Pharmaceutical preparation of ceftriaxone sodium compound and preparation method thereof

Abstract

The invention provides a pharmaceutical preparation of a cefotaxime sodium compound and a preparation method thereof. The preparation method comprises the following steps: S1, weighing 20.0 g of sodium acetate trihydrate, putting the mixture into a reactor, adding 40.0 mL of a crystallization solvent, stirring and dissolving the mixture for 10 minutes, and obtaining a sodium acetate trihydrate solution; S2, adding cefotaxime acid to the sodium acetate trihydrate solution, and obtaining a clear and transparent reaction solution after the salt-forming reaction is complete; S3, moving the reaction solution into a crystallizer, dripping 0.5-2 mL of a 40% alkyl glycoside aqueous solution into the crystallizer, and starting stirring; S4, starting a constant temperature ice machine, and starting to drip a dissolving agent when the solution temperature in the crystallizer reaches 20-24° C., adding a seed crystal when the solution is slightly turbid, growing the crystal for 30 minutes, and continuing to drip a dissolving agent, and adding a total of 265 mL of a dissolving agent; S5, after the dissolving and crystallization is completed, vacuum filtration is performed, and drying is performed to obtain the cefotaxime sodium compound. The present invention reduces supersaturation, reduces nucleation barriers, and weakens spontaneous nucleation through the participation of 40% alkyl glycoside aqueous solution, so as to obtain a product with a large average particle size and concentrated particle size distribution.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a pharmaceutical preparation of a ceftriaxone sodium compound and a preparation method thereof. Background Art

[0002] Ceftriaxone sodium is a third-generation cephalosporin semi-synthetic broad-spectrum antibiotic, which has the characteristics of broad antibacterial spectrum, strong antibacterial effect, low toxicity and side effects, and stability to β-lactamase. It has extremely high antibacterial activity against hemolytic streptococci, pneumococci, influenza bacilli and meningococci, and its G-activity is higher than that of first-generation and second-generation cephalosporins. Its structural formula is as follows: The existing Chinese patent with the publication number CN 114874237 A discloses a method for refining ceftriaxone sodium, comprising the following steps: (1) dissolving ceftriaxone acid in a mixed solvent of water, methanol and acetone, adding sodium acetate, stirring to dissolve and clarify; (2) adding activated carbon, stirring, and then filtering; (3) rapidly adding ethyl acetate to the filtrate under strong turbulence; the strong turbulence is a Reynolds number of more than 11,000; (4) growing crystals under moderate turbulence; the moderate turbulence is a Reynolds number of 4,000-6,000; (5) slowly adding ethyl acetate under rapid turbulence and continuing to grow crystals; the rapid turbulence is a Reynolds number of 6,500-8,000; (6) after the crystal growing is completed, filtering, washing, and vacuum drying to obtain ceftriaxone sodium.

[0003] In the above method, rapid turbulent crystallization is adopted, and multiple solvents are used to increase the solubility of different impurities and reduce the impurities entrained in the crystals. However, the reaction solution obtained after the reaction of cefotaxime acid and the salt-forming agent is directly and quickly dripped into the solvent, which is easy to cause explosive nucleation and rapid precipitation of the product, affecting the subsequent crystal growth and purification process, so that the obtained crystal size is small and unevenly distributed, and it is easy to agglomerate to cause mother liquor inclusion, affecting the quality of the final product. Summary of the invention

[0004] In order to solve the problems existing in the background technology, the present invention provides a pharmaceutical preparation of a ceftriaxone sodium compound and a preparation method thereof. By involving a 40% alkyl glycoside aqueous solution, the supersaturation is reduced, the nucleation barrier is reduced, and spontaneous nucleation is effectively weakened to obtain a product with a larger average particle size and a more concentrated particle size distribution.

[0005] In order to achieve the above object, the present invention provides the following technical solutions:

[0006] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0007] S1, weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent, and the volume ratio of water to the solvent is 1:4;

[0008] S2, adding cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction, and after the reaction is complete, a clear and transparent reaction solution is obtained;

[0009] S3, transfer the reaction solution obtained in S2 into a crystallizer, add 0.5-2.0 mL of 40% alkyl glycoside aqueous solution to the crystallizer, and start stirring;

[0010] S4, turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 20-24 ° C, start to drop the solvent, wait until the solution becomes slightly turbid, add the seed crystal, grow the crystal for 30 minutes, and then continue to drop the solvent, adding a total of 265 mL of solvent;

[0011] S5. After the dissolution and crystallization is completed, vacuum filtration is performed and the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound.

[0012] By adopting the above technical scheme, sodium acetate trihydrate is first fully dissolved, and then cefotaxime acid is added to the fully dissolved sodium acetate trihydrate solution to ensure a rapid and sufficient salt-forming reaction to obtain a reaction solution; the applicant found that directly dripping the solvent into the reaction solution quickly will cause explosive nucleation, the product will quickly precipitate out, affecting the subsequent crystal growth process, so that the obtained crystal particle size is smaller.

[0013] In this regard, the present application first adds a 40% aqueous solution of alkyl glycoside to the reaction solution to play a solubilizing role, forming a stable solution system of water-solvent-alkyl glycoside, which can reduce the supersaturation. The driving force of the crystallization process is supersaturation. Low and constant supersaturation is the key to controlling the quality of the crystalline product. In addition, the addition of alkyl glycoside can reduce the solid-liquid surface tension, reduce the nucleation barrier, and effectively weaken spontaneous nucleation (too many small nuclei are more likely to lead to agglomeration, making it difficult to obtain high-quality crystal products with good crystal habits and concentrated particle size distribution).

[0014] Then, turn on the constant temperature ice machine, and after the solution temperature in the crystallizer reaches 20-24°C, start adding the solvent dropwise to control the supersaturation within a certain range to avoid excessive cooling rate of the subsequent solution and cause explosive nucleation.

[0015] Then, the solvent is added dropwise to the stable solution system of water-solvent-alkyl glycoside. When the solution becomes slightly turbid, the timing of adding seed crystals is quickly determined based on this phenomenon and the seed crystals are added. The introduction of seed crystals can effectively induce nucleation. At the same time, the growth of seed crystals will consume the supersaturation in the system to prevent the supersaturation from being too high and causing explosive nucleation, making the crystallization process more stable and easier to control, and making the average particle size of the product larger and the particle size distribution more concentrated.

[0016] Preferably, in S3, the amount of 40% alkyl glycoside aqueous solution is 1.1 mL, and the carbon number of the alkyl group is in the range of 8-10.

[0017] By adopting the above technical solution, the alkyl glycoside with the alkyl carbon number in the range of 8-10 is preferred, which has a better solubilizing effect; at the same time, the use amount of the alkyl glycoside is preferred to obtain a better crystal particle size.

[0018] Preferably, the solvent is ethanol or isopropanol.

[0019] By adopting the above technical solution, preferably the solvent is ethanol or isopropanol, which is beneficial to improving the yield of ceftriaxone sodium during crystallization.

[0020] Preferably, in S4, the amount of seed crystals added is 4.2%-4.8% by mass based on the content of ceftriaxone sodium.

[0021] By adopting the above technical solution, the amount of seed crystals added is limited to avoid affecting the particle size distribution of the crystallized product due to excessive or insufficient seed crystals (when the amount of seed crystals is too much, there are too many growth points in the solution, and the solute that can be deposited on the surface of each seed crystal is relatively reduced, so the particle size of the final crystallized product will be relatively smaller; when the amount of seed crystals is too little, the surface area of ​​the seed crystals provided is not enough to consume the supersaturation, and violent explosive nucleation will occur, making the volume fraction of the main particle size of the product smaller).

[0022] Preferably, in S4, the solvent is always dripped at a uniform speed, and the dripping speed is 1.5-2 mL / min.

[0023] By adopting the above technical solution, the flow addition mode and speed of the solvent are limited, so as to avoid the co-precipitation of impurity components and ceftriaxone sodium crystals, which leads to a decrease in product purity.

[0024] Preferably, the molar ratio of sodium acetate trihydrate to cefotaxime acid is 1.1.

[0025] When preparing cefotaxime sodium, the theoretical stoichiometric ratio of sodium acetate trihydrate to cefotaxime acid is 1:1. When the molar ratio of sodium acetate trihydrate to cefotaxime acid exceeds 1.1, the product yield is basically stable. Therefore, the preferred molar ratio of sodium acetate trihydrate to cefotaxime acid is 1.1.

[0026] Preferably, in S3, the reactor is washed with 20.0 mL of the crystallization solvent, and the washing liquid is transferred into the crystallizer.

[0027] Preferably, in S5, before vacuum drying the filter cake, the filter cake is washed twice with 100 mL of the solvent.

[0028] By adopting the above technical solution, unnecessary loss / waste can be reduced and product yield can be improved.

[0029] A pharmaceutical preparation of a ceftriaxone sodium compound comprises the ceftriaxone sodium compound prepared by the above preparation method.

[0030] This application has the following beneficial effects:

[0031] 1. A 40% alkyl glycoside aqueous solution is introduced into the raw materials to solubilize, form a stable solution system of water-solvent-alkyl glycoside, reduce supersaturation, and the addition of alkyl glycoside can reduce the solid-liquid surface tension, reduce the nucleation barrier, effectively weaken spontaneous nucleation, and facilitate the concentrated distribution of the crystallized product in a large particle size range; the introduction of seed crystals can effectively induce nucleation, and at the same time, the growth of seed crystals will consume the supersaturation in the system, prevent the supersaturation from being too high and causing explosive nucleation, and facilitate the increase of the particle size of the crystallized product; the 40% alkyl glycoside aqueous solution and seed crystals work synergistically, making the crystallization process more stable and easier to control, so that the average particle size of the crystallized product is larger and the particle size distribution is more concentrated.

[0032] 2. The addition amount (ratio) of 40% alkyl glycoside aqueous solution and the addition amount (ratio) of seed crystals are limited to ensure that the two work together better and achieve the effect of one plus one being greater than two, so as to ensure that the particle size of the obtained crystalline product is large and uniform.

[0033] 3. The solvent should be added at a uniform rate of 1.5-2 mL / min to avoid the precipitation of impurities and cefotaxime sodium crystals, which may lead to a decrease in product purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The present invention is a flow chart of the preparation method of the cefotaxime sodium compound;

[0035] Figure 2 The particle size distribution diagram of the crystal products obtained in Example 1 and Comparative Examples 1-4 of the present invention;

[0036] Figure 3 The particle size distribution diagram of the crystal products obtained in Example 1 and Comparative Examples 5-7 of the present invention;

[0037] Figure 4 The particle size distribution diagram of the crystal products obtained in Example 1, Comparative Example 1, Comparative Example 5 and Comparative Example 8 of the present invention. DETAILED DESCRIPTION

[0038] The present application is further described in detail below with reference to the embodiments.

[0039] Unless otherwise specified, the raw materials used in the examples and comparative examples of the present application are all existing commercially available products. Example 1

[0040] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0041] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0042] S2. Add 60.85 g of cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0043] S3, the reaction solution obtained in S2 was transferred into a crystallizer, and the reactor was washed with 20.0 mL of the crystallization solvent, and the washing solution was transferred into the crystallizer; then, 1.1 mL of a 40% alkyl glycoside aqueous solution was added dropwise into the crystallizer, and stirring was started.

[0044] Among them, the alkyl glycoside is selected from alkyl glycosides with alkyl carbon number in the range of 8-10.

[0045] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, start adding the solvent isopropanol, and when the solution becomes slightly turbid, add seed crystals in an amount of 4.3% by mass based on the content of cefotaxime sodium; grow the crystals for 30 minutes, and then continue to add the solvent isopropanol, adding a total of 265 mL of the solvent; during the entire process of adding isopropanol, keep adding at a uniform speed, and the addition speed is 1.6 mL / min.

[0046] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound. Example 2

[0047] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0048] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0049] S2. Add 60.85 g of cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0050] S3, the reaction solution obtained in S2 is transferred into a crystallizer, and the reactor is washed with 20.0 mL of the crystallization solvent, and the washing solution is transferred into the crystallizer; then, 0.5 mL of a 40% alkyl glycoside aqueous solution is added dropwise into the crystallizer, and stirring is started.

[0051] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, start adding the solvent isopropanol, and when the solution becomes slightly turbid, add seed crystals in an amount of 4.3% by mass based on the content of cefotaxime sodium; grow the crystals for 30 minutes, and then continue to add the solvent isopropanol, adding a total of 265 mL of the solvent; during the entire process of adding isopropanol, keep adding at a uniform speed, and the addition speed is 1.6 mL / min.

[0052] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound. Example 3

[0053] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0054] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0055] S2. Add 60.85 g of cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0056] S3, the reaction solution obtained in S2 was transferred into a crystallizer, and the reactor was washed with 20.0 mL of the crystallization solvent, and the washing solution was transferred into the crystallizer; then, 2 mL of a 40% alkyl glycoside aqueous solution was added dropwise into the crystallizer, and stirring was started.

[0057] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, start adding the solvent isopropanol, and when the solution becomes slightly turbid, add seed crystals in an amount of 4.3% by mass based on the content of cefotaxime sodium; grow the crystals for 30 minutes, and then continue to add the solvent isopropanol, adding a total of 265 mL of the solvent; during the entire process of adding isopropanol, keep adding at a uniform speed, and the addition speed is 1.6 mL / min.

[0058] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound. Example 4

[0059] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0060] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0061] S2. Add 60.85 g of cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0062] S3, the reaction solution obtained in S2 was transferred into a crystallizer, and the reactor was washed with 20.0 mL of the crystallization solvent, and the washing solution was transferred into the crystallizer; then, 1.1 mL of a 40% alkyl glycoside aqueous solution was added dropwise into the crystallizer, and stirring was started.

[0063] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, start adding the solvent isopropanol, and when the solution becomes slightly turbid, add seed crystals in an amount of 4.2% by mass based on the content of cefotaxime sodium; grow the crystals for 30 minutes, and then continue to add the solvent isopropanol, adding a total of 265 mL of the solvent; during the entire process of adding isopropanol, keep adding at a uniform speed, and the addition speed is 1.6 mL / min.

[0064] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound. Example 5

[0065] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0066] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0067] S2. Add 60.85 g of cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0068] S3, the reaction solution obtained in S2 was transferred into a crystallizer, and the reactor was washed with 20.0 mL of the crystallization solvent, and the washing solution was transferred into the crystallizer; then, 1.1 mL of a 40% alkyl glycoside aqueous solution was added dropwise into the crystallizer, and stirring was started.

[0069] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, start dripping the solvent isopropanol, and when the solution becomes slightly turbid, add seed crystals in an amount of 4.8% by mass based on the content of cefotaxime sodium; grow the crystals for 30 minutes, and then continue to drip the solvent isopropanol, adding a total of 265 mL of the solvent; during the entire process of dripping isopropanol, always maintain a uniform dripping speed, and the dripping speed is 1.6 mL / min.

[0070] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound. Example 6

[0071] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0072] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0073] S2. Add 60.85 g of cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0074] S3, the reaction solution obtained in S2 was transferred into a crystallizer, and the reactor was washed with 20.0 mL of the crystallization solvent, and the washing solution was transferred into the crystallizer; then, 1.1 mL of a 40% alkyl glycoside aqueous solution was added dropwise into the crystallizer, and stirring was started.

[0075] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, start adding the solvent isopropanol, and when the solution becomes slightly turbid, add seed crystals in an amount of 4.3% by mass based on the content of cefotaxime sodium; grow the crystals for 30 minutes, and then continue to add the solvent isopropanol, adding a total of 265 mL of the solvent; during the entire process of adding isopropanol, keep adding at a uniform speed, and the addition speed is 1.5 mL / min.

[0076] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound. Example 7

[0077] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0078] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0079] S2. Add 60.85 g of cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0080] S3, the reaction solution obtained in S2 was transferred into a crystallizer, and the reactor was washed with 20.0 mL of the crystallization solvent, and the washing solution was transferred into the crystallizer; then, 1.1 mL of a 40% alkyl glycoside aqueous solution was added dropwise into the crystallizer, and stirring was started.

[0081] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, start dripping the solvent isopropanol, and when the solution becomes slightly turbid, add seed crystals in an amount of 4.3% by mass based on the content of cefotaxime sodium; grow the crystals for 30 minutes, and then continue to drip the solvent isopropanol, adding a total of 265 mL of the solvent; during the entire process of dripping isopropanol, always maintain a uniform dripping speed, and the dripping speed is 2 mL / min.

[0082] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound.

[0083] The difference between this comparative example and Example 1 is that no alkyl glycoside is added. Comparative Example 1

[0084] The details are as follows:

[0085] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0086] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0087] S2. Add cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0088] S3. The reaction solution obtained in S2 is transferred into a crystallizer, and the reactor is washed with 20.0 mL of the crystallization solvent, and the washing solution is transferred into the crystallizer, and stirring is started.

[0089] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, start adding the solvent isopropanol, and when the solution becomes slightly turbid, add seed crystals in an amount of 4.3% by mass based on the content of cefotaxime sodium; grow the crystals for 30 minutes, and then continue to add the solvent isopropanol, adding a total of 265 mL of the solvent; during the entire process of adding isopropanol, keep adding at a uniform speed, and the addition speed is 1.6 mL / min.

[0090] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound. Comparative Example 2

[0091] The difference between this comparative example and Example 1 is that the alkyl polyglycoside is replaced by an equal amount of polyether L62.

[0092] The details are as follows:

[0093] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0094] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0095] S2. Add cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0096] S3, the reaction solution obtained in S2 is transferred into a crystallizer, and the reactor is washed with 20.0 mL of the crystallization solvent, and the washing solution is transferred into the crystallizer; then, 1.1 mL of a 40% aqueous solution of polyether L62 nonionic surfactant is added dropwise into the crystallizer, and stirring is started.

[0097] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, start adding the solvent isopropanol, and when the solution becomes slightly turbid, add seed crystals in an amount of 4.3% by mass based on the content of cefotaxime sodium; grow the crystals for 30 minutes, and then continue to add the solvent isopropanol, adding a total of 265 mL of the solvent; during the entire process of adding isopropanol, keep adding at a uniform speed, and the addition speed is 1.6 mL / min.

[0098] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound. Comparative Example 3

[0099] The difference between this comparative example and Example 1 is that the amount of the 40% alkyl glycoside aqueous solution used is 0.7 mL. Comparative Example 4

[0100] The difference between this comparative example and Example 1 is that the amount of the 40% alkyl glycoside aqueous solution used is 2.3 mL. Comparative Example 5

[0101] The difference between this comparative example and Example 1 is that no seed crystal is added.

[0102] The details are as follows:

[0103] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0104] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0105] S2. Add cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0106] S3, the reaction solution obtained in S2 was transferred into a crystallizer, and the reactor was washed with 20.0 mL of the crystallization solvent, and the washing solution was transferred into the crystallizer; then, 1.1 mL of a 40% alkyl glycoside aqueous solution was added dropwise into the crystallizer, and stirring was started.

[0107] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, and start adding the solvent isopropanol dropwise at a uniform rate of 1.6 mL / min.

[0108] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound. Comparative Example 6

[0109] The difference between this comparative example and Example 1 is that the amount of seed crystal added is 3.8% by mass based on the content of ceftriaxone sodium. Comparative Example 7

[0110] The difference between this comparative example and Example 1 is that the amount of seed crystal added is 5.2% by mass based on the content of ceftriaxone sodium. Comparative Example 8

[0111] The difference between this comparative example and Example 1 is that no alkyl glycoside and seed crystals are added.

[0112] The details are as follows:

[0113] A method for preparing a ceftriaxone sodium compound comprises the following steps:

[0114] S1. Weigh 20.0 g of sodium acetate trihydrate, put it into a reactor, add 40.0 mL of a crystallization solvent, stir and dissolve for 10 min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent isopropanol, and the volume ratio of water to isopropanol is 1:4.

[0115] S2. Add cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction. After the reaction is complete, a clear and transparent reaction solution is obtained.

[0116] S3. The reaction solution obtained in S2 is transferred into a crystallizer, and the reactor is washed with 20.0 mL of the crystallization solvent, and the washing solution is transferred into the crystallizer, and stirring is started.

[0117] S4. Turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22°C, and start adding the solvent isopropanol dropwise. Keep adding at a constant speed and the addition rate is 1.6 mL / min.

[0118] S5. After the dissolution and crystallization are completed, vacuum filtration is performed, and the filter cake is washed twice with 100 mL of isopropanol, and then the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound.

[0119] Performance test

[0120] The particle size test was carried out using a laser particle size analyzer, and the test data was analyzed and summarized. The relevant test results are shown in Table 1 below.

[0121] Table 1

[0122] Analyze Examples 1-7 and Comparative Examples 1-4 and combine Table 1 and Figure 1 It can be seen that:

[0123] Embodiment 1 is the best embodiment.

[0124] In Comparative Example 1, no 40% alkyl glycoside aqueous solution was added for solubilization treatment, and the average particle size of the finally obtained crystalline product was slightly smaller than that in Example 1, while the mass fraction of the particle size of 20-85 μm was significantly smaller than that in Example 1, indicating that the participation of 40% alkyl glycoside aqueous solution is conducive to the concentrated distribution of crystals in the large particle size range of 20-85 μm.

[0125] In Comparative Example 2, an equal amount of 40% polyether L62 nonionic surfactant aqueous solution was added to the 40% alkyl polyglycoside aqueous solution in Example 1. The particle size distribution of the finally obtained crystalline product was similar to that in Comparative Example 1, indicating that the role of alkyl polyglycoside cannot be simply replaced by other nonionic surfactants.

[0126] In Comparative Example 3, the amount of 40% alkyl glycoside aqueous solution added is lower than the protection range, and in Comparative Example 4, the amount of 40% alkyl glycoside aqueous solution added is higher than the protection range. As a result, the particle size range distribution of the obtained crystalline product is less concentrated than that of Example 1. At the same time, the mass fraction of the particle size of 20-85 μm is significantly greater than that of Comparative Example 1, indicating that adding too much or too little 40% alkyl glycoside aqueous solution is not conducive to the concentrated distribution of crystals in the large particle size range of 20-85 μm.

[0127] Analyze Example 1 and Comparative Examples 5-7 and combine Table 1 and Figure 2 It can be seen that:

[0128] In Comparative Example 5, no seed crystals were added, and the average particle size of the finally obtained crystal product was significantly smaller than that in Example 1. The mass fraction of particle sizes of 1-20 μm was very close to the mass fraction of particle sizes of 20-85 μm, and accounted for 80% of the total. The mass fraction of particle sizes less than 1 μm reached 12.57, indicating that the participation of seed crystals is conducive to increasing the crystal particle size.

[0129] The amount of seed crystals added in Comparative Example 6 is lower than the protection range, and the amount of seed crystals added in Comparative Example 7 is higher than the protection range. As a result, the average particle size of the obtained crystalline products is significantly smaller than that in Example 1, and significantly larger than that in Comparative Example 5, indicating that adding too much or too little seed crystals is not conducive to the increase of the crystal particle size.

[0130] Analyze Example 1, Comparative Example 1, Comparative Example 5 and Comparative Example 8 and combine Table 1 and Figure 3 It can be seen that:

[0131] In Comparative Example 8, neither 40% alkyl glycoside aqueous solution nor seed crystals are added. As a result, the average particle size of the obtained crystalline product is significantly smaller than that of Comparative Example 5. At the same time, the mass fraction of the particle size of 20-85 μm and the mass fraction of the particle size greater than 85 are significantly smaller than those of Comparative Example 1, indicating that the 40% alkyl glycoside aqueous solution and the seed crystals can produce a synergistic effect in the preparation process of the cefotaxime sodium compound, thereby achieving an effect of one plus one being greater than two, so that the particle size of the finally obtained crystalline product is larger and the distribution is more concentrated, ensuring that the obtained crystalline product has a large and uniform particle size and good quality.

[0132] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

[0133] In addition, various embodiments of the present invention may be arbitrarily combined, and as long as they do not violate the concept of the present invention, they should also be regarded as the contents disclosed by the present invention.

Claims

1. A method for preparing a cefotaxime sodium compound, characterized in that: The steps include: S1, weigh 20.0g of sodium acetate trihydrate, put it into a reactor, add 40.0mL of a crystallization solvent, stir and dissolve for 10min to obtain a sodium acetate trihydrate solution; the crystallization solvent includes water and a solvent, the volume ratio of water to the solvent is 1:4, and the solvent is isopropanol; S2, adding cefotaxime acid to the sodium acetate trihydrate solution obtained in S1 to start a salt-forming reaction, and after the reaction is complete, a clear and transparent reaction solution is obtained; S3, the reaction solution obtained in S2 is transferred into a crystallizer, 1.1 mL of a 40% alkyl glycoside aqueous solution is added dropwise into the crystallizer, and stirring is started, wherein the molar ratio of sodium acetate trihydrate to cefotaxime acid is 1.1:1, and the alkyl glycoside is selected from an alkyl glycoside having an alkyl carbon number in the range of 8-10; S4, turn on the constant temperature ice machine, wait until the solution temperature in the crystallizer reaches 22 ° C, start dripping the solvent, wait until the solution becomes slightly turbid, add seed crystals, grow the crystals for 30 minutes, and then continue to drip the solvent, add a total of 265 mL of solvent, the amount of seed crystals added is 4.2%-4.8% by mass based on the content of cefotaxime sodium, the solvent is always dripped at a uniform speed, and the dripping speed is 1.5-2 mL / min; S5. After the dissolution and crystallization is completed, vacuum filtration is performed and the filter cake is vacuum dried for 24 hours to obtain the ceftriaxone sodium compound.

2. The method for preparing the ceftriaxone sodium compound according to claim 1, characterized in that: In S3, the reactor is washed with 20.0 mL of the crystallization solvent, and the washing liquid is transferred into the crystallizer.

3. The method for preparing the ceftriaxone sodium compound according to claim 1, characterized in that: In S5, before vacuum drying the filter cake, the filter cake is washed twice with 100 mL of the solvent.

4. A pharmaceutical preparation of a ceftriaxone sodium compound, characterized in that: The invention comprises a crystalline product of ceftriaxone sodium obtained by the preparation method according to any one of claims 1 to 3.

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