cefixime crude product is dissolved by alkali to obtain a clear solution, the pH value of the clear solution is adjusted to 4.5-6.5, preferably 5.0-6.5 by acid, and then activated carbon decoloration treatment is carried out. Wherein, the acid is one or a mixture of a plurality of sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid, and the concentration of the acid is 5 to 15 weight percent; in the decoloring treatment of the activated carbon, the using amount of the activated carbon is 2 to 5 weight percent of the weight of the cefixime crude product, the decoloring treatment time is 30 to 120 minutes, then the activated carbon is filtered, the activated carbon is washed by water 2 to 4 times of the weight of the cefixime crude product, and the washing liquid is merged into the cefixime solution decolored by the activated carbon.
The activated carbon decoloration is carried out at the pH value of 4.5-6.5, the risk of impurity rise caused by higher pH value in the decoloration process is effectively reduced (generally, the pH value of cefixime is about 7.5-8.5 after the cefixime is dissolved and cleaned by alkali liquor), the cefixime is a quaternary lactam antibiotic, the structural characteristics of the cefixime antibiotic enable the cefixime antibiotic to be easily destroyed and opened in an alkaline or weakly alkaline environment, and therefore, the control of the pH value of 4.5-6.5 plays an important role in stabilizing the structure of the cefixime antibiotic.
In the cefixime three-step crystallization in the step (2), in the first crystallization, water and acetone are added into the cefixime solution decolored by the activated carbon at 25-35 ℃, acid is gradually added under stirring to separate out the cefixime until the solution is in a mist state, and the crystallization is carried out for 30-240 minutes; then, acetone is added into the mixture, and the crystal growth is continued for 30 to 60 minutes. Among them, the acid used is 1 to 2mol/L sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid, and preferably 1 to 2mol/L hydrochloric acid.
Specifically, in the first crystallization, water and acetone are added into the cefixime solution clear solution decolorized by the activated carbon at the temperature of between 25 and 35 ℃, preferably between 30 and 35 ℃, wherein the addition amount of the water is between 2.5 and 3.5ml/g of cefixime crude product, and the addition amount of the acetone is between 0.7 and 1.2ml/g of cefixime crude product, preferably between 0.8 and 1ml/g of cefixime crude product; controlling the temperature to be 25-35 ℃, preferably 30-35 ℃, and controlling the stirring speed to be more than 250rpm under stirring, for example, controlling the stirring speed to be 250-400 rpm, dropwise adding acid at uniform speed within 30-60 minutes to separate out cefixime until the cefixime is in a fog state, namely an obvious crystallization state, wherein about 10-20 wt% of cefixime crystals are separated out based on the weight of cefixime crude product; then growing the crystal for 30-240 minutes, then supplementing acetone into the mixture, wherein the adding amount of the acetone is 0.2-1.0 ml/g of cefixime crude product, preferably 0.4-0.8 ml/g of cefixime crude product, and then continuously growing the crystal for 30-60 minutes.
In the second crystallization, after crystal growth, acid is gradually added into the first crystallization liquid under stirring at 25-35 ℃ until the pH value is 2.5-3.0, and then crystal growth is carried out for 30-240 minutes; then, adding acetone into the mixture, and continuing growing the crystals for 30 to 60 minutes; among them, the acid used is 1 to 2mol/L sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid, and preferably 1 to 2mol/L hydrochloric acid.
Specifically, in the second crystallization, the temperature is controlled to be 25 to 35 ℃, preferably 30 to 35 ℃, the stirring speed is controlled to be more than 250rpm under stirring, for example, the stirring speed is controlled to be 250 to 400rpm, acid is uniformly and dropwise added into the first crystallization liquid within 30 to 60 minutes until the pH value is 2.5 to 3.0, and then the crystallization is carried out for 30 to 240 minutes; then, acetone is supplemented into the cefixime crude product, the adding amount of the acetone is 0.2-1.0 ml/g, preferably 0.4-0.8 ml/g, and then the crystal growth is continued for 30-60 minutes.
In the third crystallization, after crystal growing, acid is gradually added into the second crystallization liquid under stirring at the temperature of 25-35 ℃ until the pH value is 1.8-2.2, and then the crystal growing is carried out for 30-240 minutes; then, adding acetone into the mixture, and continuing growing the crystals for 30 to 60 minutes; among them, the acid used is 1 to 2mol/L sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid, and preferably 1 to 2mol/L hydrochloric acid.
Specifically, in the third crystallization, the temperature is controlled to be 25 ℃ to 35 ℃, preferably 30 ℃ to 35 ℃, the stirring speed is controlled to be more than 250rpm under stirring, for example, the stirring speed is controlled to be 250rpm to 400rpm, acid is dropwise added into the second crystallization liquid at a uniform speed within 30 minutes to 60 minutes until the pH value is 1.8 to 2.2, and then the crystallization is carried out for 30 minutes to 240 minutes; then, acetone is supplemented into the cefixime crude product, the adding amount of the acetone is 0.2-1.0 ml/g, preferably 0.4-0.8 ml/g, and then the crystal growth is continued for 30-60 minutes.
And then, filtering the third crystallization liquid, washing the obtained cefixime crystal with water, and then washing with an acetone/water mixed liquid, wherein the volume ratio of acetone to water can be 1: 1-10, and finally drying under the vacuum condition to obtain the cefixime crystal product.
The present invention will be described more specifically with reference to the following examples, but the scope of the present invention is not limited to the following examples.
Example 1
(1) Dissolving and decoloring cefixime crude product
Firstly, 950g of water is put into a reaction kettle, 50g of cefixime crude product (with the purity of 98.8 percent and the HPLC area normalization method) is put into the reaction kettle, the stirring is started, the temperature is controlled to be 0-5 ℃, 9.2g of sodium bicarbonate is put into the reaction kettle in batches to ensure that cefixime is completely dissolved and clear, after the cefixime is dissolved and clear, the pH is adjusted to 6.0 by using 5wt percent hydrochloric acid, 2g of activated carbon is added for decolorization treatment for 30 minutes, then the filtration is carried out, the activated carbon is washed by using 150ml of water, and the washing liquid is merged into the cefixime solution clear liquid decolorized by the activated carbon.
(2) Three-step crystallization of cefixime
Adding 145ml of water and 40ml of acetone into cefixime solution decolourized by activated carbon, controlling the temperature of the feed liquid at 30 ℃, uniformly and dropwise adding 1.0mol/L hydrochloric acid within 30-35 minutes while stirring at 350rpm until the cefixime solution obviously appears in a crystal state (fog), growing crystals for 180 minutes, supplementing 20ml of acetone into the feed liquid after the crystal growth is finished, and continuing to grow crystals for 60 minutes;
controlling the temperature of the feed liquid to be 30 ℃, dropwise adding 1.0mol/L hydrochloric acid into the first crystallization liquid at a uniform speed within 30-35 minutes while stirring at 350rpm until the pH value is 2.5, growing the crystals for 60 minutes, then adding 20ml of acetone into the feed liquid, and continuing to grow the crystals for 60 minutes;
controlling the temperature of the feed liquid to be 30 ℃, dropwise adding 1.0mol/L hydrochloric acid into the second crystallization liquid at a uniform speed for 30-35 minutes under the stirring of 350rpm until the pH value is 2.0, growing the crystals for 60 minutes, then adding 20ml of acetone into the feed liquid, and continuing to grow the crystals for 60 minutes;
then, after filtration, washing with water, washing with a mixed solution of acetone/water (volume ratio 1).
Example 2
(1) Dissolving and decoloring cefixime crude product
Firstly, 950g of water is put into a reaction kettle, 50g of cefixime crude product (with the purity of 98.8 percent and the HPLC area normalization method) is put into the reaction kettle, the stirring is started, the temperature is controlled to be 0-5 ℃, 9.2g of sodium bicarbonate is put into the reaction kettle in batches to ensure that cefixime is completely dissolved and clear, after the cefixime is dissolved and clear, 5wt percent hydrochloric acid is used for adjusting the pH value to 6.0, 2g of active carbon is added for carrying out decoloration treatment for 60 minutes, then the filtration is carried out, the active carbon is washed by 150ml of water, and the washing liquid is merged into the cefixime solution clear liquid decolored by the active carbon.
(2) Three-step crystallization of cefixime
Adding 125ml of water and 50ml of acetone into the cefixime solution decolorized by the activated carbon, controlling the temperature of the feed liquid at 35 ℃, uniformly and dropwise adding 1.5mol/L of hydrochloric acid into the feed liquid at a speed of 50-60 minutes under stirring at 280rpm until the feed liquid obviously appears in a crystal state (fog shape), growing crystals for 180 minutes, adding 40ml of acetone into the feed liquid after the crystal growth is finished, and continuing to grow the crystals for 30 minutes;
controlling the temperature of the feed liquid to be 35 ℃, uniformly dripping 1.5mol/L hydrochloric acid into the first crystallization liquid for 50-60 minutes under the stirring of 280rpm until the pH value is 2.5, growing the crystals for 180 minutes, then adding 40ml of acetone into the feed liquid, and continuing to grow the crystals for 30 minutes;
controlling the temperature of the feed liquid to be 35 ℃, uniformly dripping 1.5mol/L hydrochloric acid into the second crystallization liquid for 50-60 minutes under the stirring of 280rpm until the pH value is 2.0, growing the crystals for 180 minutes, then adding 40ml of acetone into the feed liquid, and continuing to grow the crystals for 60 minutes;
then, after filtration, washing with water, washing with acetone/water (volume ratio 1.
Example 3
(1) Dissolving and decoloring cefixime crude product
Firstly, 950g of water is put into a reaction kettle, 50g of cefixime crude product (with the purity of 98.5 percent and the HPLC area normalization method) is put into the reaction kettle, the stirring is started, the temperature is controlled to be 7-10 ℃, 9.1g of sodium acetate is put into the reaction kettle in batches to ensure that cefixime is completely dissolved and clear, after the cefixime is dissolved and clear, the pH is adjusted to 5.0 by using 5wt percent acetic acid, 2.5g of active carbon is added for decoloration treatment for 30 minutes, then the filtration is carried out, the active carbon is washed by 150ml of water, and the washing liquid is merged into the cefixime solution which is decolored by the active carbon.
(2) Three-step crystallization of cefixime
Adding 175ml of water and 50ml of acetone into cefixime solution decolourized by activated carbon, controlling the temperature of the feed liquid at 30 ℃, uniformly and dropwise adding 1.5mol/L hydrochloric acid within 50-60 minutes while stirring at 350rpm until the crystal is obviously generated (atomized), growing the crystals for 90 minutes, supplementing 20ml of acetone into the feed liquid after the crystal growth is finished, and continuing to grow the crystals for 60 minutes;
controlling the temperature of the feed liquid to be 30 ℃, uniformly dripping 1.5mol/L hydrochloric acid into the first crystallization liquid for 30-40 minutes under the stirring of 350rpm until the pH value is 3.0, growing crystals for 90 minutes, then adding 20ml of acetone into the feed liquid, and continuing to grow crystals for 60 minutes;
controlling the temperature of the feed liquid to be 30 ℃, dropwise adding 1.5mol/L hydrochloric acid into the second crystallization liquid at a uniform speed for 30-40 minutes under the stirring of 350rpm until the pH value is 2.0, growing the crystals for 180 minutes, then adding 20ml of acetone into the feed liquid, and continuing to grow the crystals for 60 minutes;
then, 46.1g of cefixime crystal product is obtained by filtering, washing with water, washing with acetone/water (volume ratio 1.
Example 4
(1) Dissolving and decoloring cefixime crude product
Firstly, 950g of water is put into a reaction kettle, 50g of cefixime crude product (with the purity of 98.5 percent and the HPLC area normalization method) is put into the reaction kettle, stirring is started, the temperature is controlled to be 0-5 ℃, 9.1g of sodium acetate is put into the reaction kettle in batches to ensure that cefixime is completely dissolved and clear, after the cefixime is dissolved and clear, the pH is adjusted to 5.0 by using 5wt percent phosphoric acid, 2.5g of active carbon is added for decoloration treatment for 30 minutes, then filtration is carried out, 150ml of water is used for washing the active carbon, and washing liquid is merged into cefixime solution which is decolored by the active carbon.
(2) Three-step crystallization of cefixime
Adding 145ml of water and 40ml of acetone into the cefixime solution decolorized by the activated carbon, controlling the temperature of the feed liquid at 30 ℃, uniformly and dropwise adding 2.0mol/L hydrochloric acid within 50-60 minutes while stirring at 300rpm until the cefixime solution is in an obvious crystal appearance state (fog), growing crystals for 240 minutes, supplementing 40ml of acetone into the feed liquid after the crystal growth is finished, and continuing to grow the crystals for 60 minutes;
controlling the temperature of the feed liquid to be 30 ℃, dropwise adding 2.0mol/L hydrochloric acid into the first crystallization liquid at a uniform speed for 30-40 minutes under the stirring of 300rpm until the pH value is 3.0, growing the crystals for 120 minutes, then adding 20ml of acetone into the feed liquid, and continuing to grow the crystals for 60 minutes;
controlling the temperature of the feed liquid to be 30 ℃, dropwise adding 2.0mol/L hydrochloric acid into the second crystallization liquid at a uniform speed for 30-40 minutes under the stirring of 300rpm until the pH value is 2.0, growing the crystals for 180 minutes, then adding 40ml of acetone into the feed liquid, and continuing to grow the crystals for 60 minutes;
then, after filtration, washing with water, washing with a mixed solution of acetone and water (volume ratio 1).
Example 5
(1) Dissolving and decoloring cefixime crude product
Firstly, 950g of water is put into a reaction kettle, 50g of cefixime crude product is put into the reaction kettle again (the purity is 99 percent, the HPLC area normalization method) is started and stirred, the temperature is controlled to be 8-10 ℃, 5.9g of sodium carbonate is put into the reaction kettle in batches to ensure that cefixime is completely dissolved and clear, after the cefixime is dissolved and clear, 5wt percent of sulfuric acid is used for adjusting the pH value to 6.5, 1.5g of activated carbon is added for carrying out decoloration treatment for 30 minutes, then filtration is carried out, the activated carbon is washed by 150ml of water, and the washing liquid is merged into the cefixime solution clear liquid decolored by the activated carbon.
(2) Three-step crystallization of cefixime
Adding 150ml of water and 40ml of acetone into the cefixime solution decolorized by the activated carbon, controlling the temperature of the feed liquid at 35 ℃, uniformly and dropwise adding 1.5mol/L of hydrochloric acid within 50-60 minutes while stirring at 300rpm until the cefixime solution is in an obvious crystal appearance state (fog), growing crystals for 120 minutes, supplementing 20ml of acetone into the feed liquid after the crystal growth is finished, and continuing to grow the crystals for 30 minutes;
controlling the temperature of the feed liquid to be 35 ℃, uniformly dripping 1.5mol/L hydrochloric acid into the first crystallization liquid for 30-40 minutes under the stirring of 300rpm until the pH value is 2.5, growing the crystals for 120 minutes, then adding 20ml of acetone into the feed liquid, and continuing to grow the crystals for 30 minutes;
controlling the temperature of the feed liquid to be 35 ℃, uniformly dripping 1.5mol/L hydrochloric acid into the second crystallization liquid for 30-40 minutes under the stirring of 300rpm until the pH value is 2.0, growing the crystals for 120 minutes, then adding 20ml of acetone into the feed liquid, and continuing to grow the crystals for 60 minutes;
then, 46.3g of cefixime crystal product was obtained by filtration, washing with water, washing with a mixed solution of acetone and water (volume ratio 1).
Comparative example 1
Refining 35g of cefixime crude product (purity 98.5%, HPLC area normalization) according to CN103980292B example 1 to obtain 31.5g of cefixime crystal product.
Comparative example 2
Refining 35g of cefixime crude product (purity 98.5%, HPLC area normalization) according to CN103980292B example 2 to obtain 31.7g of cefixime crystal product.
Test examples
The cefixime crystals prepared in examples 1 to 5 of the present invention and the cefixime crystals prepared in comparative examples 1 to 2 were subjected to the following tests:
measuring the purity of the obtained cefixime according to a method for measuring related substances of the cefixime in 2020 edition Chinese pharmacopoeia;
measuring the content of the polymer in the obtained cefixime by adopting a high performance liquid chromatography;
measuring the content of genotoxic impurity M in the obtained cefixime by adopting a high performance liquid chromatography;
carrying out a stability experiment at 60 ℃ for 5 days according to a method for preparing related substances of cefixime in the Chinese pharmacopoeia of 2020 edition;
the water activity was measured using a water activity tester from NOVASINA, switzerland;
particle size analysis was performed using a malvern laser particle sizer, and fig. 1 to 7 show the results of particle size analysis, including particle size distribution, of the cefixime crystals refined in examples 1 to 5 and comparative examples 1 to 2 using a malvern laser particle sizer.
The experimental results are as follows:
table 1: cefixime crystals prepared in examples 1-5 of the present invention and comparative examples 1-2, respectively, gave data on yield, purity, polymer content and stability
Table 2 genotoxic impurity M detection data:
| name (R) | M test value | Removal rate |
| Crude product | 56.3ppm | |
| Example 1 | Undetected | 100％ |
| Example 2 | Not detected out | 100％ |
| Example 3 | 0.15ppm | 99.7％ |
| Example 4 | 0.25ppm | 99.5％ |
| Example 5 | 0.09ppm | 99.8％ |
| Comparative example 1 | 23.7ppm | 57.9％ |
| Comparative example 2 | 29.6ppm | 47.4％ |
Table 3: water activity measurement:
| name(s) | Water Activity test value |
| Example 1 | 0.23％ |
| Example 2 | 0.20％ |
| Example 3 | 0.15％ |
| Example 4 | 0.17％ |
| Example 5 | 0.19％ |
| Comparative example 1 | 1.26％ |
| Comparative example 2 | 1.63％ |
Therefore, the cefixime crystal obtained by the refining method of cefixime has high purity, low polymer content, high crystallinity and good stability, and the removal rate of genotoxic impurity 2-mercaptobenzothiazole can even reach 100 percent (undetected).
Table 4 particle size data:
| name(s) | Radial distance | Consistency |
| Example 1 | 1.545 | 0.435 |
| Example 2 | 1.416 | 0.339 |
| Example 3 | 1.365 | 0.335 |
| Example 4 | 1.389 | 0.326 |
| Example 5 | 1.536 | 0.426 |
| Comparative example 1 | 2.470 | 1.520 |
| Comparative example 2 | 2.250 | 0.718 |
The main parameters "pitch" and "consistency" in the particle size distribution diagram, the pitch "indicating the width of the distribution of the particles: (D (0.9) -D (0.1))/D (0.5). The larger the radius, the wider the distribution width, and the larger and more uneven the particle size span. The smaller the diameter distance, the narrower the distribution width is, and the more concentrated and uniform the crystal size is. "consistency" means the degree of deviation of the particle size distribution from the middle, meaning the standard deviation of the numerical sequence, and the larger the "consistency" data, the more uneven the particle size, and the smaller the data, the more uniform the particle size. In addition, the particle size distribution diagram of cefixime prepared by the process of the present invention is unimodal in view of the peak shape of the particle size distribution diagram, while the particle size distribution diagram of cefixime prepared by the comparative example is multimodal and the product particle size is not uniform.
Claims (9)
1. A refining method of cefixime comprises the following steps:
(1) Dissolving and decoloring cefixime crude product
Mixing the cefixime crude product with water at 0-10 ℃, and then adding alkali to dissolve the cefixime crude product to obtain a clear solution; adjusting the pH value of the solution to 4.5-6.5 by acid, and then carrying out activated carbon decoloration treatment;
(2) Three-step crystallization of cefixime
First crystallization: adding water and acetone into the cefixime solution clear solution decolorized by the activated carbon at 25-35 ℃, gradually adding acid while stirring to separate out the cefixime until the solution is in a mist shape, and growing the crystals for 30-240 minutes; then, adding acetone into the mixture, and continuing growing the crystals for 30 to 60 minutes;
second crystallization: after crystal growth at 25-35 ℃, acid is gradually added into the first crystallization liquid under stirring until the pH value is 2.5-3.0, and then crystal growth is carried out for 30-240 minutes; then, acetone is added into the mixture, and crystal growth is continued for 30 to 60 minutes;
and (3) third crystallization: after growing the crystal, gradually adding acid into the second crystal liquid under stirring at 25-35 ℃ until the pH value is 1.8-2.2, and then growing the crystal for 30-240 minutes; then, acetone is added into the mixture, and crystal growth is continued for 30 to 60 minutes;
and then, filtering, washing and drying the third crystallization liquid to obtain the cefixime crystal.
2. The method for refining cefixime according to claim 1, wherein in the step (1) of dissolving and decoloring the cefixime crude product, the cefixime crude product is mixed with water, and then alkali is added to dissolve the mixture to obtain a clear solution, wherein the ratio of the cefixime crude product to the water is 1:15 to 20; the alkali is one or more of sodium carbonate, sodium bicarbonate, sodium acetate, disodium hydrogen phosphate, sodium isooctanoate, and ammonia water.
3. The method for refining cefixime according to claim 2, wherein in the step (1) of dissolving and decoloring the cefixime crude product, the used alkali is selected from sodium carbonate, sodium bicarbonate and sodium acetate, and when the alkali is monobasic alkali, the molar ratio of the cefixime crude product to the monobasic alkali is 1:1 to 1.2; when the base is a binary base, the molar ratio of the cefixime crude product to the binary base is 1:0.5 to 0.6.
4. The cefixime refining method according to claim 1, wherein in the step (1), after the cefixime crude product is dissolved in alkali to obtain a clear solution, the pH of the clear solution is adjusted to 5.0-6.5 by acid, and then activated carbon decolorization treatment is performed, wherein the acid is one or a mixture of sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid, and the concentration of the acid is 5-15 wt%; in the decoloring treatment of the activated carbon, the dosage of the activated carbon is 2 to 5 weight percent of the weight of the cefixime crude product, and the decoloring treatment time is 30 to 120 minutes.
5. The method for refining cefixime according to claim 1, wherein in the step (2) of the three-step crystallization of cefixime, water is added to the cefixime solution supernatant decolorized with activated carbon in an amount of 2.5 to 3.5ml/g of cefixime crude product and acetone is added to the cefixime crude product in an amount of 0.7 to 1.2ml/g of cefixime crude product in the first crystallization at 25 to 35 ℃; controlling the temperature at 25-35 ℃, stirring at a stirring speed of more than 250rpm, and dripping acid at an even speed within 30-60 minutes to separate out cefixime until the solution is in a mist state, namely an obvious crystallization state, wherein 10-20 wt% of cefixime crystals are separated out based on the weight of cefixime crude product, and the used acid is 1-2 mol/L sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid.
6. The cefixime refining method according to claim 1, wherein in the step (2), the cefixime is crystallized in three steps, acetone is added to the crystallization liquid after the crystallization is carried out for 30-240 minutes, the amount of acetone added is 0.2-1.0 ml/g of cefixime crude product, and then the crystallization is continued for 30-60 minutes.
7. The cefixime refining process according to claim 1, wherein in the step (2), the cefixime is crystallized in the three-step, i.e., the second crystallization, the temperature is controlled to 25-35 ℃, the stirring speed is controlled to be above 250rpm under stirring, the acid is uniformly dropped into the first crystallization solution within 30-60 minutes until the pH value is 2.5-3.0, and then the crystals are grown for 30-240 minutes; and then, supplementing acetone into the cefixime crude product, wherein the addition amount of the acetone is 0.2-1.0 ml/g, and then continuously growing the crystals for 30-60 minutes, wherein the used acid is 1-2 mol/L sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid.
8. The cefixime refining process according to claim 1, wherein in the step (2) of the three-step cefixime crystallization, in the third crystallization, the temperature is controlled to be 25-35 ℃, the stirring speed is controlled to be above 250rpm under stirring, acid is uniformly dropped into the second crystallization liquid within 30-60 minutes until the pH value is 1.8-2.2, and then the crystals are grown for 30-240 minutes; and then, supplementing acetone into the cefixime crude product, wherein the addition amount of the acetone is 0.2-1.0 ml/g, and then continuously growing the crystals for 30-60 minutes, wherein the used acid is 1-2 mol/L sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid.
9. The method for refining cefixime according to claim 1, wherein in the step (2) of the three-step crystallization of cefixime, water is added to the cefixime solution supernatant decolorized with activated carbon in an amount of 2.5 to 3.5ml/g of cefixime crude product and acetone is added to the cefixime crude product in an amount of 0.7 to 1.2ml/g of cefixime crude product in the first crystallization at 25 to 35 ℃; controlling the temperature at 25-35 ℃, controlling the stirring speed at more than 250rpm under stirring, and dropwise adding acid at uniform speed within 30-60 minutes to separate out cefixime until the solution is in a vaporous state, namely an obvious crystallization state, wherein 10-20 wt% of cefixime crystals are separated out based on the weight of cefixime crude product, wherein the used acid is 1-2 mol/L sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid; then growing the crystal for 30-240 minutes, adding acetone into the crystallization liquid, wherein the adding amount of the acetone is 0.2-1.0 ml/g of cefixime crude product, and then continuously growing the crystal for 30-60 minutes;
in the second crystallization, the temperature is controlled to be 25-35 ℃, the stirring speed is controlled to be more than 250rpm under stirring, acid is uniformly dripped into the first crystallization liquid within 30-60 minutes until the pH value is 2.5-3.0, and then the crystallization is carried out for 30-240 minutes; then, supplementing acetone into the cefixime crude product, wherein the addition amount of the acetone is 0.2-1.0 ml/g, and then continuously growing the crystals for 30-60 minutes, wherein the used acid is 1-2 mol/L sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid;
in the third crystallization, the temperature is controlled to be 25-35 ℃, the stirring speed is controlled to be more than 250rpm under stirring, acid is uniformly and dropwise added into the second crystallization liquid within 30-60 minutes until the pH value is 1.8-2.2, and then the crystallization is carried out for 30-240 minutes; and then, supplementing acetone into the cefixime crude product, wherein the addition amount of the acetone is 0.2-1.0 ml/g, and then continuously growing the crystals for 30-60 minutes, wherein the used acid is 1-2 mol/L sulfuric acid, hydrochloric acid, acetic acid or phosphoric acid.
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| CN101319246A (en) * | 2008-07-17 | 2008-12-10 | 浙江昂利康制药有限公司 | Process for preparing cefixime |
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| CN103980292A (en) * | 2013-06-14 | 2014-08-13 | 杭州领业医药科技有限公司 | Crystallization method of cefixime trihydrate |
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| JP2007536378A (en) * | 2004-05-10 | 2007-12-13 | ルピン・リミテッド | New cefixime pharmaceutical formulation with enhanced bioavailability |
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