Method for preparing stabilized pharmaceutical composition based on cefixime crystal form III

Abstract

The present invention relates to a method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, and relates to the technical field of drug preparation. A crude cefixime product is added to a solvent A to obtain a cefixime solution; seed crystals of cefixime crystal form III are added to the cefixime solution and stirred and mixed; the cefixime solution containing the seed crystals is stirred, cooled, and crystallized; the crystallized solution is subjected to solid-liquid separation, a solid is collected, the solid is washed with a solvent B, and vacuum dried to obtain cefixime crystal form III; the cefixime crystal form III, a filler, a terpolymer disintegrant, a binder, and a lubricant are stirred and mixed uniformly, prepared into granules using a wet granulation process, and then tabletted to obtain stabilized pharmaceutical composition tablets. The cefixime crystal form III prepared by the present invention has high purity, and the degradation rate of the active ingredients of the stabilized pharmaceutical composition is low, thereby ensuring the effectiveness and safety of the drug.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, in particular to a method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III. Background Art

[0002] Cefixime is a third-generation oral cephalosporin antibiotic with broad-spectrum antibacterial activity against a variety of Gram-positive and Gram-negative bacteria, and is widely used in clinical treatment. However, cefixime exists in multiple crystalline forms, each with distinct physicochemical properties. These differences can significantly affect the drug's solubility, stability, and bioavailability, thereby impacting its efficacy and safety.

[0003] The invention patent with the authorization announcement number CN113968874B discloses a method for refining cefixime, which comprises: (1) dissolving and decolorizing the crude cefixime; and (2) crystallizing the cefixime in three steps, followed by filtering, washing, and drying to obtain cefixime crystals.

[0004] The invention patent with authorization announcement number CN113332441B discloses a cefixime composition, which includes the following raw materials in parts by weight: 35-45 parts of cefixime, 22-30 parts of microcrystalline cellulose, 15-20 parts of calcium hydrogen phosphate dihydrate, 3-8 parts of pregelatinized starch, 3-8 parts of mannitol, and 0.5-1 part of silicon dioxide.

[0005] The invention patent, authorized with publication number CN102311452B, discloses cefixime crystals, a preparation method, and a tablet composition containing the crystals. The cefixime crystals can significantly improve stability and solubility. The core of the cefixime tablet composition is made from the following ingredients: 35-65 parts cefixime crystals, 17-29 parts starch, 3-6 parts hydroxypropyl cellulose, 3-5 parts sodium starch glycolate, 7-13.5 parts microcrystalline cellulose, 0.3-0.7 parts sodium starch glycolate, and 0.3-0.7 parts magnesium stearate.

[0006] At present, in the research and application of cefixime on the market, the stability and consistency of its crystal form are difficult to guarantee, resulting in unstable drug quality and affecting clinical treatment effect. Among them, cefixime crystal form III is found to have good solubility and stability potential, but the existing preparation method has the problems of complex process, poor reproducibility, high cost and low purity of the prepared crystal form, which limits its application in actual production and drug development. In addition, the pharmaceutical composition prepared with cefixime crystal form III as raw material is prone to problems such as crystal form transformation and active ingredient degradation during storage, affecting the quality and efficacy of the drug. Therefore, it is urgent to develop a method that is simple, efficient, low in cost and can prepare high-purity cefixime crystal form III, and on this basis develop a stable pharmaceutical composition to meet clinical drug demand. Summary of the Invention

[0007] In order to solve the above problems, the present invention provides a method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, the operating steps of which are:

[0008] Preparation of S1 solution:

[0009] 10-15 parts of crude cefixime are added to 100-200 parts of solvent A, and the mixture is stirred and dissolved to obtain a cefixime solution;

[0010] S2 seed addition:

[0011] Add 0.1-0.75 parts of cefixime crystal form III seed crystals to the cefixime solution and stir to mix;

[0012] S3 crystallization:

[0013] The cefixime solution containing the seed crystals is stirred at a constant temperature of 20-40°C for 1-5 hours, then cooled to 0-10°C at a rate of 1-5°C / h, and stirred for crystallization for 3-8 hours;

[0014] S4 separation and drying:

[0015] The crystallized solution is subjected to solid-liquid separation, the solid is collected, and the solid is washed 1-3 times with solvent B, and then the washed solid is vacuum-dried at 40-60° C. for 5-10 hours to obtain cefixime crystal form III;

[0016] Preparation of S5 stabilized pharmaceutical composition:

[0017] 50-80 parts of cefixime crystal form III, 10-30 parts of filler, 3-10 parts of terpolymer disintegrant, 1-5 parts of binder, and 0.5-2 parts of lubricant are stirred and mixed uniformly, and granules are prepared by wet granulation process, and then tabletted to obtain stabilized pharmaceutical composition tablets.

[0018] In some embodiments, the solvent A is one of acetone, acetonitrile, and methanol.

[0019] In some embodiments, the solvent B is one of ethanol and isopropanol.

[0020] In some embodiments, the filler is one of lactose, microcrystalline cellulose, and mannitol.

[0021] In some embodiments, the preparation method of the terpolymer disintegrant is:

[0022] Dissolve A1 monomer: Add 8-15 parts of 2-hydroxyethyl acrylamide, 12-20 parts of 2-hydroxyethyl methacrylate, 5-10 parts of 2-hydroxypropyl-β-cyclodextrin acrylate, 0.1-2 parts of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, and 500-1000 parts of deionized water to a reactor and stir at 300-500 rpm for 15-45 minutes at 20-30°C to form a homogeneous solution;

[0023] A2 Deoxygenation and Initiator Addition: Add nitrogen to the solution for 10-25 minutes to deoxygenate at a nitrogen flow rate of 50-100 mL / min; add the photoinitiator and continue stirring for 5-15 minutes;

[0024] A3 photopolymerization reaction: under 365nm ultraviolet light with a power of 20-30W, stir and react at a constant temperature of 25-35℃ for 2-6 hours;

[0025] A4 post-treatment: Pour the product into 3-5 times the volume of anhydrous ethanol for precipitation, let it stand for 0.5-2 hours, filter it, and wash it with 60-80% ethanol 2-4 times; vacuum dry it at 45-65℃ for 5-10 hours, and crush it through a 60-100 mesh sieve to obtain a terpolymer disintegrant.

[0026] In some embodiments, the binder is one of povidone K30 and hydroxypropyl methylcellulose.

[0027] In some embodiments, the lubricant is one of magnesium stearate and micro-powdered silica gel.

[0028] In some embodiments, the photoinitiator is one of benzoin methyl ether, benzoin ethyl ether, 2,2-dimethoxy-2-phenylacetophenone, and 1-hydroxycyclohexyl phenyl ketone.

[0029] The method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III of the present invention has the following significant effects compared with the prior art:

[0030] 1. The preparation method of Cefixime Crystal Form III of the present invention has a simple preparation process and is easy to operate and control. At the same time, the organic solvent of the present invention can be recycled, thereby reducing production costs. The present invention can prepare high-purity Cefixime Crystal Form III, providing high-quality raw materials for subsequent drug development.

[0031] 2. The stabilized pharmaceutical composition of the present invention can effectively improve the stability of the pharmaceutical composition, avoid problems such as crystal transformation and degradation of active ingredients during storage, ensure the rapid release and absorption of the drug in the body, and improve the bioavailability and clinical efficacy of the drug. DETAILED DESCRIPTION

[0032] In order to further illustrate the technical means and effects adopted by the present invention to achieve the predetermined purpose of the invention, the specific implementation methods, structures, features and effects of the present invention are described in detail below in combination with preferred embodiments.

[0033] 1. Crystal purity test of Cefixime Form III: High performance liquid chromatography (HPLC) using a C18 column.

[0034] 2. Degradation rate test of the active ingredient in the stabilized pharmaceutical composition: After being placed at a temperature of 40° C. and a relative humidity of 75% for 3 months, the degradation rate of cefixime Form III in the stabilized pharmaceutical composition was tested.

[0035] Example 1: A method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, wherein the steps are as follows:

[0036] Preparation of S1 solution:

[0037] 10 g of crude cefixime was added to 100 g of solvent A, and the mixture was stirred and dissolved to obtain a cefixime solution;

[0038] S2 seed addition:

[0039] Add 0.1 g of cefixime crystal form III seed crystals to the cefixime solution and stir to mix;

[0040] S3 crystallization:

[0041] The cefixime solution containing the seed crystals was stirred at a constant temperature of 20°C for 1 hour, then cooled to 0°C at a rate of 1°C / h, and stirred for crystallization for 3 hours;

[0042] S4 separation and drying:

[0043] The crystallized solution was subjected to solid-liquid separation, the solid was collected, and the solid was washed once with solvent B, and then the washed solid was vacuum dried at 40° C. for 5 hours to obtain cefixime crystal form III;

[0044] Preparation of S5 stabilized pharmaceutical composition:

[0045] 50 g of cefixime crystal form III, 10 g of filler, 3 g of terpolymer disintegrant, 1 g of binder, and 0.5 g of lubricant were stirred and mixed uniformly, prepared into granules by wet granulation process, and then tableted to obtain stabilized pharmaceutical composition tablets.

[0046] The solvent A is acetone.

[0047] The solvent B is ethanol.

[0048] The filler is lactose.

[0049] The preparation method of the terpolymer disintegrant is:

[0050] A1 monomer dissolution: 8 g 2-hydroxyethyl acrylamide, 12 g 2-hydroxyethyl methacrylate, 5 g 2-hydroxypropyl-β-cyclodextrin acrylate, 0.1 g 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, and 500 g deionized water were added to a reaction kettle and stirred at 300 rpm for 15 minutes at 20°C to form a homogeneous solution;

[0051] A2 Deoxygenation and Initiator Addition: Nitrogen was introduced into the solution for 10 minutes to deoxygenate the solution at a flow rate of 50 mL / min; after adding the photoinitiator, stirring was continued for 5 minutes;

[0052] A3 photopolymerization reaction: under 365nm ultraviolet light with a power of 20W, the reaction was stirred at a constant temperature of 25℃ for 2 hours;

[0053] A4 post-treatment: The product was poured into 3 times the volume of anhydrous ethanol for precipitation, allowed to stand for 0.5 hours, filtered, and washed twice with 60% ethanol; vacuum dried at 45°C for 5 hours, and crushed through a 60-mesh sieve to obtain a terpolymer disintegrant.

[0054] The adhesive is povidone K30.

[0055] The lubricant is magnesium stearate.

[0056] The photoinitiator is benzoin methyl ether.

[0057] Example 2: A method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, wherein the steps are as follows:

[0058] Preparation of S1 solution:

[0059] 12 g of crude cefixime was added to 140 g of solvent A, and the mixture was stirred and dissolved to obtain a cefixime solution;

[0060] S2 seed addition:

[0061] Add 0.35 g of cefixime crystal form III seed crystals to the cefixime solution and stir to mix;

[0062] S3 crystallization:

[0063] The cefixime solution containing the seed crystals was stirred at a constant temperature of 25°C for 2 hours, then cooled to 5°C at a rate of 2°C / h, and stirred for crystallization for 5 hours;

[0064] S4 separation and drying:

[0065] The crystallized solution was subjected to solid-liquid separation, the solid was collected, and the solid was washed twice with solvent B, and then the washed solid was vacuum dried at 45° C. for 6 hours to obtain cefixime crystal form III;

[0066] Preparation of S5 stabilized pharmaceutical composition:

[0067] 60 g of cefixime crystal form III, 15 g of filler, 5 g of terpolymer disintegrant, 2 g of binder, and 1 g of lubricant were stirred and mixed uniformly, prepared into granules by wet granulation process, and then tableted to obtain stabilized pharmaceutical composition tablets.

[0068] The solvent A is acetonitrile.

[0069] The solvent B is ethanol.

[0070] The filler is microcrystalline cellulose.

[0071] The preparation method of the terpolymer disintegrant is:

[0072] A1 monomer dissolution: Add 10 g of 2-hydroxyethyl acrylamide, 14 g of 2-hydroxyethyl methacrylate, 6 g of 2-hydroxypropyl-β-cyclodextrin acrylate, 1 g of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, and 600 g of deionized water to a reactor and stir at 400 rpm for 25 minutes at 25°C to form a homogeneous solution;

[0073] A2 Deoxygenation and Initiator Addition: Nitrogen was introduced into the solution for 15 minutes to deoxygenate the solution at a flow rate of 60 mL / min; after adding the photoinitiator, stirring was continued for 10 minutes;

[0074] A3 photopolymerization reaction: under 365nm ultraviolet light with a power of 25W, the reaction was stirred at a constant temperature of 30℃ for 3 hours;

[0075] A4 post-treatment: The product was poured into 4 times the volume of anhydrous ethanol for precipitation, allowed to stand for 1 hour, filtered, and washed three times with 65% ethanol; vacuum dried at 50°C for 6 hours, and crushed through a 70-mesh sieve to obtain a terpolymer disintegrant.

[0076] The adhesive is povidone K30.

[0077] The lubricant is magnesium stearate.

[0078] The photoinitiator is benzoin ethyl ether.

[0079] Example 3: A method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, wherein the steps are as follows:

[0080] Preparation of S1 solution:

[0081] 14 g of crude cefixime was added to 180 g of solvent A, and the mixture was stirred and dissolved to obtain a cefixime solution;

[0082] S2 seed addition:

[0083] Add 0.65 g of cefixime crystal form III seed crystals to the cefixime solution and stir to mix;

[0084] S3 crystallization:

[0085] The cefixime solution containing the seed crystals was stirred at a constant temperature of 35°C for 4 hours, then cooled to 5°C at a rate of 4°C / h, and stirred for crystallization for 7 hours;

[0086] S4 separation and drying:

[0087] The crystallized solution was subjected to solid-liquid separation, the solid was collected, and the solid was washed twice with solvent B, and then the washed solid was vacuum dried at 55° C. for 8 hours to obtain cefixime crystal form III;

[0088] Preparation of S5 stabilized pharmaceutical composition:

[0089] 70 g of cefixime crystal form III, 25 g of filler, 8 g of terpolymer disintegrant, 4 g of binder, and 1.5 g of lubricant were stirred and mixed uniformly, prepared into granules by wet granulation process, and then tableted to obtain stabilized pharmaceutical composition tablets.

[0090] The solvent A is acetonitrile.

[0091] The solvent B is ethanol.

[0092] The filler is microcrystalline cellulose.

[0093] The preparation method of the terpolymer disintegrant is:

[0094] A1 monomer dissolution: 13 g 2-hydroxyethyl acrylamide, 18 g 2-hydroxyethyl methacrylate, 8 g 2-hydroxypropyl-β-cyclodextrin acrylate, 1.5 g 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, and 800 g deionized water were added to a reaction kettle and stirred at 400 rpm for 35 minutes at 25°C to form a homogeneous solution;

[0095] A2 Deoxygenation and Initiator Addition: Nitrogen was introduced into the solution for 20 minutes to deoxygenate the solution at a flow rate of 80 mL / min; after adding the photoinitiator, stirring was continued for 10 minutes;

[0096] A3 photopolymerization reaction: under 365nm ultraviolet light with a power of 25W, the reaction was stirred at a constant temperature of 30℃ for 5 hours;

[0097] A4 post-treatment: The product was poured into 4 times the volume of anhydrous ethanol for precipitation, allowed to stand for 1.5 hours, filtered, and washed three times with 75% ethanol; vacuum dried at 60°C for 8 hours, and crushed through a 90-mesh sieve to obtain a terpolymer disintegrant.

[0098] The adhesive is hydroxypropyl methylcellulose.

[0099] The lubricant is micro powder silica gel.

[0100] The photoinitiator is 2,2-dimethoxy-2-phenylacetophenone.

[0101] Example 4: A method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, wherein the steps are as follows:

[0102] Preparation of S1 solution:

[0103] 15 g of crude cefixime was added to 200 g of solvent A, and the mixture was stirred and dissolved to obtain a cefixime solution;

[0104] S2 seed addition:

[0105] Add 0.75 g of cefixime crystal form III seed crystals to the cefixime solution and stir to mix;

[0106] S3 crystallization:

[0107] The cefixime solution containing the seed crystals was stirred at a constant temperature of 40°C for 5 hours, then cooled to 10°C at a rate of 5°C / h, and stirred for crystallization for 8 hours;

[0108] S4 separation and drying:

[0109] The crystallized solution was subjected to solid-liquid separation, the solid was collected, and the solid was washed three times with solvent B, and then the washed solid was vacuum dried at 60° C. for 10 hours to obtain cefixime crystal form III;

[0110] Preparation of S5 stabilized pharmaceutical composition:

[0111] 80 g of cefixime crystal form III, 30 g of filler, 10 g of terpolymer disintegrant, 5 g of binder, and 2 g of lubricant were stirred and mixed uniformly, prepared into granules by wet granulation process, and then tableted to obtain stabilized pharmaceutical composition tablets.

[0112] The solvent A is methanol.

[0113] The solvent B is isopropanol.

[0114] The filler is mannitol.

[0115] The preparation method of the terpolymer disintegrant is:

[0116] A1 monomer dissolution: 15 g 2-hydroxyethyl acrylamide, 20 g 2-hydroxyethyl methacrylate, 10 g 2-hydroxypropyl-β-cyclodextrin acrylate, 2 g 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, and 1000 g deionized water were added to a reaction kettle and stirred at 500 rpm for 45 minutes at 30°C to form a homogeneous solution;

[0117] A2 Deoxygenation and Initiator Addition: Nitrogen was introduced into the solution for 25 minutes to deoxygenate the solution at a nitrogen flow rate of 100 mL / min; after adding the photoinitiator, stirring was continued for 15 minutes;

[0118] A3 photopolymerization reaction: under 365nm ultraviolet light, power of 30W, constant temperature stirring reaction at 35℃ for 6 hours;

[0119] A4 post-treatment: The product was poured into 5 times the volume of anhydrous ethanol for precipitation, allowed to stand for 2 hours, filtered, and washed with 80% ethanol four times; vacuum dried at 65°C for 10 hours, and crushed through a 100-mesh sieve to obtain a terpolymer disintegrant.

[0120] The adhesive is hydroxypropyl methylcellulose.

[0121] The lubricant is micro powder silica gel.

[0122] The photoinitiator is 1-hydroxycyclohexyl phenyl ketone.

[0123] Comparative Example 1: A method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, wherein the operating steps are as follows:

[0124] Preparation of S1 solution:

[0125] 10 g of crude cefixime was added to 100 g of solvent A, and the mixture was stirred and dissolved to obtain a cefixime solution;

[0126] S2 seed addition:

[0127] Add 0.1 g of cefixime crystal form III seed crystals to the cefixime solution and stir to mix;

[0128] S3 crystallization:

[0129] The cefixime solution containing the seed crystals was stirred at a constant temperature of 20°C for 1 hour, then cooled to 0°C at a rate of 1°C / h, and stirred for crystallization for 3 hours;

[0130] S4 separation and drying:

[0131] The crystallized solution was subjected to solid-liquid separation, the solid was collected, and the solid was washed once with solvent B, and then the washed solid was vacuum dried at 40° C. for 5 hours to obtain cefixime crystal form III;

[0132] Preparation of S5 stabilized pharmaceutical composition:

[0133] 50 g of cefixime crystal form III, 10 g of filler, 3 g of sodium carboxymethyl starch disintegrant, 1 g of binder, and 0.5 g of lubricant were stirred and mixed uniformly, prepared into granules by wet granulation process, and then tableted to obtain stabilized pharmaceutical composition tablets.

[0134] The solvent A is acetone.

[0135] The solvent B is ethanol.

[0136] The filler is lactose.

[0137] The adhesive is povidone K30.

[0138] The lubricant is magnesium stearate.

[0139] The photoinitiator is benzoin methyl ether.

[0140] Comparative Example 2: A method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, wherein the steps are as follows:

[0141] Preparation of S1 solution:

[0142] 10 g of crude cefixime was added to 100 g of solvent A, and the mixture was stirred and dissolved to obtain a cefixime solution;

[0143] S2 seed addition:

[0144] Add 0.1 g of cefixime crystal form III seed crystals to the cefixime solution and stir to mix;

[0145] S3 crystallization:

[0146] The cefixime solution containing the seed crystals was stirred at a constant temperature of 20°C for 1 hour, then cooled to 0°C at a rate of 1°C / h, and stirred for crystallization for 3 hours;

[0147] S4 separation and drying:

[0148] The crystallized solution was subjected to solid-liquid separation, the solid was collected, and the solid was washed once with solvent B, and then the washed solid was vacuum dried at 40° C. for 5 hours to obtain cefixime crystal form III;

[0149] Preparation of S5 stabilized pharmaceutical composition:

[0150] 50 g of cefixime crystal form III, 10 g of filler, 3 g of disintegrant, 1 g of binder, and 0.5 g of lubricant were stirred and mixed uniformly, and prepared into granules by wet granulation process, and then tableted to obtain stabilized pharmaceutical composition tablets.

[0151] The solvent A is acetone.

[0152] The solvent B is ethanol.

[0153] The filler is lactose.

[0154] The preparation method of the disintegrant is:

[0155] Dissolve A1 monomer: Add 8 g of 2-hydroxyethyl acrylamide, 12 g of 2-hydroxyethyl methacrylate, 0.1 g of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, and 500 g of deionized water to a reactor and stir at 300 rpm for 15 minutes at 20°C to form a homogeneous solution.

[0156] A2 Deoxygenation and Initiator Addition: Nitrogen was introduced into the solution for 10 minutes to deoxygenate the solution at a flow rate of 50 mL / min; after adding the photoinitiator, stirring was continued for 5 minutes;

[0157] A3 photopolymerization reaction: under 365nm ultraviolet light with a power of 20W, the reaction was stirred at a constant temperature of 25℃ for 2 hours;

[0158] A4 post-processing: Pour the product into 3 times the volume of anhydrous ethanol for precipitation, let it stand for 0.5 hours, filter it, and wash it twice with 60% ethanol; dry it in a vacuum at 45°C for 5 hours, and grind it through a 60-mesh sieve to obtain a disintegrant.

[0159] The adhesive is povidone K30.

[0160] The lubricant is magnesium stearate.

[0161] The photoinitiator is benzoin methyl ether.

[0162] Comparative Example 3: A method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, wherein the operating steps are as follows:

[0163] Preparation of S1 solution:

[0164] 10 g of crude cefixime was added to 100 g of solvent A, and the mixture was stirred and dissolved to obtain a cefixime solution;

[0165] S2 seed addition:

[0166] Add 0.1 g of cefixime crystal form III seed crystals to the cefixime solution and stir to mix;

[0167] S3 crystallization:

[0168] The cefixime solution containing the seed crystals was stirred at a constant temperature of 20°C for 1 hour, then cooled to 0°C at a rate of 1°C / h, and stirred for crystallization for 3 hours;

[0169] S4 separation and drying:

[0170] The crystallized solution was subjected to solid-liquid separation, the solid was collected, and the solid was washed once with solvent B, and then the washed solid was vacuum dried at 40° C. for 5 hours to obtain cefixime crystal form III;

[0171] Preparation of S5 stabilized pharmaceutical composition:

[0172] 50 g of cefixime crystal form III, 10 g of filler, 3 g of disintegrant, 1 g of binder, and 0.5 g of lubricant were stirred and mixed uniformly, and prepared into granules by wet granulation process, and then tableted to obtain stabilized pharmaceutical composition tablets.

[0173] The solvent A is acetone.

[0174] The solvent B is ethanol.

[0175] The filler is lactose.

[0176] The preparation method of the disintegrant is:

[0177] A1 Monomer Dissolution: Add 8 g of 2-hydroxyethyl acrylamide, 12 g of 2-hydroxyethyl methacrylate, 5 g of 2-hydroxypropyl-β-cyclodextrin acrylate, and 500 g of deionized water to a reactor and stir at 300 rpm for 15 minutes at 20°C to form a homogeneous solution;

[0178] A2 Deoxygenation and Initiator Addition: Nitrogen was introduced into the solution for 10 minutes to deoxygenate the solution at a flow rate of 50 mL / min; after adding the photoinitiator, stirring was continued for 5 minutes;

[0179] A3 photopolymerization reaction: under 365nm ultraviolet light with a power of 20W, the reaction was stirred at a constant temperature of 25℃ for 2 hours;

[0180] A4 post-processing: Pour the product into 3 times the volume of anhydrous ethanol for precipitation, let it stand for 0.5 hours, filter it, and wash it twice with 60% ethanol; dry it in a vacuum at 45°C for 5 hours, and grind it through a 60-mesh sieve to obtain a disintegrant.

[0181] The adhesive is povidone K30.

[0182] The lubricant is magnesium stearate.

[0183] The photoinitiator is benzoin methyl ether.

[0184] The test results of the embodiments and comparative examples obtained by the above method are shown in Table 1 below.

[0185] Table 1: Test results of various embodiments and comparative examples

[0186]

[0187] Through the data analysis of the above examples and comparative examples, it can be seen that the cefixime crystal form III prepared by the present invention has high purity, and the degradation rate of the active ingredient of the stabilized pharmaceutical composition is low, which can ensure the effectiveness and safety of the drug.

[0188] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as above in terms of a preferred embodiment, it is not intended to limit the present invention. Any person skilled in the art can, without departing from the scope of the technical solution of the present invention, make some changes or modifications to equivalent embodiments using the technical contents disclosed above. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III, characterized in that: The operation steps are as follows, calculated by mass: Preparation of S1 solution: 10-15 parts of crude cefixime are added to 100-200 parts of solvent A, and the mixture is stirred and dissolved to obtain a cefixime solution; S2 seed addition: Add 0.1-0.75 parts of cefixime crystal form III seed crystals to the cefixime solution and stir to mix; S3 crystallization: The cefixime solution containing the seed crystals is stirred at a constant temperature of 20-40°C for 1-5 hours, then cooled to 0-10°C at a rate of 1-5°C / h, and stirred for crystallization for 3-8 hours; S4 separation and drying: The crystallized solution is subjected to solid-liquid separation, the solid is collected, and the solid is washed 1-3 times with solvent B, and then the washed solid is vacuum-dried at 40-60° C. for 5-10 hours to obtain cefixime crystal form III; Preparation of S5 stabilized pharmaceutical composition: 50-80 parts of cefixime crystal form III, 10-30 parts of a filler, 3-10 parts of a terpolymer disintegrant, 1-5 parts of a binder, and 0.5-2 parts of a lubricant are stirred and mixed uniformly, and granulated by a wet granulation process, and then tableted to obtain stabilized pharmaceutical composition tablets; The terpolymer disintegrant is prepared by photopolymerization reaction of 2-hydroxyethyl acrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl-β-cyclodextrin acrylate and 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone.

2. The method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III according to claim 1, wherein: The solvent A is one of acetone, acetonitrile and methanol.

3. The method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III according to claim 1, wherein: The solvent B is one of ethanol and isopropanol.

4. The method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III according to claim 1, wherein: The filler is one of lactose, microcrystalline cellulose and mannitol.

5. The method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III according to claim 1, wherein: The preparation method of the terpolymer disintegrant is: Dissolve A1 monomer: Add 8-15 parts of 2-hydroxyethyl acrylamide, 12-20 parts of 2-hydroxyethyl methacrylate, 5-10 parts of 2-hydroxypropyl-β-cyclodextrin acrylate, 0.1-2 parts of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone, and 500-1000 parts of deionized water to a reactor and stir at 300-500 rpm for 15-45 minutes at 20-30°C to form a homogeneous solution; A2 Deoxygenation and Initiator Addition: Add nitrogen to the solution for 10-25 minutes to deoxygenate at a nitrogen flow rate of 50-100 mL / min; add the photoinitiator and continue stirring for 5-15 minutes; A3 photopolymerization reaction: under 365nm ultraviolet light with a power of 20-30W, stir and react at a constant temperature of 25-35℃ for 2-6 hours; A4 post-treatment: Pour the product into 3-5 times the volume of anhydrous ethanol for precipitation, let it stand for 0.5-2 hours, filter it, and wash it with 60-80% ethanol 2-4 times; vacuum dry it at 45-65℃ for 5-10 hours, and crush it through a 60-100 mesh sieve to obtain a terpolymer disintegrant.

6. The method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III according to claim 1, wherein: The adhesive is one of povidone K30 and hydroxypropyl methylcellulose.

7. The method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III according to claim 1, wherein: The lubricant is one of magnesium stearate and micro-powder silica gel.

8. The method for preparing a stabilized pharmaceutical composition based on cefixime crystal form III according to claim 5, wherein: The photoinitiator is one of benzoin methyl ether, benzoin ethyl ether, 2,2-dimethoxy-2-phenylacetophenone and 1-hydroxycyclohexyl phenyl ketone.

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