Preparation method of amorphous cefditoren pivoxil mixture

Abstract

The invention discloses a preparation method of an amorphous cefditoren pivoxil mixture, which comprises the following steps: S1, mixing quantitative dichloromethane and ethanol to prepare a required solvent, and controlling the temperature of the solvent to be 10-15 DEG C; s2, adding a certain amount of cefditoren pivoxil into the solvent, stirring until the solution is clear, then sequentially adding a certain amount of surfactant and water-soluble polymer material, stirring until the solution is clear, and filtering; and S3, carrying out spray drying on the medicine carrying solution by using a fluidized bed to obtain the solid dispersion. Compared with an acid-base reaction of an original preparation method, the preparation method disclosed by the invention has no corrosion to preparation equipment; the time for preparing the amorphous cefditoren pivoxil mixture is shortened to be within 5 hours; meanwhile, the sucrose fatty acid ester is added, so that the raw material medicines and the auxiliary materials can be distributed more uniformly, and the uniformity of the prepared amorphous cefditoren pivoxil mixture is better; according to the invention, the temperature of the solution is controlled to be 10-15 DEG C during preparation, so that the impurities in the amorphous cefditoren pivoxil mixture are reduced.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to a method for preparing an amorphous cefditoren pivoxil mixture. Background Art

[0002] Cefditoren pivoxil is a third-generation oral cephalosporin antibiotic developed by Meiji Confectionery Co., Ltd. in Japan in 1994. It is used to treat infections caused by Gram-positive and Gram-negative bacteria, especially Gram-positive bacteria of Staphylococcus, Streptococcus including Streptococcus pneumoniae, Gram-negative bacteria such as Escherichia coli, Branhamella catarrhalis, Klebsiella, Proteus, Haemophilus influenzae, and anaerobic bacteria such as Peptostreptococcus, Propionibacterium acnes, and Bacteroides. Cefditoren pivoxil has a wide antibacterial spectrum and is therefore widely used in clinical practice.

[0003] Cefditoren pivoxil exists in two crystal forms: crystalline and amorphous. The advantage of crystalline cefditoren pivoxil over amorphous is its high stability, including crystal stability and chemical stability under high humidity and heat conditions. It is convenient for storage and transportation, so the cefditoren pivoxil raw materials currently on sale are all in crystalline form.

[0004] Crystalline cefditoren pivoxil has a significant disadvantage compared to the amorphous form: poor water solubility. Poor water solubility leads to poor dissolution rate and solubility, which has a great impact on its dissolution in the body, so it cannot meet the formulation requirements. However, amorphous cefditoren pivoxil has good water solubility and can meet the formulation requirements. At present, the original formulation, Meiji Seika Co., Ltd. of Japan, produces cefditoren pivoxil granules / tablets on the market in China, which all use amorphous cefditoren pivoxil compositions.

[0005] Among them, the original patent CN1151845C contains a composition of crystallographically stable amorphous cephalosporin and its preparation method. The noted preparation of amorphous cefditoren pivoxil mixture requires low temperature reaction and a long reaction time, which reaches more than 20 hours. In addition, the original preparation adopts an acid-base reaction, using hydrochloric acid and ammonia water. Hydrochloric acid and ammonia water are more harmful to the human respiratory tract, and hydrochloric acid solution is more corrosive to stainless steel equipment in the production environment.

[0006] At the same time, application number CN110251467A was retrieved, which disclosed a method for preparing an amorphous cefditoren pivoxil composition, in which crystalline cefditoren pivoxil was dissolved in an organic solvent, a certain proportion of water-soluble polymer material was suspended in the organic solvent, and finally an amorphous cefditoren pivoxil mixture was prepared by spray drying. Although this patent solves the drawbacks of the acid-base reaction of the original patent, the product prepared by this patent is uneven, and some crystalline raw materials are mixed in it. Summary of the invention

[0007] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a method for preparing an amorphous cefditoren pivoxil mixture, a preparation process and use thereof, which solves the problems of long preparation time in the prior art, easy equipment corrosion caused by acid-base reaction, and poor uniformity of the products prepared in the prior art.

[0008] To achieve the above object, the present invention adopts the following technical solution:

[0009] A method for preparing an amorphous cefditoren pivoxil mixture comprises the following steps:

[0010] S1. Mix a certain amount of dichloromethane and ethanol to prepare a desired solvent, and control the solvent temperature to 10-15°C;

[0011] S2, adding a certain amount of cefditoren pivoxil to the solvent in step S1 and stirring until it is clear, then adding a certain amount of surfactant and water-soluble polymer material in sequence, stirring until it is clear, and filtering the drug-loaded solution;

[0012] S3. The drug-loaded solution is spray-dried using a fluidized bed to obtain a solid dispersion, i.e., an amorphous cefditoren pivoxil mixture.

[0013] Preferably, the surfactant in step S2 is sucrose fatty acid ester, and the water-soluble polymer material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene glycol, and polyacrylamide.

[0014] Preferably, the sucrose fatty acid esters include sucrose stearate and sucrose palmitate.

[0015] Preferably, the solvent may be two or more of dichloromethane, ethanol, chloroform, ethyl acetate, acetone, acetonitrile, N,N-dimethylformamide, methanol, and isopropanol to replace the dichloromethane and ethanol in step S1.

[0016] Preferably, the usage ratio of cefditoren pivoxil to the water-soluble polymer material may be 100:1 or 10:1 or 50:1 or 125:1 or 20:1; the usage ratio of cefditoren pivoxil to the surfactant may be 409:1 or 204:1 or 102:1.

[0017] Preferably, the inlet air temperature of the spray drying is 50-90°C, and the inlet air volume is 0.1-0.5 m 3 / min, the atomization pressure is controlled at 0.01-0.07Mpa, the solution temperature is controlled at 10-15°C during the spray drying process, and the drying time is 0.5-1 hour.

[0018] Preferably, the time for preparing the amorphous cefditoren pivoxil mixture from step S1 to step S3 is less than 5 hours.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. Compared with the acid-base reaction of the original preparation method, the preparation method of the present invention is non-corrosive to the preparation equipment;

[0021] 2. The present invention shortens the time for preparing the amorphous cefditoren pivoxil mixture. The preparation time of the original patent is more than 20 hours, while the present invention can shorten the time to within 5 hours;

[0022] 3. The present invention can make the API and excipients more evenly distributed by adding sucrose fatty acid ester, thereby improving the uniformity of the prepared amorphous cefditoren pivoxil mixture;

[0023] 4. The present invention controls the solution temperature at 10-15° C. during preparation, thereby reducing the impurities in the amorphous cefditoren pivoxil mixture. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a schematic diagram of the process of the original patented preparation method;

[0025] Figure 2 It is a schematic diagram of the process of the preparation method of the present invention;

[0026] Figure 3 It is the crystal form detection spectrum of the raw material drug;

[0027] Figure 4 This is the crystal form spectrum of the sample prepared by the original patent in comparative example 1;

[0028] Figure 5 This is the sample crystal form spectrum of Comparative Example 2;

[0029] Figure 6 It is the crystal form spectrum of the sample of the present invention. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention is clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] Example 1

[0032] See also Figure 2 , a method for preparing an amorphous cefditoren pivoxil mixture, comprising the following steps:

[0033] S1. Mix a certain amount of dichloromethane and ethanol to prepare a desired solvent, and control the solvent temperature at 10-15° C.; wherein the solvent can be two or more of dichloromethane, ethanol, chloroform, ethyl acetate, acetone, acetonitrile, N,N-dimethylformamide, methanol, and isopropanol to replace the dichloromethane and ethanol in step S1.

[0034] S2. Add a certain amount of cefditoren pivoxil to the solvent in step S1 and stir until it is clear, then add a certain amount of surfactant and water-soluble polymer material in sequence, stir until it is clear, and filter the drug-loaded solution; use a surfactant to completely dissolve the crystalline raw material and the water-soluble polymer material in the organic solvent, so that the final amorphous product has better uniformity and there is no mixed crystalline raw material.

[0035] The surfactant is sucrose fatty acid ester, and the sucrose fatty acid ester includes sucrose stearate and sucrose palmitate. The water-soluble polymer material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene glycol, and polyacrylamide.

[0036] S3, spray drying the drug-loaded solution in a fluidized bed to obtain a solid dispersion, i.e., an amorphous cefditoren pivoxil mixture. The inlet air temperature of the spray drying is 50-90°C, and the inlet air volume is 0.1-0.5 m 3 / min, the atomization pressure is controlled at 0.01-0.07Mpa, the solution temperature is controlled at 10-15°C during the spray drying process, and the drying time is 0.5-1 hour.

[0037] In this embodiment, the time for preparing the amorphous cefditoren pivoxil mixture from step S1 to step S3 is less than 5 hours, which is much less than the original preparation time of 20 hours, and the prepared cefditoren pivoxil mixture is in an amorphous state.

[0038] In this example, the quantitative raw materials are 500 g of cefditoren pivoxil, 1.223 g of sucrose fatty acid ester, 25 g of hypromellose, 3500 g of dichloromethane, and 2500 g of ethanol.

[0039] The ratio of cefditoren pivoxil to water-soluble polymer material may be 100:1 or 10:1 or 50:1 or 125:1 or 20:1; the ratio of cefditoren pivoxil to surfactant may be 409:1 or 204:1 or 102:1.

[0040] Comparative Example 1

[0041] See also Figure 1 , the original patent CN1151845C preparation method: at a temperature of ≤5°C, take 5g of cefditoren pivoxil and dissolve it in 35ml of 1M hydrochloric acid solution, then add 50mg of hydroxypropyl methylcellulose. Titrate the above solution to pH=7.0 with 1M ammonia solution, keep the temperature ≤5°C and stir overnight. Filter the precipitate, wash the precipitate with 15ml of 0.5% hydroxypropyl cellulose, filter the washed precipitate and dry it under reduced pressure to obtain amorphous cefditoren pivoxil.

[0042] The amorphous cefditoren pivoxil composition is prepared by using the composition containing amorphous cephalosporin with crystallographic stability and the preparation method thereof disclosed in the original patent CN1151845C. It can be seen from the XRD detection spectrum that it is basically amorphous.

[0043] Comparative Example 2

[0044] The preparation method of patent CN110251467A is adopted: 3500g of dichloromethane and 2500g of ethanol are mixed, the temperature of the drug-loaded solution is controlled at 30-50°C, 500g of cefditoren pivoxil is added, stirred until clear, and then 25g of hypromellose is added, stirred to make it evenly dispersed, and then spray-dried. The inlet air temperature of the spray-drying is 50-80°C, and the inlet air volume is 0.1-0.5m 3 / min, the atomization pressure is controlled at 0.01-0.07Mpa, and the solution temperature is controlled at 30-50°C during the spray drying process.

[0045] The amorphous cefditoren pivoxil composition was prepared by a preparation method of an amorphous cefditoren pivoxil composition disclosed in application number CN110251467A. From the XRD detection spectrum, it can be seen that it is basically amorphous, but there is also an obvious diffraction peak, indicating that the product prepared according to the disclosed method cannot be completely converted into an amorphous raw material drug, and there are crystalline raw materials mixed in it, that is, the uniformity cannot be guaranteed.

[0046] According to the preparation methods of Example 1, Comparative Example 1 and Comparative Example 2, the cefditoren pivoxil compositions were prepared respectively, and the impurities and crystal forms were compared as shown in the following table:

[0047] project Comparative Example 1 Comparative Example 2 Example 1 Impurity P1 0.18％ 0.14％ 0.05％ Impurity P3 0.18％ 0.20％ 0.07％ Impurity P4 Not detected Not detected Not detected Impurity P13 0.05％ 0.04％ Not detected Impurity P17 Not detected Not detected Not detected Impurity P15 0.19％ 0.20％ 0.06％ Impurity P16 0.20％ 0.12％ 0.04％ Other largest single impurities 0.08％ 0.06％ 0.02％ Total impurities 1.03％ 0.89％ 0.37％ Crystal form Amorphous Amorphous, but mixed with a small amount of crystals Amorphous

[0048] According to the above table and combined Figures 3 to 6 It can be known that the preparation method in this scheme is adopted, compared with the original patent comparative example 1, it solves the acid-base reaction of the original preparation method, and is not corrosive to the preparation equipment; At the same time, the time for preparing amorphous cefditoren pivoxil mixture is shortened, the original patent preparation time is more than 20 hours, the present invention can shorten the time to within 5 hours, and the prepared cefditoren pivoxil mixture is all amorphous state, and at the same time due to the influence of acid and alkali, the raw material drug is degraded faster, and the impurity content is significantly higher than the present invention. At the same time, compared with comparative example 2, the addition of sucrose stearate in this scheme can make the raw material drug and the auxiliary material more evenly distributed, and then the uniformity of the prepared amorphous cefditoren pivoxil mixture is better, and it can be seen from the detection spectrum of XRD in comparative example 2 that it is basically amorphous, but there is also an obvious diffraction peak, indicating that the product prepared according to the disclosed method can not be completely converted into amorphous raw material drug, and there is a crystalline raw material drug mixed therein, that is, uniformity cannot be guaranteed, and at the same time due to the high temperature of the comparative example 2 solvent, the raw material drug is degraded at high temperature, and the impurities are also significantly higher than the present invention.

[0049] At the same time, since the solution temperature is controlled at 10-15° C. during preparation in the present invention, it can be seen from the above table that the impurities in the amorphous cefditoren pivoxil mixture prepared in this scheme are significantly lower than those in Comparative Example 1 and Comparative Example 2.

[0050] According to the disclosure and teaching of the above description, those skilled in the art to which the present invention belongs may also make changes and modifications to the above embodiments. Therefore, the present invention is not limited to the specific embodiments disclosed and described above, and some modifications and changes to the present invention should also fall within the protection scope of the claims of the present invention. In addition, although some specific terms are used in this specification, these terms are only for the convenience of description and do not constitute any limitation to the present invention. Other devices that are the same or similar to the above are all within the protection scope of the present invention.

Claims

1. A method for preparing an amorphous cefditoren pivoxil mixture, characterized in that: The steps include: S1. Mix a certain amount of dichloromethane and ethanol to prepare a desired solvent, and control the solvent temperature to 10-15°C; S2, adding a certain amount of cefditoren pivoxil to the solvent in step S1 and stirring until it is clear, then adding a certain amount of surfactant and water-soluble polymer material in sequence, stirring until it is clear, and filtering the drug-loaded solution; S3. The drug-loaded solution is spray-dried using a fluidized bed to obtain a solid dispersion, i.e., an amorphous cefditoren pivoxil mixture.

2. The method for preparing an amorphous cefditoren pivoxil mixture as claimed in claim 1, characterized in that: The surfactant in step S2 is sucrose fatty acid ester, and the water-soluble polymer material is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, polyethylene glycol, and polyacrylamide.

3. The method for preparing an amorphous cefditoren pivoxil mixture as claimed in claim 2, characterized in that: The sucrose fatty acid esters include sucrose stearate and sucrose palmitate.

4. The method for preparing an amorphous cefditoren pivoxil mixture as claimed in claim 1, characterized in that: The solvent may be two or more of dichloromethane, ethanol, chloroform, ethyl acetate, acetone, acetonitrile, N,N-dimethylformamide, methanol, and isopropanol to replace the dichloromethane and ethanol in step S1.

5. The method for preparing an amorphous cefditoren pivoxil mixture as claimed in claim 1, characterized in that: The usage ratio of cefditoren pivoxil to the water-soluble polymer material can be 100:1 or 10:1 or 50:1 or 125:1 or 20:1; the usage ratio of cefditoren pivoxil to the surfactant can be 409:1 or 204:1 or 102:

1.

6. The method for preparing an amorphous cefditoren pivoxil mixture as claimed in claim 1, characterized in that: The inlet air temperature of the spray drying is 50-90°C, and the inlet air volume is 0.1-0.5m 3 / min, the atomization pressure is controlled at 0.01-0.07Mpa, the solution temperature is controlled at 10-15°C during the spray drying process, and the drying time is 0.5-1 hour.

7. The method for preparing an amorphous cefditoren pivoxil mixture as claimed in claim 1, characterized in that: The time for preparing the amorphous cefditoren pivoxil mixture from step S1 to step S3 is less than 5 hours.

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