Small particle meropenem crystals and methods of making same

Abstract

The application discloses small-granularity meropenem crystals and a preparation method thereof. Through a further reaction-dissolution coupling crystallization process after dissolving a raw material crude product by adding a lye, uniform small-granularity meropenem crystal products can be obtained. The obtained crystal products are white block or flaky shuttle-shaped crystal habits, have high content (≥99.5%), low total residual solvent (≤0.2%), and high process yield (≥90%); the aqueous solution is colorless, clear and transparent, and has an acidity of 4.84-5.12; the granularity is uniform, the fluidity is good (the angle of repose is ≤35°), the granularity distribution is small (D50 is ≤25 μm, and D90 is ≤70 μm), and the product redissolution time is fast (≤75 s); after the obtained products are placed under the condition of 30 ± 2 ℃ and 60 ± 5% RH for three months, no obvious changes are found in various indexes, and the products have good stability. The required equipment is simple, the processing scale is large, the operation is simple, industrial production can be carried out, and the method has good technical economy and high industrial application value.

Description

Technical Field

[0001] This invention belongs to the fields of pharmaceutical and chemical technology, specifically relating to a small-particle meropenem crystal and its preparation method. Background Technology

[0002] Meropenem (CAS: 119478-56-7), also known by trade names such as Meronem, was first developed by Sumitomo Pharmaceutical Co., Ltd. of Japan. Its chemical name is (4R,5S,6S)-3-[(3S,5S)-5-dimethylcarbamoylpyrrolidine-3-thio]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, and its molecular formula is C2. 17 H 25 N3O5S·3H2O, with a molecular weight of 437.51, is a white to slightly yellow crystalline powder, slightly soluble in water. It belongs to the carbapenem β-lactam antibiotic class and possesses broad-spectrum and potent antibacterial activity. It exhibits strong bactericidal activity against Gram-positive, Gram-negative, and anaerobic bacteria, particularly against aerobic Gram-negative bacteria (such as Enterobacteriaceae and Pseudomonas aeruginosa). It is suitable for various serious infections caused by drug-resistant bacteria, including but not limited to: pneumonia, intra-abdominal infections, urinary tract infections, meningitis, and skin and soft tissue infections. Its structural formula is shown in the figure below.

[0003]

[0004] Meropenem structure

[0005] Meropenem is primarily synthesized chemically and is one of the more challenging antibiotics to synthesize. Typically, it requires first constructing its carbapenem core and introducing specific side chains. Key preparation steps include the synthesis of side chain fragments and their stereoselective linkage with the core. Classical methods involve using (3S,4S)-3-[(R)-1-(tert-butyldimethylsiloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azacyclobutanone or its protected form as a key intermediate, followed by a thiolated linkage reaction with side chain units such as (2S,4S)-2-(dimethylcarbamoyl)-4-mercapto-1-(p-nitrobenzyloxycarbamoyl)-1-pyrrolidine. This process is highly sensitive to water and oxygen, requires stringent conditions, and results in poor stability of intermediates and products, leading to increased byproducts. Furthermore, leaching of heavy metal catalysts is a concern, making separation and purification difficult and ultimately affecting product purity, solvent residue, and long-term stability. Therefore, the crystallization process is a necessary step in meropenem production, and its rational design determines the physicochemical properties of the final product.

[0006] Currently, several methods for purifying meropenem crystallization have been reported. For example, US20090299057, WO2006035300, and CN116947861A disclose a method that uses protected meropenem as a raw material, directly prepares a meropenem solution after deprotection, then concentrates it using reverse osmosis or vacuum evaporation, removes impurities by extraction or column chromatography, and finally uses an organic solvent as a countersolvent for crystallization. Such methods are complex, difficult to control, and require a large amount of organic solvent. CN101891742A, CN103570719A, and CN101914098A disclose a method for dissolving crude meropenem by heating, followed by cooling and crystallization, and then using an organic solvent for anti-solvent crystallization or recovering meropenem from the mother liquor. However, such methods cannot solve the problems of poor water solubility, low purity, and uneven particle size of meropenem. Furthermore, this process requires a large amount of organic solvent (approximately 40-50 times the amount of meropenem fed), making organic solvent recovery difficult, imposing significant environmental pressure, and limiting the scale of processing. CN102977102A discloses a method for dissolving meropenem in an alkaline solution; however, directly adding crude meropenem to the alkaline solution leads to significant decomposition, resulting in a final yield of less than 80%. CN101921276A discloses a method for dissolving meropenem using methanol; however, meropenem undergoes a rapid crystal transformation in methanol, posing risks of crystal formation and solvent residue, which is detrimental to large-scale production.

[0007] The above-mentioned existing technologies generally have the following defects: (1) The product has a wide particle size distribution, with fine powder and large particles coexisting, resulting in poor flowability and affecting the efficiency of preparation dispensing and clinical solution preparation; (2) The reconstitution time is relatively long, which poses a risk of deterioration for injectables that need to be prepared and used quickly.

[0008] Therefore, developing a new crystallization method that can stably prepare meropenem crystals with small particle size, uniform particle size distribution, good flowability, and fast resolution rate has important industrial application value and clinical significance. Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing small-particle meropenem crystals. The crystallization technique disclosed in this invention can yield meropenem crystal products with high crystallinity, high purity, stability, good flowability, uniform particle size, high water solubility, and fast reconstitution time. The process is simple, low-cost, and easy for industrial production.

[0010] To achieve the above objectives, the present invention provides the following technical solution:

[0011] The first aspect of this invention is to provide a method for preparing small-particle meropenem crystals, comprising the following steps:

[0012] Step 1: Add water and crude meropenem to a crystallizer at 10 ~ 50℃ to prepare a suspension, and add alkaline solution dropwise at a certain flow rate. Start stirring at a speed of 100 ~ 500 rpm. After dissolving the solution, filter to remove insoluble impurities.

[0013] Step 2: Maintain the stirring rate, cool the filtrate to -5 ~ 10 ℃ and then keep it at a constant temperature. Add solvent I all at once, and add acid dropwise at a certain flow rate to make the pH of the filtrate ≤ 7.0. Stir to induce crystal formation and allow crystals to grow for 0.5 ~ 3 h. The solvent I is at least one of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, acetonitrile, and tetrahydrofuran.

[0014] Step 3: After crystal growth is completed, maintain the system temperature and stirring rate, and add a certain amount of solvent II at a certain rate. After the addition of solvent II is completed, continue aging for 1 to 5 hours. The solvent II is at least one of methyl ethyl ketone, n-propanol, isopropanol, n-butanol, acetone, acetonitrile, and tetrahydrofuran.

[0015] Step 4: Filter and dry the resulting solid to obtain the final product.

[0016] Furthermore, the alkaline solution is a solution of at least one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, triethylamine, isopropylamine, and pyridine diluted with water, with a mass ratio of alkali to water of 1:5 to 1:30, and the flow rate of the alkaline solution is controlled at 0.5 to 5 mL / min.

[0017] Furthermore, the acid solution is a solution of hydrochloric acid, acetic acid, phosphoric acid, or sulfuric acid diluted with solvent I, and the mass ratio of acid to solvent I is 1:1 to 1:20.

[0018] In further step 1, the mass ratio of crude meropenem to the total amount of water and diluted alkaline solution added is 1:3 to 1:10.

[0019] Furthermore, in step 2, the volume ratio of solvent I to the water added in step 1 is 1:2 to 1:10.

[0020] Furthermore, in step 2, the flow rate of the acid solution is controlled to be 0.2 ~ 3 mL / min.

[0021] Furthermore, in step 3, the flow rate of solvent II is controlled to be 0.3 ~ 5 mL / min.

[0022] Furthermore, in step 3, the volume ratio of the amount of solvent II to the total amount of solvent in step 1 is 1:1 to 5:1.

[0023] Furthermore, in step 4, the product is dried by vacuum drying, with a vacuum degree of -0.06 ~ -0.1 MPa, a drying temperature of 25 ~ 50 ℃, and a drying time of 4 ~ 16 h.

[0024] A second aspect of the present invention is to provide a small-particle meropenem crystal, prepared by the method described above, wherein the particle size distribution of the crystal satisfies: D50≤25 μm, D90≤70 μm, angle of repose≤35°, reconstitution time≤75 seconds, crystal content≥99.5%, and total residual solvent≤0.2%.

[0025] Advantages and beneficial effects of the present invention:

[0026] 1. This invention pre-changes the polarity environment of the solution by using solvent I to make the acid neutralization nucleation process more gentle and uniform; by slowly adding solvent II, it avoids secondary nucleation caused by a sudden increase in supersaturation, ensuring that the crystal grows uniformly under low supersaturation and obtains crystals with small particle size and narrow distribution.

[0027] 2. The purity of the product obtained by this invention is much higher than that required by the pharmacopoeia, and the process yield is ≥90%; it is a white crystalline crystal with high crystallinity, good fluidity (angle of repose ≤35°), uniform particle size distribution (D50≤25 μm, D90≤70 μm), fast reconstitution time (≤75 s), and is extremely easy to separate into solid and liquid (filtration).

[0028] 3. The equipment required for this invention is simple, the processing scale is large, and the operation is simple. It can be industrialized and has good technical and economic benefits and high industrial application value. Attached Figure Description

[0029] Figure 1 Microscopic image of the morphology of meropenem crystals prepared in Example 1 of this invention;

[0030] Figure 2 This is a SEM image of the meropenem crystal prepared in Example 1 of the present invention;

[0031] Figure 3 This is a SEM image of the meropenem crystal prepared in Example 2 of the present invention;

[0032] Figure 4 SEM image of the morphology of meropenem crystals prepared for Comparative Example 2;

[0033] Figure 5 XRD patterns of the methanol solvate and trihydrate crystal forms of Comparative Example 3;

[0034] Figure 6 Microscopic image of the morphology of meropenem crystals prepared for comparative example 4A;

[0035] Figure 7 Microscopic image of the morphology of meropenem crystals prepared for Comparative Example 5;

[0036] Figure 8 Microscopic image of the morphology of meropenem crystals prepared for Comparative Example 6. Detailed Implementation

[0037] The present invention will be described more clearly and completely through the following embodiments, but the described examples are only a part of the embodiments of the present invention, and not all of them. The embodiments are provided to help understand the present invention and should not be construed as limiting the scope of protection of the present invention.

[0038] Example 1:

[0039] A novel reaction-dissolution coupled crystallization method for uniform, small-particle-size meropenem crystals, comprising the following steps:

[0040] Step 1: At 25 ℃, add 4.00 g of crude meropenem and 14 mL of water to a crystallizer, set the stirring speed to 300 rpm, and stir to form a suspension. Add 2 mL of triethylamine to 16 mL of water and mix well. Add the solution at a flow rate of 0.5 mL / min, and filter after dissolution.

[0041] Step 2: Maintain the above stirring rate, cool the filtrate to -5 ℃ crystallizer, add 10 mL of acetone at once, and add acetone-diluted hydrochloric acid solution (mass ratio of concentrated hydrochloric acid to acetone is 1:5) at a flow rate of 0.4 mL / min until the pH of the filtrate is 6.00; continue stirring until crystals appear and continue crystal growth for 1 h.

[0042] Step 3: After crystal growth is complete, maintain the system temperature and stirring rate, and continue to add 90 mL of a mixed solution of acetone and acetonitrile (the volume ratio of acetone to acetonitrile is 3:1) into the crystallizer at a flow rate of 2 mL / min. After the addition is complete, continue aging for 2 h to obtain crystal slurry.

[0043] Step 4: Solid-liquid separation. The obtained solid was vacuum dried at 25 °C for 12 h to obtain 3.77 g of meropenem crystals.

[0044] The final product is a white, spindle-shaped blocky crystal with a morphology like Figure 1 and Figure 2 As shown. Meropenem content was 99.6%, the largest area impurity before the main peak was 0.07%, the largest area impurity after the main peak was 0.08%, the largest unknown single impurity content was 0.02%, the yield was 94%, the total residual solvent was 0.1%, D50 = 20 μm, D90 = 63 μm, and the angle of repose was 30°. The aqueous solution was colorless, clear, and transparent, with an acidity of 4.84 and a reconstitution time of 54 s.

[0045] Example 2:

[0046] A novel reaction-dissolution coupled crystallization method for uniform, small-particle-size meropenem crystals, comprising the following steps:

[0047] Step 1: At 50 °C, add 10.00 g of crude meropenem and 10 mL of water to a crystallizer, set the stirring speed to 200 rpm, and stir to form a suspension. Add 4 mL of pyridine to 20 mL of water and mix well. Add the pyridine at a flow rate of 5 mL / min, and filter after dissolution.

[0048] Step 2: Maintain the above stirring rate, cool the filtrate to 0 ℃ in the crystallizer, add 3 mL of ethanol at once, and add ethanol-diluted hydrochloric acid solution (the mass ratio of concentrated hydrochloric acid to ethanol is 1:20) at a flow rate of 0.8 mL / min until the pH of the filtrate is 6.20; continue stirring until crystals appear, and continue crystal growth for 0.5 h.

[0049] Step 3: After crystal growth is complete, maintain the system temperature and stirring rate, and continue to add 150 mL of a mixed solution of n-propanol and n-butanol (volume ratio of n-propanol to n-butanol is 2:1) into the crystallizer at a flow rate of 3 mL / min. After the addition is complete, continue aging for 2 h to obtain crystal slurry.

[0050] Step 4: Solid-liquid separation. The obtained solid is vacuum dried at 50 °C for 4 hours to obtain 9.02 g of meropenem crystals.

[0051] The final product is a white, flaky crystal with a morphology like... Figure 3 As shown. Meropenem content was 99.5%, the largest area impurity before the main peak was 0.09%, the largest area impurity after the main peak was 0.12%, the largest unknown single impurity content was 0.03%, the yield was 90%, the total residual solvent was 0.14%, D50 = 23 μm, D90 = 70 μm, and the angle of repose was 33°. The aqueous solution was colorless, clear, and transparent, with an acidity of 4.98 and a reconstitution time of 60 s.

[0052] Example 3:

[0053] A novel reaction-dissolution coupled crystallization method for uniform, small-particle-size meropenem crystals, comprising the following steps:

[0054] Step 1: At 40 ℃, add 3.00 g of crude meropenem and 15 mL of water to a crystallizer, set the stirring speed to 100 rpm, and stir to form a suspension. Add 0.5 g of sodium carbonate to 15 mL of water and mix well. Add the solution at a flow rate of 3 mL / min, and filter after dissolution.

[0055] Step 2: Maintain the above stirring rate, cool the filtrate to 10 °C in the crystallizer, add 10 mL of tetrahydrofuran and 5 mL of acetonitrile at once, and add a tetrahydrofuran diluted acetic acid solution (acetic acid to tetrahydrofuran volume ratio of 1:1) at a flow rate of 0.2 mL / min until the pH of the filtrate is 5.80; continue stirring until crystals appear, and continue crystal growth for 0.5 h.

[0056] Step 3: After crystal growth is complete, maintain the system temperature and stirring rate, and continue to add 30 mL of a mixed solution of tetrahydrofuran and acetonitrile (the volume ratio of tetrahydrofuran to acetonitrile is 3:1) to the crystallizer at a flow rate of 0.3 mL / min. After the addition is complete, continue aging for 3 h to obtain crystal slurry.

[0057] Step 4: Solid-liquid separation. The obtained solid was vacuum dried at 30 °C for 12 h to obtain 2.72 g of meropenem crystals.

[0058] The final product is a white, spindle-shaped, blocky crystal. Meropenem content is 99.5%, the largest area impurity before the main peak is 0.06%, the largest area impurity after the main peak is 0.08%, the largest unknown single impurity content is 0.04%, the yield is 91%, the total residual solvent is 0.07%, D50 = 25 μm, D90 = 60 μm, and the angle of repose is 33°. The aqueous solution is colorless, clear, and transparent, with an acidity of 4.93 and a reconstitution time of 67 s.

[0059] Example 4:

[0060] A novel reaction-dissolution coupled crystallization method for uniform, small-particle-size meropenem crystals, comprising the following steps:

[0061] Step 1: At 10 ℃, add 6.00 g of crude meropenem and 10 mL of water to a crystallizer, set the stirring speed to 500 rpm, and stir to form a suspension. Add 0.75 g of sodium hydroxide and 0.75 g of potassium hydroxide solid to 20 mL of water and mix well. Add the mixture at a flow rate of 0.8 mL / min, and filter after dissolving.

[0062] Step 2: Maintain the above stirring rate, cool the filtrate to 0 ℃ in the crystallizer, add 5 mL of methanol and 5 mL of isopropanol at once, and add concentrated sulfuric acid solution diluted with water at a flow rate of 1.0 mL / min (the mass ratio of concentrated sulfuric acid to water is 1:7.5) until the pH of the filtrate is 6.10; continue stirring until crystals appear and continue crystal growth for 3 h.

[0063] Step 3: After crystal growth is complete, maintain the system temperature and stirring rate, and continue to add 80 mL of isopropanol into the crystallizer at a flow rate of 2 mL / min. After the addition is complete, continue aging for 1 h to obtain crystal slurry.

[0064] Step 4: Solid-liquid separation. The obtained solid was vacuum dried at 25 °C for 16 h to obtain 5.38 g of meropenem crystals.

[0065] The final product is a white, spindle-shaped, blocky crystal. Meropenem content is 99.5%, the largest area impurity before the main peak is 0.08%, the largest area impurity after the main peak is 0.10%, the largest unknown single impurity content is 0.04%, the yield is 90%, the total residual solvent is 0.12%, D50 = 18 μm, D90 = 70 μm, and the angle of repose is 34°. The aqueous solution is colorless, clear, and transparent, with an acidity of 5.12 and a reconstitution time of 73 s.

[0066] Example 5:

[0067] A novel reaction-dissolution coupled crystallization method for uniform, small-particle-size meropenem crystals, comprising the following steps:

[0068] Step 1: At 50 ℃, add 20.00 g of crude meropenem and 50 mL of water to a crystallizer, set the stirring speed to 250 rpm, and stir to form a suspension. Add 10 mL of isopropylamine to 100 mL of water and mix well. Add the solution at a flow rate of 5 mL / min, and filter after dissolution.

[0069] Step 2: Maintain the above stirring rate, cool the filtrate to 5 ℃ in the crystallizer, add 10 mL of n-propanol and 5 mL of n-butanol at once, and add water-diluted phosphoric acid solution (the mass ratio of phosphoric acid to water is 1:3) at a flow rate of 3 mL / min until the pH of the filtrate is 6.00; continue stirring until crystals appear and continue crystal growth for 1 h.

[0070] Step 3: After crystal growth is complete, maintain the system temperature and stirring rate, and continue to add 300 mL of n-propanol into the crystallizer at a flow rate of 5 mL / min. After the addition is complete, continue aging for 5 h to obtain crystal slurry.

[0071] Step 4: Solid-liquid separation. The obtained solid was vacuum dried at 30 °C for 10 h to obtain 17.6 g of meropenem crystals.

[0072] The final product is a white, spindle-shaped, blocky crystal. Meropenem content is 99.5%, the largest area impurity before the main peak is 0.08%, the largest area impurity after the main peak is 0.10%, the largest unknown single impurity content is 0.04%, the yield is 90%, the total residual solvent is 0.15%, D50 = 25 μm, D90 = 68 μm, and the angle of repose is 33°. The aqueous solution is colorless, clear, and transparent, with an acidity of 5.04 and a reconstitution time of 64 s.

[0073] Example 6:

[0074] A novel reaction-dissolution coupled crystallization method for uniform, small-particle-size meropenem crystals, comprising the following steps:

[0075] Step 1: At 30 ℃, add 10.00 g of crude meropenem and 45 mL of water to a crystallizer, set the stirring speed to 350 rpm, and stir to form a suspension. Add 3 g of sodium bicarbonate and 2 g of potassium hydroxide to 25 mL of water and mix well. Add the mixture at a flow rate of 2 mL / min, and filter after dissolving.

[0076] Step 2: Maintain the above stirring rate, cool the filtrate to 5 ℃ in the crystallizer, add 10 mL of tetrahydrofuran at once, and add diluted sulfuric acid solution (concentrated sulfuric acid to water mass ratio of 1:5) at a flow rate of 1 mL / min until the pH of the filtrate is 6.20; continue stirring until crystals appear and continue crystal growth for 1 h.

[0077] Step 3: After crystal growth is complete, maintain the system temperature and stirring rate, and continue to add 150 mL of methyl ethyl ketone to the crystallizer at a flow rate of 2.0 mL / min. After the addition is complete, continue aging for 1 h to obtain crystal slurry.

[0078] Step 4: Solid-liquid separation. The obtained solid is vacuum dried at 40 °C for 6 h to obtain 8.6 g of meropenem crystals.

[0079] The final product is a white, spindle-shaped, blocky crystal. Meropenem content is 99.5%, the largest area impurity before the main peak is 0.07%, the largest area impurity after the main peak is 0.08%, the largest unknown single impurity content is 0.04%, the yield is 92%, the total residual solvent is 0.19%, D50 = 25 μm, D90 = 60 μm, and the angle of repose is 34°. The aqueous solution is colorless, clear, and transparent, with an acidity of 4.98 and a reconstitution time of 54 s.

[0080] The chemical properties of meropenem prepared in Examples 1-6 of this invention were tested.

[0081] 1) The chemical stability of meropenem prepared in Examples 1-6 of this invention was investigated. During storage at 30 ± 2℃ and 60 ± 5% RH for 3 months, the color, purity, and morphology of the product remained unchanged, indicating that the crystal has good chemical stability. The results are shown in Table 1.

[0082] Table 1. Chemical stability study of meropenem in this invention.

[0083]

[0084] Comparative Example 1

[0085] The only difference from Example 1 is that in step 1, the meropenem crystals are directly added to the alkaline solution during the dissolution process; the other conditions are the same as in Example 1.

[0086] Meropenem content was 96.6%, with the largest area impurity before the main peak being 0.37%, the largest area impurity after the main peak being 0.58%, and the largest unknown single impurity being 0.23%. The yield was 47%. The morphology was light yellow spindle-shaped blocky crystals with D50=84 μm, D90=142 μm, and an angle of repose of 41°. The aqueous solution was pale yellow with an acidity of 5.46 and a reconstitution time of 133 s.

[0087] Comparative Example 2

[0088] The specific steps, referring to the embodiment in CN101914098A, are as follows:

[0089] Step 1: At 70℃, add 10.00 g of crude meropenem and 200 mL of water to a crystallizer, set the stirring speed to 300 rpm, stir until dissolved, add 1.0 g of activated carbon, quickly cool to 10℃, and filter to remove the activated carbon.

[0090] Step 2: Maintain the above stirring rate, cool the filtrate to 2°C in the crystallizer, add 1% seed crystals, age for 2 hours, and then filter to obtain crystal slurry.

[0091] Step 3: Solid-liquid separation. The obtained solid is dried at 30°C for 16 h to obtain 5.28 g of meropenem crystals.

[0092] Step 4: Maintain the above stirring rate, cool the mother liquor to 2 ℃ in the crystallizer, add 400 ml of acetone at once, stir for 1 h, then add 400 ml of acetone dropwise at 2 ml / min, and recover 1.83 g of meropenem.

[0093] The final product consists of white to light yellow spindle-shaped blocky crystals with uneven particle size distribution, and its morphology is as follows: Figure 4 As shown. Meropenem content was 99.2%, the largest area impurity before the main peak was 0.12%, the largest area impurity after the main peak was 0.19%, the largest unknown single impurity content was 0.08%, the product yield was 53%, the overall yield was 71%, the total residual solvent was 0.12%, D50 = 75 μm, D90 = 177 μm, and the angle of repose was 44°. The aqueous solution was pale yellow, with an acidity of 5.11 and a reconstitution time of 138 s.

[0094] Comparative Example 3

[0095] Referring to CN101921276A, the specific steps are as follows:

[0096] Step 1: Dissolve 10 g of crude meropenem in 40 ml of methanol, keep the temperature at 15°C, set the stirring speed to 250 rpm, add 1.5 g of activated carbon for decolorization for 20 min, and solid will re-precipitate.

[0097] Step 2: Filter the solution from Step 1, keep the stirring rate constant, cool to 10℃, and add 200ml of a mixed solution of water and tetrahydrofuran (volume ratio of water to tetrahydrofuran is 1:4) dropwise at a rate of 1.5 ml / min. After the addition is complete, stop stirring, let it stand to crystallize for 1 hour, and recover 4.32 g of meropenem.

[0098] The XRD results of the solid precipitated in step 1 are as follows: Figure 5 The image shows meropenem in methanol. Methanol is a Class II solvent, and there are strict requirements for residual solvent. This process is prone to crystal transformation during production, which is not conducive to industrial production. The final product is a white to light yellow spindle-shaped solid with a meropenem content of 99.3%. The maximum area impurity before the main peak is 0.14%, the maximum area impurity after the main peak is 0.16%, the maximum unknown single impurity content is 0.10%, the yield is 43%, the total residual solvent is 0.15%, D50 = 68 μm, D90 = 143 μm, and the angle of repose is 42°. The aqueous solution is clear and transparent with an acidity of 5.11 and a reconstitution time of 127 s.

[0099] Comparative Example 4A

[0100] The pre-addition of solvent I is cancelled (the rest is the same as in Example 1).

[0101] The final product is a white, spindle-shaped, blocky crystal, such as Figure 6 As shown, the crystal grain size is not uniform, and the resolution time increases to 142s.

[0102] Comparative Example 4B

[0103] Solvent II is added all at once (the rest is the same as in Example 1).

[0104] The final product contained a large number of fine crystals, with D50=20 μm, D90=98 μm, and the angle of repose changed to 44°. The meropenem content was 99.2%, the maximum area impurity before the main peak was 0.14%, the maximum area impurity after the main peak was 0.21%, the content of the largest unknown single impurity was 0.13%, the yield was 94%, and the total residual solvent was 0.23%. The purity of the product decreased and the residual solvent increased.

[0105] Comparative Example 5

[0106] The only difference from Example 1 is the pH value for crystallization:

[0107] When pH ≥ 8.0, no crystal nuclei should precipitate within three hours;

[0108] When pH=7~8, the number of crystal nuclei precipitated is small, the crystal size is large (D50=125 μm, D90=180 μm), and the resolution time increases to 197 s;

[0109] When the crystallization pH is ≤ 4.0, the final product yield is 51%, a significant decrease. A representative product is... Figure 7 As shown, the crystal morphology is poor, the meropenem content is 99.3%, the maximum area impurity before the main peak is 0.16%, the maximum area impurity after the main peak is 0.20%, the content of the largest unknown single impurity is 0.15%, and the total residual solvent is 0.19%.

[0110] Comparative Example 6

[0111] The only difference from Example 1 is the stirring rate:

[0112] When the stirring rate is <100 rpm (equivalent to 80 rpm), representative products include... Figure 8 As shown, insufficient shear force resulted in poor heat and mass transfer, a small number of crystal nuclei, and uneven particle size (D50 = 127 μm, D90 = 242 μm), increasing the resolution time to 246 s.

[0113] When the stirring speed is greater than 500 rpm (600 rpm), the shear force is too large, the crystals break apart and produce a large number of fragments, and the product forms scale on the impeller and crystallizer wall, which is not conducive to industrial production.

[0114] This invention provides a meropenem method, which can be implemented by those skilled in the art by appropriately modifying raw materials, process parameters, and other aspects, based on the content of this document. The method and product of this invention have been described through preferred embodiments. Those skilled in the art can obviously modify or appropriately change and combine the methods and products described herein without departing from the content, spirit, and scope of this invention to achieve the technical requirements of this invention. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the spirit, scope, and content of this invention.

Claims

1. A method for preparing small-particle-size meropenem crystals, characterized in that, The steps are as follows: Step 1: Add water and crude meropenem to a crystallizer at 10 ~ 50℃ to prepare a suspension, and add alkaline solution dropwise at a certain flow rate. Start stirring at a speed of 100 ~ 500 rpm. After dissolving the solution, filter to remove insoluble impurities. Step 2: Maintain the stirring rate, cool the filtrate to -5 ~ 10 ℃ and then keep it at a constant temperature. Add solvent I all at once, and add acid dropwise at a certain flow rate to make the pH of the filtrate ≤ 7.

0. Stir to induce crystal formation and allow crystals to grow for 0.5 ~ 3 h. The solvent I is at least one of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, acetonitrile, and tetrahydrofuran. Step 3: After crystal growth is completed, maintain the system temperature and stirring rate, and add a certain amount of solvent II at a certain rate. After the addition of solvent II is completed, continue aging for 1 to 5 hours. The solvent II is at least one of methyl ethyl ketone, n-propanol, isopropanol, n-butanol, acetone, acetonitrile, and tetrahydrofuran. Step 4: Filter and dry the resulting solid to obtain the final product.

2. The preparation method according to claim 1, characterized in that, The alkaline solution is a solution of at least one of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, triethylamine, isopropylamine, and pyridine diluted with water. The mass ratio of alkali to water is 1:5 to 1:30, and the flow rate of the alkaline solution is controlled at 0.5 to 5 mL / min.

3. The preparation method according to claim 1, characterized in that, The acid solution is a solution of hydrochloric acid, acetic acid, phosphoric acid, and sulfuric acid diluted with solvent I, and the mass ratio of acid to solvent I is 1:1 to 1:

20.

4. The preparation method according to claim 1, characterized in that, In step 1, the mass ratio of crude meropenem to the total amount of water added directly and the diluted alkaline solution is 1:3 to 1:

10.

5. The preparation method according to claim 1, characterized in that, In step 2, the volume ratio of solvent I to the water added in step 1 is 1:2 to 1:

10.

6. The preparation method according to claim 1, characterized in that, In step 2, the flow rate of the acid solution is controlled to be 0.2 ~ 3 mL / min.

7. The preparation method according to claim 1, characterized in that, In step 3, the flow rate of solvent II is controlled to be 0.3 ~ 5 mL / min.

8. The preparation method according to claim 1, characterized in that, In step 3, the volume ratio of the amount of solvent II to the total amount of solvent in step 1 is 1:1 to 5:

1.

9. The preparation method according to claim 1, characterized in that, In step 4, the product is dried by vacuum drying, with a vacuum degree of -0.06 ~ -0.1 MPa, a drying temperature of 25 ~ 50 ℃, and a drying time of 4 ~ 16 h.

10. A small-particle-size meropenem crystal, characterized in that, The crystals are prepared by the method described in any one of claims 1-9, and the particle size distribution of the crystals satisfies the following conditions: D50≤25 μm, D90≤70 μm, angle of repose≤35°, reconstitution time≤75 seconds, crystal content≥99.5%, and total residual solvent≤0.2%.

Images