CN110105374B - Crystallization method of phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid with controllable granularity and crystal habit - Google Patents
Crystallization method of phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid with controllable granularity and crystal habit Download PDFInfo
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- CN110105374B CN110105374B CN201910517514.7A CN201910517514A CN110105374B CN 110105374 B CN110105374 B CN 110105374B CN 201910517514 A CN201910517514 A CN 201910517514A CN 110105374 B CN110105374 B CN 110105374B
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- 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
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- 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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Abstract
The invention provides a crystallization method of phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid with controllable granularity and crystal habit, which comprises the following steps: adding the crude product of the phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid into ammonia water, uniformly mixing, and filtering to obtain a solution of the phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid; adding hydrochloric acid into the phenylacetyl-7-amino-3-desacetoxycephalosporanic acid solution at the temperature of 5-30 ℃ and under the stirring condition of 90-180r/min, adjusting the pH to 1.5-3.0, and growing crystals for 1-5h to obtain the phenylacetyl-7-ADCA. The phenylacetyl-7-ADCA prepared by the preparation method provided by the invention has the purity of 99.7%, and the crystal habit is long rod-shaped or needle-shaped, so that the preparation method has the advantages of complete crystal habit, high purity, good fluidity, difficulty in agglomeration and the like, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical production, in particular to a crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable granularity and crystal habit.
Background
Cephalosporin antibiotics are widely used in the treatment of bacterial infections due to their spectral properties and low toxicity. The demand of 7-amino-3-desacetoxycephalosporanic acid (7-ADCA) as an important intermediate of semi-synthetic cephalosporin antibiotics is increasing, and 7-ADCA is mainly obtained by deacylation of phenylacetyl-7-ADCA. The traditional phenylacetyl-7-ADCA synthesis method takes penicillin G sulfoxide as a raw material, and adopts chemical esterification, rearrangement ring expansion, hydrolysis and alkaline hydrolysis reactions to obtain a water solution containing the phenylacetyl-7-ADCA salt. In the process, the aqueous solution of the phenylacetyl-7-ADCA salt contains a large amount of organic impurities which are difficult to remove, so the phenylacetyl-7-ADCA can be applied to the subsequent synthesis process after crystallization treatment. The product obtained by the existing crystallization and purification method of phenylacetyl-7-ADCA has small and uneven granularity and agglomeration, the purity of the product can reach 81.7 percent at most, and the purity is low, so that the pharmaceutical active ingredients of the cephalosporin antibiotics synthesized by the subsequent process are reduced, the content of related substances is increased, and the requirements on pharmaceutical purity are not met. Therefore, the search for a method for preparing high-content and high-purity phenylacetyl-7-ADCA so as to prepare high-quality cephalosporin drugs is an important direction for researchers to explore.
Disclosure of Invention
Aiming at the problems of low and uneven granularity, conglomeration and low product purity of a product prepared by the prior phenylacetyl-7-ADCA crystallization and purification process, the invention provides a crystallization method of phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid with controllable granularity and crystal habit.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit, wherein the crystal habit is long rod-shaped or needle-shaped crystals, and the preparation method comprises the following steps:
adding a crude product of phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid into ammonia water, uniformly mixing, and filtering to obtain a solution of the phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid;
and step two, adding hydrochloric acid into the phenylacetyl-7-amino-3-desacetoxycephalosporanic acid solution under the stirring condition of 90-180r/min at the temperature of 5-30 ℃, adjusting the pH value to 1.5-3.0, and growing crystals for 1-5h to obtain the phenylacetyl-7-amino-3-desacetoxycephalosporanic acid.
Compared with the prior art, the method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable granularity and crystal habit, which is provided by the invention, adopts ammonia water-dilute hydrochloric acid as a crystallization solvent, and ammonium chloride generated in the crystallization process, residual ammonia water, dilute hydrochloric acid and other impurities can be automatically decomposed and volatilized out of a product system when the product is heated and dried, so that impurities introduced by the crystallization solvent are reduced, and the generation of impurities in the crystallization process is reduced to the maximum extent; the long rod-shaped or needle-shaped crystals with complete crystal habit and no agglomeration are obtained by controlling the conditions of the crystallization process. According to the method for crystallizing phenylacetyl-7-ADCA, the purity of prepared phenylacetyl-7-ADCA can reach 99.7%, the main particle size of the phenylacetyl-7-ADCA is 85-95 mu m, the particle size distribution shows unimodal distribution, and crystals of the prepared phenylacetyl-7-ADCA are long rod-shaped or needle-shaped, are complete and have no agglomeration phenomenon. The phenylacetyl-7-ADCA prepared by the preparation process is used as a raw material of the subsequent 7-ADCA or downstream cephalosporin antibiotics, so that the impurity water content of the 7-ADCA and the cephalosporin antibiotics can be greatly reduced, the market competitiveness of products can be improved, and the toxic and side effects of the medicaments on users can be reduced.
Preferably, in the first step, the mass ratio of the crude phenylacetyl-7-amino-3-desacetoxycephalosporanic acid to the ammonia water is 1-5: 100.
More preferably, in the step one, the mass ratio of the crude phenylacetyl-7-amino-3-desacetoxycephalosporanic acid to the ammonia water is 3.02: 100.
The mass ratio of the phenylacetyl-7-ADCA to the ammonia water is too low, so that the product yield is reduced; the quality ratio is too high, and although the yield of the product can be improved, the supersaturation degree in the system is not easy to control in a range favorable for good crystal growth, and the phenylacetyl-7-ADCA crystal is also easy to generate impurity occlusion, which is not favorable for improving the purity of the product. Too high a concentration of phenylacetyl-7-ADCA also results in too fast crystallization rate, fine crystallites adhered to the surface of the crystals, uneven product granularity, agglomeration and incomplete crystal habit.
Preferably, the mass concentration of the ammonia water is 0.25-3%.
More preferably, the mass concentration of the aqueous ammonia is 1%.
The preferable ammonia water concentration is favorable for ensuring the full precipitation of crystals on the premise of reducing the production cost.
Preferably, in the first step, the filtration is performed by using a microporous filter membrane, and the pore diameter of the microporous filter membrane is 0.22-0.45 μm.
More preferably, in the first step, the microporous filter membrane is a 0.45 μm mixed filter membrane.
In the invention, an organic filter membrane or a mixed filter membrane can be adopted for filtration, preferably a 0.45-micron mixed filter membrane, and the preferable filter membrane can remove insoluble impurities in the phenylacetyl-7-ADCA crude product as much as possible and reduce the impurity occlusion problem in the crystallization process as much as possible.
Preferably, in the second step, the hydrochloric acid is added into the phenylacetyl-7-amino-3-desacetoxycephalosporanic acid solution in a dropwise manner, and the dropwise adding rate is 0.1-0.5 mL/min.
More preferably, the hydrochloric acid is added dropwise at a rate of 0.3 mL/min.
Preferably, the concentration of the hydrochloric acid is 0.25-1.25 mol/L.
More preferably, the concentration of the hydrochloric acid is 0.5 mol/L.
Too high concentration of hydrochloric acid or too fast dripping speed of hydrochloric acid can cause the pH value of a system to be reduced too fast and the local supersaturation degree to be too high, thereby causing larger driving force in the crystallization process, crystal nucleation and crystal growth to be too fast, causing impurity occlusion phenomena and reducing the purity of products; meanwhile, the amount of nucleation is increased, so that the crystals are easily agglomerated, and since the nucleation rate is greater than the crystal growth rate, the resulting crystals have a small particle size and an uneven particle size distribution. The preferable concentration and dropping speed of hydrochloric acid can avoid the primary nucleation phenomenon caused by overhigh local supersaturation, so that the crystal habit growth is good and the particle size distribution is relatively concentrated.
Preferably, in the second step, the stirring speed is 120 r/min.
The stirring speed is too low, so that local supersaturation is easy to occur, local outbreak nucleation is caused, crystal deposition can occur in dead zones, and uniform growth of crystals is not facilitated; the stirring speed is too high, crystals can be broken, crystal habit is incomplete, fine crystals appear, the particle size distribution of products is uneven, and coalescence occurs.
Preferably, in step two, the pH is adjusted to 2.1.
Preferably, in the second step, the crystallization temperature is 20 ℃.
Preferably, in the second step, the time for growing the crystals is 4 h.
The optimal crystallization temperature and crystal growing time provide sufficient aging time for the crystals, so that the phenylacetyl-7-ADCA crystals are complete in crystal habit, large and uniform in crystal particle size, the subsequent filtration is facilitated, the filtration time is shortened, and the production efficiency is improved.
Drawings
FIG. 1 is a photomicrograph of phenylacetyl-7-ADCA prepared in example 1;
FIG. 2 is a graph showing the particle size distribution of phenylacetyl-7-ADCA prepared in example 1;
FIG. 3 is an X-ray diffraction (XRD) pattern of phenylacetyl-7-ADCA prepared in example 1;
FIG. 4 is a microphotograph of phenylacetyl-7-ADCA prepared in comparative example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable granularity and crystal habit comprises the following steps:
weighing 3.02g of fully dried phenylacetyl-7-ADCA crude product, placing the weighed crude product in a beaker, adding 100g of diluted ammonia water solution with the mass fraction of 1%, stirring to dissolve, filtering by adopting a 0.45-micrometer mixed filter membrane, and removing insoluble impurities to obtain a phenylacetyl-7-ADCA solution;
and step two, transferring the phenylacetyl-7-ADCA solution into a jacket crystallizer, starting a stirring device, controlling the rotating speed to be 120r/min, starting a constant-temperature water bath device, controlling the temperature of the crystallization environment in the jacket crystallizer to be 20 ℃, dropwise adding 0.5mol/L of dilute hydrochloric acid solution into the phenylacetyl-7-ADCA solution at the dropwise adding rate of 0.3mL/min, stopping dropwise adding the dilute hydrochloric acid solution when the pH value of a detection system is 2.1, starting crystal growth, controlling the crystal growth time to be 4h, filtering after the crystal growth is finished, and drying in a vacuum drying oven to obtain the phenylacetyl-7-ADCA product.
The microphotograph of the product of phenylacetyl-7-ADCA prepared in this example is shown in FIG. 1, from which it can be seen that the crystals of phenylacetyl-7-ADCA prepared in the present invention are long rod-shaped, the crystal habit is complete, and there is no agglomeration.
The particle size of the product obtained in this example was measured by a Mastersizer 3000 Malvern particle sizer, and the particle size distribution diagram is shown in FIG. 2, with a monomodal distribution of the particle size distribution and a major particle size of 93.5. mu.m.
The purity of the product is measured by an Agilent 1220 Agilent high performance liquid chromatograph, and the measurement result shows that the purity is 99.7%.
The XRD pattern of the phenylacetyl-7-ADCA product prepared in this example is shown in FIG. 3.
Example 2
A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable granularity and crystal habit comprises the following steps:
step one, weighing 1g of fully dried phenylacetyl-7-ADCA crude product, placing the crude product in a beaker, adding 100g of dilute ammonia water solution with the mass fraction of 0.25%, stirring to dissolve, filtering by adopting a 0.45-micrometer organic filter membrane, and removing insoluble impurities to obtain a phenylacetyl-7-ADCA solution;
and step two, transferring the phenylacetyl-7-ADCA solution into a jacket crystallizer, starting a stirring device, controlling the rotating speed to be 90r/min, starting a constant-temperature water bath device, controlling the temperature of the crystallization environment in the jacket crystallizer to be 5 ℃, dropwise adding 0.25mol/L of dilute hydrochloric acid solution into the phenylacetyl-7-ADCA solution at the dropwise adding rate of 0.1mL/min, stopping dropwise adding the dilute hydrochloric acid solution when the pH value of a detection system is 3.0, starting crystal growth, controlling the crystal growth time to be 1h, filtering after the crystal growth is finished, and drying in a vacuum drying oven to obtain the phenylacetyl-7-ADCA product.
The particle size of the product obtained in this example was determined by a Mastersizer 3000 Malvern particle sizer, the particle size distribution being unimodal and the primary particle size being 89.1. mu.m.
The purity of the product is measured by an Agilent 1220 Agilent high performance liquid chromatograph, and the measurement result shows that the purity is 98.9%.
Example 3
A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable granularity and crystal habit comprises the following steps:
step one, weighing 5g of fully dried phenylacetyl-7-ADCA crude product, placing the weighed phenylacetyl-7-ADCA crude product in a beaker, adding 100g of dilute ammonia water solution with the mass fraction of 3%, stirring to dissolve, filtering by adopting a 0.22 mu m mixed filter membrane, and removing insoluble impurities to obtain a phenylacetyl-7-ADCA solution;
and step two, transferring the phenylacetyl-7-ADCA solution into a jacket crystallizer, starting a stirring device, controlling the rotating speed to be 180r/min, starting a constant-temperature water bath device, controlling the temperature of the crystallization environment in the jacket crystallizer to be 30 ℃, dropwise adding 1.25mol/L of dilute hydrochloric acid solution into the phenylacetyl-7-ADCA solution at the dropwise adding rate of 0.5mL/min, stopping dropwise adding the dilute hydrochloric acid solution when the pH value of a detection system is 1.5, starting crystal growth, controlling the crystal growth time to be 5h, filtering after the crystal growth is finished, and drying in a vacuum drying oven to obtain the phenylacetyl-7-ADCA product.
The particle size of the product obtained in this example was determined by a Mastersizer 3000 Malvern particle sizer, the particle size distribution being unimodal and the main particle size being 92.8. mu.m.
The purity of the product is measured by an Agilent 1220 Agilent high performance liquid chromatograph, and the measurement result shows that the purity is 99.1%.
Comparative example 1
A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid comprises the following steps:
weighing 3.02g of fully dried phenylacetyl-7-ADCA crude product, placing the weighed phenylacetyl-7-ADCA crude product in a beaker, adding 100g of ammonium bicarbonate aqueous solution with the mass fraction of 1%, stirring to dissolve, filtering by adopting a 0.45-micrometer mixed filter membrane, and removing insoluble impurities to obtain a phenylacetyl-7-ADCA solution;
and step two, transferring the phenylacetyl-7-ADCA solution into a jacket crystallizer, starting a stirring device, controlling the rotating speed to be 120r/min, starting a constant-temperature water bath device, controlling the temperature of the crystallization environment in the jacket crystallizer to be 20 ℃, dropwise adding 20% dilute sulfuric acid solution into the phenylacetyl-7-ADCA solution at the dropwise adding rate of 0.3mL/min, stopping dropwise adding the dilute hydrochloric acid solution when the pH value of a detection system is 2.1, starting crystal growth, wherein the crystal growth time is 4h, filtering after the crystal growth is finished, and drying in a vacuum drying oven to obtain the phenylacetyl-7-ADCA product.
The microphotograph of the phenylacetyl-7-ADCA product prepared in this comparative example is shown in FIG. 4, where it can be seen that the particle size of the phenylacetyl-7-ADCA product prepared by the above-mentioned method is small and non-uniform, and has agglomeration.
The particle size of the product obtained in this comparative example was measured by a Mastersizer 3000 malvern particle sizer, the particle size distribution being unimodal and the major particle size being 63.5 μm.
The purity of the product is measured by an Agilent 1220 Agilent high performance liquid chromatograph, and the measurement result shows that the purity is 81.7%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit is characterized by comprising the following steps:
adding a crude product of phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid into ammonia water, uniformly mixing, and filtering to obtain a solution of the phenylacetyl-7-amino-3-desacetoxy cephalosporanic acid;
and step two, adding hydrochloric acid into the phenylacetyl-7-amino-3-desacetoxycephalosporanic acid solution under the stirring condition of 90-180r/min at the temperature of 5-30 ℃, adjusting the pH value to 1.5-3.0, and growing crystals for 1-5h to obtain the phenylacetyl-7-amino-3-desacetoxycephalosporanic acid.
2. The method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit according to claim 1, wherein in the step one, the mass ratio of the crude phenylacetyl-7-amino-3-desacetoxycephalosporanic acid to the ammonia water is 1-5: 100.
3. The method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit according to claim 2, wherein in the step one, the mass ratio of the crude phenylacetyl-7-amino-3-desacetoxycephalosporanic acid to the ammonia water is 3.02: 100.
4. The method for crystallization of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controlled particle size and crystal habit according to any one of claims 1 to 3, wherein the mass concentration of the ammonia water is 0.25 to 3%.
5. The method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controlled particle size and crystal habit according to claim 4, wherein the mass concentration of the ammonia water is 1%.
6. The method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controlled particle size and crystal habit as claimed in claim 1, wherein in the step one, the filtration is performed by using a microporous membrane, and the pore diameter of the microporous membrane is 0.22-0.45 μm.
7. The method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controlled particle size and crystal habit according to claim 1, wherein in the second step, the hydrochloric acid is added into the solution of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid in a dropwise manner, and the dropwise adding rate is 0.1-0.5 mL/min.
8. The method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controlled particle size and crystal habit according to claim 7, wherein the hydrochloric acid is added dropwise at a rate of 0.3 mL/min.
9. The method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controlled particle size and crystal habit according to claim 7 or 8, wherein the concentration of the hydrochloric acid is 0.25-1.25 mol/L.
10. The method for crystallizing phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controlled particle size and crystal habit according to claim 1, wherein in the second step, the temperature is 20 ℃; and/or the stirring speed is 120 r/min; and/or adjusting the pH to 2.1; and/or the time for growing the crystals is 4 hours.
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| WO1999024441A1 (en) * | 1997-11-10 | 1999-05-20 | Dsm N.V. | Crystallization of beta-lactam compounds |
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| WO1999024441A1 (en) * | 1997-11-10 | 1999-05-20 | Dsm N.V. | Crystallization of beta-lactam compounds |
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