Crystal form of cefpiramide sodium, cefpiramide sodium containing crystal form and preparation method of cefpiramide sodium

Abstract

The invention provides a crystal form of cefpiramide sodium, cefpiramide sodium containing the crystal form and a preparation method of the cefpiramide sodium, and belongs to the technical field of medicine preparation and the technical field of medicine separation. An X-ray powder diffraction spectrum of the crystal form of the cefpiramide sodium, which takes 2theta as a diffraction angle, comprises a diffraction peak at 5.0 degrees + / -0.2 degrees.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation and the technical field of pharmaceutical separation, and in particular to a crystal form of cefpiramide sodium, cefpiramide sodium containing the crystal form and a preparation method thereof. Background Art

[0002] Cefpiramide Sodium is a third-generation cephalosporin antibiotic with a broad antibacterial spectrum and bactericidal power. It has strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and anaerobic bacteria, and is quite stable to β-lactamase. Compared with other cephalosporin drugs, Cefpiramide Sodium has the advantage of better stability, so it is favored by the domestic market. It is mainly used clinically for pharyngitis, tonsillitis, acute and chronic bronchitis, pneumonia, suppurative lung diseases, pyelonephritis, cystitis, prostatitis, meningitis and gynecological infections caused by sensitive bacteria.

[0003] The chemical name of cefpiramide sodium is (6R,7R)-7-[[(2R)-2-(4-hydroxyphenyl)-2-[(6-methyl-4-oxo-1H-pyridin-3-carboxylic acid)amino]acetyl]amino]-3-[(1-methyltetrazol-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate sodium, and the molecular formula is C 25 H 23 N8NaO7S2, molecular weight is 634.62, appearance is white powder, structural formula is as shown in formula (I).

[0004]

[0005] Formula (I)

[0006] The cefpiramide sodium currently available on the market is an amorphous solid product. Generally speaking, amorphous drug products have poor product stability and high impurity content compared with crystalline products. Summary of the invention

[0007] In view of this, the present invention provides a crystal form of cefpiramide sodium, cefpiramide sodium containing the crystal form, and a preparation method thereof.

[0008] According to an embodiment of one aspect of the present invention, a crystal form of cefpiramide sodium is provided, wherein an X-ray powder diffraction spectrum of the crystal form with a diffraction angle of 2θ includes a diffraction peak at 5.0°±0.2°.

[0009] According to an embodiment of the present invention, the X-ray powder diffraction spectrum of the above-mentioned crystal form at a diffraction angle of 2θ includes diffraction peaks at one or more of 6.3°±0.2°, 11.1°±0.2°, 18.6°±0.2°, 20.0°±0.2°, 23.0°±0.2° and 25.2°±0.2°.

[0010] According to an embodiment of the present invention, the X-ray powder diffraction spectrum of the above-mentioned crystal form is substantially as follows: Figure 1 , 4 ~As shown in any of 9.

[0011] According to another embodiment of the present invention, there is provided a cefpiramide sodium, which contains the above-mentioned crystal form of cefpiramide sodium.

[0012] According to an embodiment of the present invention, the above-mentioned cefpiramide sodium contains at least 97 wt % of the crystal form of cefpiramide sodium.

[0013] According to another embodiment of the present invention, a method for preparing the above-mentioned cefpiramide sodium is provided, comprising: reacting cefpiramide acid and a salt-forming agent in a polar solvent to obtain a cefpiramide sodium solution; and dissolving and crystallizing the above-mentioned cefpiramide sodium solution using a solvent to obtain cefpiramide sodium.

[0014] According to an embodiment of the present invention, the polar solvent is one or more of methanol and acetonitrile, or a combination of water and one or more of methanol and acetonitrile, or a combination of ethylene glycol and acetonitrile.

[0015] According to an embodiment of the present invention, the mass ratio of the cefoperazone to the salt-forming agent is 1:(0.13-0.3).

[0016] According to an embodiment of the present invention, the ratio of the mass of the cefuroxime acid to the volume of the polar solvent is 1 g: (5-22) mL.

[0017] According to an embodiment of the present invention, the volume ratio of the above-mentioned solvent to the above-mentioned polar solvent is 1:(3~7).

[0018] According to an embodiment of the present invention, the temperature of the above reaction is 0-40°C.

[0019] According to an embodiment of the present invention, the temperature of the dissolution crystallization is 5-40°C.

[0020] According to an embodiment of the present invention, the salt-forming agent is selected from one or more of sodium 2-ethylhexanoate, sodium acetate, sodium bicarbonate, and sodium octanoate.

[0021] According to an embodiment of the present invention, the above-mentioned solvent is selected from one or more of ethanol, propanol, isopropanol, ethyl acetate, acetone, and acetonitrile.

[0022] The crystal form of cefpiramide sodium provided in the embodiment of the present invention has good stability.

[0023] According to the embodiments of the present invention, compared with amorphous cefpiramide sodium, the cefpiramide sodium containing the above-mentioned crystal form has higher purity and better stability, and is suitable for the manufacture and long-term storage of pharmaceutical preparations.

[0024] According to an embodiment of the present invention, cefpiramide and a salt-forming agent are reacted in a polar solvent to obtain a cefpiramide sodium solution, and then a dissolving agent is used to dissolve and crystallize the cefpiramide sodium solution to obtain cefpiramide sodium containing the above-mentioned crystal form. The preparation method provided by the embodiment of the present invention has the advantages of simple preparation process, stable process, high reproducibility, low energy consumption, high economy, etc., and the product yield reaches more than 90%, and the product purity reaches more than 97%. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The X-ray powder diffraction spectrum of the crystal form of cefpiramide sodium provided in an embodiment of the present invention is shown;

[0026] Figure 2 The infrared spectrum of cefpiramide sodium provided in Example 1 of the present invention is shown;

[0027] Figure 3 A polarizing microscope image of cefpiramide sodium provided in Example 1 of the present invention is shown;

[0028] Figure 4 The X-ray powder diffraction spectrum of cefpiramide sodium provided in Example 1 of the present invention is shown;

[0029] Figure 5 The X-ray powder diffraction spectrum of cefpiramide sodium provided in Example 2 of the present invention is shown;

[0030] Figure 6 The X-ray powder diffraction spectrum of cefpiramide sodium provided in Example 3 of the present invention is shown;

[0031] Figure 7 The X-ray powder diffraction spectrum of cefpiramide sodium provided in Example 4 of the present invention is shown;

[0032] Figure 8 The X-ray powder diffraction spectrum of cefpiramide sodium provided in Example 5 of the present invention is shown;

[0033] Fig. 9 The X-ray powder diffraction spectrum of cefpiramide sodium provided in Example 6 of the present invention is shown;

[0034] Fig.10 The X-ray powder diffraction spectrum of cefpiramide sodium provided in Example 7 of the present invention is shown;

[0035] Fig.11 The X-ray powder diffraction spectrum of cefpiramide sodium provided in Comparative Example 1 of the present invention is shown;

[0036] Fig.12 The X-ray powder diffraction spectrum of cefpiramide sodium provided in Comparative Example 2 of the present invention is shown. DETAILED DESCRIPTION

[0037] Below, embodiments of the present invention will be described with reference to the accompanying drawings. However, it should be understood that these descriptions are exemplary only and are not intended to limit the scope of the present invention. In the following detailed description, for ease of explanation, many specific details are set forth to provide a comprehensive understanding of embodiments of the present invention. However, it is apparent that one or more embodiments may also be implemented without these specific details. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion of concepts of the present invention.

[0038] The terms used herein are only for describing specific embodiments and are not intended to limit the present invention. The term "comprising" used herein indicates the existence of features, steps, operations, but does not exclude the existence or addition of one or more other features.

[0039] In the case of using expressions such as "at least one of A, B, and C, etc.", it should generally be interpreted in accordance with the meaning of the expression generally understood by those skilled in the art (for example, "a system having at least one of A, B, and C" should include but is not limited to a system having A alone, B alone, C alone, A and B, A and C, B and C, and / or A, B, C, etc.). In the case of using expressions such as "at least one of A, B, or C, etc.", it should generally be interpreted in accordance with the meaning of the expression generally understood by those skilled in the art (for example, "a system having at least one of A, B, or C" should include but is not limited to a system having A alone, B alone, C alone, A and B, A and C, B and C, and / or A, B, C, etc.).

[0040] The cefpiramide sodium currently on the market is an amorphous solid product, and compared with crystalline products, amorphous drug products have problems such as poor product stability and high impurity content. Polymorphism is a common phenomenon in drug molecules. Different crystal forms will show different physical and chemical properties, which will affect the efficacy of the drug.

[0041] In the process of realizing the concept of the present invention, it is found that a specific crystal form of cefpiramide sodium can improve the stability and medication safety of cefpiramide sodium. To this end, the present invention provides a crystal form of cefpiramide sodium, cefpiramide sodium containing the same, and a preparation method thereof.

[0042] Specifically, according to an embodiment of one aspect of the present invention, a crystal form of cefpiramide sodium is provided, wherein an X-ray powder diffraction spectrum of the crystal form with a diffraction angle of 2θ includes a diffraction peak at 5.0°±0.2°.

[0043] The crystal form of cefpiramide sodium provided in the embodiment of the present invention has good stability.

[0044] According to an embodiment of the present invention, the X-ray powder diffraction spectrum of the crystal form of cefpiramide sodium at a diffraction angle of 2θ also includes diffraction peaks at one or more of 6.3°±0.2°, 11.1°±0.2°, 18.6°±0.2°, 20.0°±0.2°, 23.0°±0.2° and 25.2°±0.2°.

[0045] According to an embodiment of the present invention, the X-ray powder diffraction spectrum of the crystal form of cefpiramide sodium with a diffraction angle of 2θ may include diffraction peaks at 5.0°±0.2° and 20.0°±0.2°.

[0046] According to an embodiment of the present invention, the X-ray powder diffraction spectrum of the crystal form of cefpiramide sodium with a diffraction angle of 2θ may include diffraction peaks at 5.0°±0.2° and 25.2°±0.2°.

[0047] According to an embodiment of the present invention, the X-ray powder diffraction spectrum of the crystal form of cefpiramide sodium with a diffraction angle of 2θ may include diffraction peaks at 5.0°±0.2°, 20.0°±0.2° and 25.2°±0.2°.

[0048] According to an embodiment of the present invention, the X-ray powder diffraction spectrum of the crystal form of cefpiramide sodium with a diffraction angle of 2θ may include diffraction peaks at 5.0°±0.2°, 6.3°±0.2°, 11.1°±0.2°, 18.6°±0.2°, 20.0°±0.2°, 23.0°±0.2° and 25.2°±0.2°.

[0049] According to an embodiment of the present invention, a crystal form refers to a crystal structure (or polymorph) having a specific molecular stacking arrangement in a crystal lattice. Crystal forms can be identified and distinguished from each other by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), etc. The crystal form of cefpiramide sodium in an embodiment of the present invention refers to a unique crystal form that can be identified and distinguished from each other by one or more characterization techniques, including, for example, X-ray powder diffraction (XRPD), etc. According to an embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form of cefpiramide sodium has one or more diffraction peaks at one or more specified 2θ diffraction angles.

[0050] According to an embodiment of the present invention, X-ray powder diffraction is a method of diffraction analysis of powdered polycrystalline samples using monochromatic X-rays in X-ray diffraction analysis. An X-ray powder diffraction spectrum refers to an experimentally obtained spectrum that plots signal position (abscissa) relative to signal intensity (ordinate). For amorphous materials, an X-ray powder diffraction spectrum may include one or more broad and flat diffraction peaks; for crystalline materials, an X-ray powder diffraction spectrum may include one or more thin, high and sharp diffraction peaks, each of which is identified by its angle value, which is measured as an angle 2θ and is depicted on the abscissa of the X-ray powder diffraction spectrum.

[0051] According to an embodiment of the present invention, the repeatability of the measured angle value is within the range of ±0.2°, that is, the angle value can be an angle value of +0.2°, an angle value of -0.2°, or any value between these two endpoints (angle value of +0.2° and angle value of -0.2°). Optionally, the repeatability of the measured angle value is within the range of ±0.1°.

[0052] According to an embodiment of the present invention, the X-ray powder diffraction spectrum of the crystalline form is substantially as follows: Figure 1 , 4 ~As shown in any of 9. Figure 1 The X-ray powder diffraction spectrum of the crystal form of cefpiramide sodium provided in the embodiment of the present invention is shown.

[0053] According to embodiments of the present invention, "substantially" means that with respect to an X-ray powder diffraction pattern, the positions and intensities of the diffraction peaks may vary. For example, the diffraction peak positions (2θ) may show some inter-device variability, typically up to 0.2°. Sometimes, depending on device calibration differences, the variability may be higher than 0.2°.

[0054] According to another embodiment of the present invention, there is provided a cefpiramide sodium, which contains the above-mentioned crystal form of cefpiramide sodium.

[0055] According to the embodiments of the present invention, compared with amorphous cefpiramide sodium, the cefpiramide sodium containing the above-mentioned crystal form has higher purity and better stability, and is suitable for the manufacture and long-term storage of pharmaceutical preparations.

[0056] According to an embodiment of the present invention, cefpiramide sodium contains at least 97 wt % of the crystalline form of cefpiramide sodium. Further, cefpiramide sodium contains at least 97.6 wt % of the crystalline form of cefpiramide sodium.

[0057] According to an embodiment of another aspect of the present invention, a method for preparing cefpiramide sodium is provided, comprising: reacting cefpiramide acid and a salt-forming agent in a polar solvent to obtain a cefpiramide sodium solution; and dissolving and crystallizing the cefpiramide sodium solution using a dissolving agent to obtain cefpiramide sodium.

[0058] According to an embodiment of the present invention, cefpiramide and a salt-forming agent are reacted in a polar solvent to obtain a cefpiramide sodium solution, and then a dissolving agent is used to dissolve and crystallize the cefpiramide sodium solution to obtain cefpiramide sodium containing the above-mentioned crystal form. The preparation method provided by the embodiment of the present invention has the advantages of simple preparation process, stable process, high reproducibility, low energy consumption, high economy, etc., and the product yield reaches more than 90%, and the product purity reaches more than 97%.

[0059] According to an embodiment of the present invention, the polar solvent is one or more of methanol and acetonitrile, or a combination of water and one or more of methanol and acetonitrile, or a composition of ethylene glycol and acetonitrile. Specifically, the polar solvent can be methanol, acetonitrile, a composition of methanol and acetonitrile, a composition of water and methanol, a composition of water and acetonitrile, a composition of water, methanol and acetonitrile, or a composition of ethylene glycol and acetonitrile.

[0060] According to an embodiment of the present invention, by selecting a suitable solvent, cefpiramide acid and a salt-forming agent can be effectively dissolved and the formation of cefpiramide sodium can be promoted, the reaction time can be shortened, and the formation of related impurities can be reduced. Suitable solvents are also beneficial to subsequent crystallization operations. By regulating the composition of the solvent, the coordination effect between the solvent and the sodium ion is suppressed, thereby promoting the crystallization of cefpiramide sodium and avoiding the unfavorable gelation and oil formation. In addition, by regulating the composition of the solvent, the conformation and molecular accumulation of cefpiramide sodium in the solution can also be selectively regulated, thereby affecting the formation of subsequent crystal forms.

[0061] According to an embodiment of the present invention, the mass ratio of cefuroxime to the salt-forming agent is 1:(0.13-0.3), preferably 1:(0.2-0.25). Specifically, the mass ratio of cefuroxime to the salt-forming agent may be 1:0.13, 1:0.15, 1:0.18, 1:0.2, 1:0.22, 1:0.25, 1:0.28 or 1:0.3.

[0062] According to an embodiment of the present invention, a suitable mass ratio of cefoperazone and a salt-forming agent can promote the formation of cefoperazone sodium, reduce the occurrence of side reactions and the impurity content, and at the same time reduce the unreacted cefoperazone and a salt-forming agent from entering the subsequent crystallization process, affecting the product purity.

[0063] According to an embodiment of the present invention, the ratio of the mass of cefuroxime to the volume of the polar solvent is 1g: (5-22) mL, preferably 1g: (10-15) mL. Specifically, the ratio of the mass of cefuroxime to the volume of the polar solvent may be 1g: 5 mL, 1g: 7 mL, 1g: 10 mL, 1g: 12 mL, 1g: 15 mL, 1g: 17 mL, 1g: 20 mL or 1g: 22 mL.

[0064] According to an embodiment of the present invention, the volume ratio of the solvent to the polar solvent is 1: (3-15), preferably 1: (4-10). Specifically, the volume ratio of the solvent to the polar solvent can be 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14 or 1:15.

[0065] According to the embodiments of the present invention, the appropriate ratio of the mass of cefpiramide to the volume of the polar solvent and the volume ratio of the solvent to the polar solvent can take into account both the formation of the cefpiramide sodium crystal form and the cost.

[0066] According to an embodiment of the present invention, the reaction temperature is 0-40° C., preferably 10-30° C. Specifically, the reaction temperature can be 0° C., 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., 35° C. or 40° C., preferably 20° C.

[0067] According to an embodiment of the present invention, the reaction time is 0.5 to 4.0 h, preferably 1.0 to 2.0 h. Specifically, the reaction time can be 0.5 h, 1.0 h, 1.5 h, 2.0 h, 2.5 h, 3.0 h, 3.5 h or 4.0 h.

[0068] According to an embodiment of the present invention, the temperature of dissolution crystallization is 5-40° C., preferably 10-30° C. Specifically, the reaction temperature can be 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., 35° C. or 40° C., preferably 20° C.

[0069] According to the embodiments of the present invention, suitable reaction temperature and dissolution crystallization temperature can promote the formation of cefpiramide sodium crystals. The preparation method of cefpiramide sodium provided by the embodiments of the present invention has mild reaction temperature, stable process and high economy.

[0070] According to an embodiment of the present invention, the salt-forming agent is selected from one or more of sodium 2-ethylhexanoate, sodium acetate, sodium bicarbonate, and sodium octanoate. When a single salt-forming agent is used, the mass ratios of cefoperazone to sodium bicarbonate, sodium acetate, sodium 2-ethylhexanoate, and sodium octanoate can be 0.13, 1:0.15, 1:0.3, and 1:0.3, respectively.

[0071] According to an embodiment of the present invention, a suitable salt-forming agent can be beneficial to the formation of a crystalline form of cefpiramide sodium.

[0072] According to an embodiment of the present invention, the solvent is selected from one or more of ethanol, propanol, isopropanol, ethyl acetate, acetone, and acetonitrile.

[0073] According to an embodiment of the present invention, the addition rate of the solvent is 0.2-1.0 mL / min.

[0074] According to an embodiment of the present invention, the addition time of the dissolving agent is 30 to 120 min.

[0075] According to an embodiment of the present invention, a suitable solvent can be combined with a polar solvent to reduce the solubility of cefpiramide sodium, thereby promoting the crystallization of cefpiramide sodium to obtain cefpiramide sodium containing the above-mentioned crystal form.

[0076] In an embodiment of the present invention, cefpiramide sodium containing the above-mentioned crystal form is obtained by reacting cefpiramide as a raw material, forming a salt, dissolving and crystallizing. After dissolving and crystallizing, filtering, washing, drying and other steps may also be included. The washing solvent may be selected from one or more of anhydrous ethanol, acetone, dichloromethane, ethyl acetate and the like. The drying temperature may be 10-40 °C vacuum drying for 2-4 hours, preferably 20 °C vacuum drying for 4 hours.

[0077] The following lists a number of specific embodiments to illustrate the technical solution of the present invention in detail. It should be noted that the specific embodiments below are only used for illustration and are not used to limit the present invention.

[0078] Example 1

[0079] This embodiment provides a method for preparing cefpiramide sodium, comprising the following steps:

[0080] (1) Place 1.0 g of cefoperazone and 0.13 g of sodium acetate solid in a mixed solvent (12 mL of methanol, 8 mL of acetonitrile, and 0.5 mL of water) at 20 °C and stir for 1 h to allow cefoperazone to react completely with the salt-forming agent to obtain a cefoperazone sodium solution.

[0081] (2) Filter the cefpiramide sodium solution and add 100 mL of solvent (isopropanol) at a rate of 0.4 mL / min at 5 °C.

[0082] (3) Filter the product, wash the filter cake with ethanol, and then filter by vacuum extraction.

[0083] (4) The obtained crystals were placed in a vacuum drying oven at 20°C and dried to obtain crystalline cefpiramide sodium with a yield of 91.8% and a purity of 97.9%.

[0084] The infrared spectrum of the prepared cefpiramide sodium is shown in the figure below: Figure 2 As shown. Figure 2 Analysis shows that the product obtained in Example 1 is cefpiramide sodium.

[0085] The prepared cefpiramide sodium was tested using a polarizing microscope. The polarizing microscope image is shown in FIG. Figure 3 shown.

[0086] The prepared cefpiramide sodium was subjected to PXRD detection, and the detection results were as follows: Figure 4 As shown, the PXRD spectrum has diffraction peaks at 2θ=5.0±0.2, 6.3±0.2, 11.1±0.2, 18.6±0.2, 20.0±0.2, 23.0±0.2, and 25.2±0.2 degrees.

[0087] Example 2

[0088] This embodiment provides a method for preparing cefpiramide sodium, comprising the following steps:

[0089] (1) Place 1.0 g of cefoperazone and 0.20 g of solid sodium acetate in a mixed solvent (12 mL of methanol, 8 mL of acetonitrile, and 0.5 mL of water) at 20 °C and stir for 1 h to allow cefoperazone to react completely with the salt-forming agent to obtain a cefoperazone sodium solution.

[0090] (2) Filter the cefpiramide sodium solution and add 140 mL of solvent isopropanol at a rate of 0.4 mL / min at 20 °C.

[0091] (3) Filter the product, wash the filter cake with ethanol, and then filter by vacuum extraction.

[0092] (4) The obtained crystals were placed in a vacuum drying oven at 20°C and dried to obtain crystalline cefpiramide sodium with a yield of 91.7% and a purity of 97.8%.

[0093] The prepared cefpiramide sodium was subjected to PXRD detection, and the test results were as follows: Figure 5 As shown, the PXRD spectrum has diffraction peaks at 2θ=5.0±0.2, 6.3±0.2, 11.1±0.2, 18.6±0.2, 20.0±0.2, 23.0±0.2, and 25.2±0.2 degrees.

[0094] Example 3

[0095] This embodiment provides a method for preparing cefpiramide sodium, comprising the following steps:

[0096] (1) Place 1.0 g of cefoperazone and 0.30 g of solid sodium acetate in a mixed solvent (12 mL of methanol, 8 mL of acetonitrile, and 0.5 mL of water) at 20 °C and stir for 1 h to allow cefoperazone to react completely with the salt-forming agent to obtain a cefoperazone sodium solution.

[0097] (2) Filter the cefpiramide sodium solution and add 80 mL of solvent isopropanol at a rate of 0.4 mL / min at 40 °C.

[0098] (3) Filter the product, wash the filter cake with ethanol, and then filter by vacuum extraction.

[0099] (4) The obtained crystals were placed in a vacuum drying oven at 20°C and dried to obtain crystalline cefpiramide sodium with a yield of 91.5% and a purity of 97.4%.

[0100] The prepared cefpiramide sodium was subjected to PXRD detection, and the detection results were as follows: Figure 6 As shown, the PXRD spectrum has diffraction peaks at 2θ=5.0±0.2, 6.3±0.2, 11.1±0.2, 18.6±0.2, 20.0±0.2, 23.0±0.2, and 25.2±0.2 degrees.

[0101] Example 4

[0102] This embodiment provides a method for preparing cefpiramide sodium, comprising the following steps:

[0103] (1) Place 1.0 g of cefoperazone and 0.13 g of solid sodium bicarbonate in a mixed solvent (5 mL of ethylene glycol, 5 mL of acetonitrile, and 0.5 mL of water) at 20 °C and stir for 1 h to allow cefoperazone to react completely with the salt-forming agent to obtain a cefoperazone sodium solution.

[0104] (2) Filter the cefpiramide sodium solution and add 120 mL of solvent isopropanol at a rate of 0.4 mL / min at 5 °C.

[0105] (3) Filter the product, wash the filter cake with ethanol, and then filter by vacuum extraction.

[0106] (4) The obtained crystals were placed in a vacuum drying oven at 20°C and dried to obtain crystalline cefpiramide sodium with a yield of 91.6% and a purity of 97.7%.

[0107] The prepared cefpiramide sodium was subjected to PXRD detection, and the detection results were as follows: Figure 7 As shown, the PXRD spectrum has diffraction peaks at 2θ=5.0±0.2, 6.3±0.2, 11.1±0.2, 18.6±0.2, 20.0±0.2, 23.0±0.2, and 25.2±0.2 degrees.

[0108] Example 5

[0109] This embodiment provides a method for preparing cefpiramide sodium, comprising the following steps:

[0110] (1) Place 1.0 g of cefoperazone and 0.20 g of solid sodium bicarbonate in a mixed solvent (5 mL of ethylene glycol, 5 mL of acetonitrile, and 0.5 mL of water) at 20 °C and stir for 1 h to allow cefoperazone to react completely with the salt-forming agent to obtain a cefoperazone sodium solution.

[0111] (2) Filter the cefpiramide sodium solution and add 70 mL of solvent isopropanol at a rate of 0.4 mL / min at 20 °C.

[0112] (3) Filter the product, wash the filter cake with ethanol, and then filter by vacuum extraction.

[0113] (4) The obtained crystals were placed in a vacuum drying oven at 20°C and dried to obtain crystalline cefpiramide sodium with a yield of 91.4% and a purity of 97.3%.

[0114] The prepared cefpiramide sodium was subjected to PXRD detection, and the detection results were as follows: Figure 8 As shown, the PXRD spectrum has diffraction peaks at 2θ=5.0±0.2, 6.3±0.2, 11.1±0.2, 18.6±0.2, 20.0±0.2, 23.0±0.2, and 25.2±0.2 degrees.

[0115] Example 6

[0116] This embodiment provides a method for preparing cefpiramide sodium, comprising the following steps:

[0117] (1) Place 1.0 g of cefoperazone and 0.30 g of solid sodium bicarbonate in a mixed solvent (5 mL of ethylene glycol, 5 mL of acetonitrile, and 0.5 mL of water) at 20 °C and stir for 1 h to allow cefoperazone to react completely with the salt-forming agent to obtain a cefoperazone sodium solution.

[0118] (2) Filter the cefpiramide sodium solution and add 120 mL of solvent isopropanol at a rate of 0.4 mL / min at 40 °C.

[0119] (3) Filter the product, wash the filter cake with ethanol, and then filter by vacuum extraction.

[0120] (4) The obtained crystals were placed in a vacuum drying oven at 20°C and dried to obtain crystalline cefpiramide sodium with a yield of 91.3% and a purity of 97.2%.

[0121] The prepared cefpiramide sodium was subjected to PXRD detection, and the detection results were as follows: Fig. 9As shown, the PXRD spectrum has diffraction peaks at 2θ=5.0±0.2, 6.3±0.2, 11.1±0.2, 18.6±0.2, 20.0±0.2, 23.0±0.2, and 25.2±0.2 degrees.

[0122] Example 7

[0123] This embodiment provides a method for preparing cefpiramide sodium, comprising the following steps:

[0124] (1) Place 1.0 g of cefuroxime and 0.20 g of solid sodium 2-ethylhexanoate in 12 mL of methanol at 35 °C and stir for 1 h to allow cefuroxime and the salt-forming agent to react completely to obtain a cefuroxime sodium solution.

[0125] (2) Filter the cefpiramide sodium solution and add 100 mL of solvent acetone at a rate of 0.8 mL / min at 40 °C.

[0126] (3) Filter the product, wash the filter cake with acetone, and then filter by vacuum extraction.

[0127] (4) The obtained crystals were placed in a vacuum drying oven at 30° C. and dried to obtain crystalline cefpiramide sodium with a yield of 91.5% and a purity of 97.6%.

[0128] The prepared cefpiramide sodium was subjected to PXRD detection, and the detection results were as follows: Fig.10 The PXRD spectrum has diffraction peaks at 2θ=5.0±0.2, 6.3±0.2, 11.1±0.2, 18.6±0.2, 20.0±0.2, 23.0±0.2, and 25.2±0.2 degrees.

[0129] Comparative Example 1

[0130] This comparative example provides a method for preparing cefpiramide sodium, comprising the following steps:

[0131] (1) Place 1.0 g of cefuroxime and 0.10 g of solid sodium hydroxide (salting agent) in 10 mL of methanol at 20 °C and stir continuously for 1 h to allow cefuroxime and the salting agent to react completely to obtain cefuroxime sodium solution.

[0132] (2) Filter the cefpiramide sodium solution and add 70 mL of acetone at a rate of 0.4 mL / min at 20 °C for dissolution and crystallization.

[0133] (3) Filter the product, wash the filter cake with acetone, and then filter by vacuum extraction.

[0134] (4) The obtained crystals are placed in a vacuum drying oven at 20°C and dried to obtain cefpiramide sodium.

[0135] The prepared cefpiramide sodium was subjected to PXRD detection, and the detection results were as follows: Fig.11 The PXRD spectrum shows a broad and flat diffraction peak, without a thin, high and sharp diffraction peak.

[0136] Comparative Example 2

[0137] This comparative example provides a method for preparing cefpiramide sodium, comprising the following steps:

[0138] (1) Dissolve 1.0 g of cefuroxime and triethylamine in 10 mL of N,N-dimethylformamide at 20 °C to obtain a cefuroxime salt solution.

[0139] (2) Dissolve 0.20 g of sodium isooctanoate (salting agent) in 6 mL of acetone at 20 °C to obtain a salting agent solution.

[0140] (3) Add the salt-forming agent solution to the cefpiramide salt solution at 20 °C to allow the reaction to complete, filter, and then add 70 mL of solvent acetone at a rate of 0.4 mL / min to dissolve and crystallize.

[0141] (4) Filter the product, wash the filter cake with acetone, and then filter by vacuum extraction.

[0142] (5) The obtained crystals are placed in a vacuum drying oven at 20°C and dried to obtain cefpiramide sodium.

[0143] The prepared cefpiramide sodium was subjected to PXRD detection, and the detection results were as follows: Fig.12 The PXRD spectrum shows a broad and flat diffraction peak, without a thin, high and sharp diffraction peak.

[0144] The chemical stability of the cefpiramide sodium prepared in Example 1 and the commercially available amorphous cefpiramide sodium was compared and stored for 15 days at 40°C and normal pressure. The results of the investigation are shown in Tables 1 and 2, respectively, wherein Table 1 is a chemical stability investigation table of the cefpiramide sodium prepared in Example 1, and Table 2 is a chemical stability investigation table of the commercially available amorphous cefpiramide sodium. The investigation results show that the chemical stability of the cefpiramide sodium provided in the embodiment of the present invention is good, and is more stable than the amorphous form.

[0145] Table 1

[0146]

[0147] Table 2

[0148]

[0149] In summary, the preparation process of cefpiramide sodium provided by the embodiment of the present invention is simple, the process is stable, the energy consumption is low, the economy is high, the yield of the crystal product is as high as more than 90%, the product purity is more than 97%, the preparation process is stable, and the reproducibility is high. Compared with the amorphous product, the crystal form 1 product has higher purity and better stability, and is suitable for the manufacture and long-term storage of pharmaceutical preparations.

[0150] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made to the technical method by any technician familiar with the art within the spirit and principle of the present invention is still included in the protection scope of the technical solution of the present invention.

Claims

1. A crystal form of cefpiramide sodium, characterized in that: The X-ray powder diffraction spectrum of the crystal form with a diffraction angle of 2θ includes a diffraction peak at 5.0°±0.2°.

2. The crystal form according to claim 1, characterized in that The X-ray powder diffraction spectrum of the crystalline form at a diffraction angle of 2θ includes diffraction peaks at one or more of 6.3°±0.2°, 11.1°±0.2°, 18.6°±0.2°, 20.0°±0.2°, 23.0°±0.2° and 25.2°±0.2°.

3. The crystal form according to claim 1 or 2, characterized in that: The X-ray powder diffraction spectrum of the crystal form is basically as shown in any one of Figures 1 and 4 to 9.

4. A cefpiramide sodium, characterized in that: The cefpiramide sodium contains the crystal form of cefpiramide sodium according to any one of claims 1 to 3.

5. Cefpiramide sodium according to claim 4, characterized in that The cefpiramide sodium contains at least 97 wt % of the crystal form of cefpiramide sodium.

6. The method for preparing cefpiramide sodium according to any one of claims 4 or 5, characterized in that: The preparation method comprises: reacting cefpiramide and a salt-forming agent in a polar solvent to obtain a cefpiramide sodium solution; The cefpiramide sodium solution is eluted and crystallized using a dissolving agent to obtain cefpiramide sodium.

7. The preparation method according to claim 6, characterized in that: The polar solvent is one or more of methanol and acetonitrile, or a combination of water and one or more of methanol and acetonitrile, or a combination of ethylene glycol and acetonitrile.

8. The preparation method according to claim 6 or 7, characterized in that: The mass ratio of the cefoperazone to the salt-forming agent is 1:(0.13-0.3); The ratio of the mass of the cefoperazone to the volume of the polar solvent is 1 g: (5-22) mL; The volume ratio of the solvent to the polar solvent is 1:(3-15).

9. The preparation method according to claim 6 or 7, characterized in that: The reaction temperature is 0-40°C; The temperature of the dissolution crystallization is 5-40°C.

10. The preparation method according to claim 6 or 7, characterized in that: The salt-forming agent is selected from one or more of sodium octanoate, sodium acetate, sodium bicarbonate, and sodium octanoate; The solvent is selected from one or more of ethanol, propanol, isopropanol, ethyl acetate, acetone and acetonitrile.

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