High density metamizole and method for its preparation

Abstract

The application provides a high-packing-density metamizole and a preparation method thereof, and relates to the technical field of metamizole production. The preparation method of the high-packing-density metamizole comprises the following steps: uniformly mixing crude metamizole, activated carbon, a specific type of additive and a solvent with a specific concentration, heating to dissolve the crude metamizole, stirring, filtering the activated carbon, obtaining a filtrate, slowly stirring the filtrate and slowly cooling to make the metamizole crystallize and precipitate, and obtaining the high-packing-density metamizole. The preparation method can ensure the product quality, simplify the production process, reduce the production cost and meet the requirements of industrial production. The metamizole prepared by the preparation method has a high packing density, a simple monoclinic crystal shape and a smooth and dense surface structure. As a raw medicine, compared with a commercial product, the metamizole can significantly improve the flowability of the medicine product, reduce the space volume of the product with the same quality and reduce the transportation cost.

Description

Technical Field

[0001] This invention relates to the field of aminopyrine production technology, and particularly to a high-density aminopyrine and its preparation method. Background Technology

[0002] Metamizole is readily soluble in water. Its antipyretic and analgesic effects are faster and stronger than those of aminopyrine. It is generally not a first-line drug, but is used only for emergency fever reduction in cases of acute high fever, severe illness, and when no other effective antipyretics are available. Metamizole is primarily available in tablet form. Currently, most metamizole products manufactured using current processes have a long needle-like or thin rod-like structure, and the crystals are brittle, generating a large amount of dust during application and exhibiting poor flowability, which affects its application in tablet compression.

[0003] Because metamizole has a relatively low density, ranging from approximately 0.25 g / mL to 0.35 g / mL, it is difficult to process large quantities of the drug into tablets with consistent weight and ideal hardness, thus failing to meet the needs of some customers who require a density of 0.40 g / mL or higher.

[0004] Therefore, it is necessary to explore a preparation process for aminopyrine with large particles, high bulk density and good flowability to solve the problems of poor flowability and low bulk density of the product; at the same time, to ensure product quality, simplify the production process, reduce production costs and make it suitable for industrial production requirements.

[0005] In view of this, the present invention is hereby proposed. Summary of the Invention

[0006] The purpose of this invention is to provide a high-density aminopyrine and its preparation method, so as to improve at least one of the above-mentioned technical problems.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] The primary objective of this invention is to provide a method for preparing high-density aminopyrine, comprising the following steps:

[0009] (a) Mix crude aminopyrine with activated carbon, additives and solvent evenly, heat until crude aminopyrine dissolves, stir, filter carbon, and obtain filtrate;

[0010] The additives include glycerol and / or Tween 80, and the mass of the additives is 0.1% to 0.5% of the crude aminopyrine mass; the solvent is an aqueous ethanol solution with a volume concentration of 50% to 80%.

[0011] (b) The filtrate obtained in step (a) is slowly stirred and cooled to allow aminopyrine to crystallize and precipitate, resulting in high-density aminopyrine.

[0012] Furthermore, based on the above technical solution of the present invention, in step (a), the mass ratio of the crude aminopyrine to the solvent is 1:1 to 1:2.5.

[0013] Furthermore, based on the above-mentioned technical solution of the present invention, in step (a), the mass of the activated carbon is 0.1% to 0.5% of the crude mass of aminopyrine.

[0014] Furthermore, based on the above-described technical solution of this invention, in step (a), the method for preparing the crude aminopyrine includes:

[0015] 4-Methylaminoantipyrine was condensed with formaldehyde and sodium metabisulfite to produce a liquid.

[0016] After cooling and crystallizing, centrifuging and drying, crude aminopyrine was obtained.

[0017] Furthermore, based on the above technical solution of the present invention, in step (a), the purity of the crude aminopyrine is ≥95%.

[0018] Furthermore, based on the above-mentioned technical solution of the present invention, in step (a), the temperature is raised to 60-80°C;

[0019] And / or, the stirring speed is 60-100 r / min and the stirring time is 20-40 min.

[0020] Furthermore, based on the above technical solution of the present invention, in step (b), the stirring rate of the slow stirring is 10 to 100 r / min;

[0021] And / or, the cooling rate is 0.1–5 °C / h.

[0022] Furthermore, based on the above-described technical solution of this invention, step (b), specifically the slow stirring and slow cooling, includes the following steps:

[0023] The filtrate obtained in step (a) is first cooled to near the crystallization point of 55-65℃ at a cooling rate of 3-5℃ / h, with the stirring rate controlled at 60-100 r / min during this process; then cooled to 40-50℃ at a cooling rate of 0.1-1℃ / h, with the stirring rate controlled at 10-20 r / min during this process; and then cooled to 15-20℃ at a cooling rate of 3-5℃ / h, with the stirring rate controlled at 30-40 r / min during this process.

[0024] Furthermore, based on the above-mentioned technical solution of the present invention, the loose density range of the high loose density aminopyrine is 0.4g / mL to 0.55g / mL.

[0025] The second objective of this invention is to provide a high-density aminopyrine, which is prepared using the high-density aminopyrine preparation method provided in the first objective of this invention, wherein the high-density aminopyrine has a density range of 0.4 g / mL to 0.55 g / mL.

[0026] Compared with the prior art, the technical solution of the present invention has at least the following technical effects:

[0027] (1) This invention provides a method for preparing high-density aminopyrine. Specifically, crude aminopyrine is first mixed evenly with activated carbon, a specific type of additive and a solvent of a specific concentration, heated until the crude aminopyrine dissolves, stirred, filtered through carbon to obtain a filtrate, and then the filtrate is slowly stirred and slowly cooled to allow aminopyrine to crystallize and precipitate, thus obtaining high-density aminopyrine. This preparation method can obtain high-density aminopyrine, and at the same time, it can simplify the production process, reduce production costs, and is suitable for industrial production requirements.

[0028] (2) This invention also provides a high-density aminopyrine, prepared using the above-described preparation method. The prepared aminopyrine has a high density (density ≥ 0.4 g / mL) and a simple monoclinic crystal shape with a smooth and dense surface structure. As a raw material, compared with commercially available products, it significantly improves the flowability of the drug product, while reducing the volume occupied by the same weight of product and lowering transportation costs. Attached Figure Description

[0029] The accompanying drawings, which form part of this application, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. Wherein:

[0030] Figure 1 This is a microscope image of aminopyrine obtained in Example 1 of the present invention, magnified 40 times;

[0031] Figure 2 This is a microscope image of aminopyrine prepared in Comparative Example 6 of the present invention, magnified 40 times. Detailed Implementation

[0032] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions in the embodiments of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Those skilled in the art should understand that the embodiments described are merely illustrative of the invention and should not be considered as specific limitations thereof. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention. Process parameters not specifically specified in the following embodiments are generally performed under conventional conditions.

[0033] The endpoints and any values ​​of the ranges disclosed in this invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this invention.

[0034] According to a first aspect of the present invention, a method for preparing high-density aminopyrine is provided, comprising the following steps:

[0035] (a) Mix crude aminopyrine with activated carbon, additives and solvent evenly, heat until crude aminopyrine dissolves, stir, filter carbon, and obtain filtrate;

[0036] The additives include glycerol and / or Tween 80, and the mass of the additives is 0.1% to 0.5% of the crude aminopyrine mass; the solvent is an aqueous ethanol solution with a volume concentration of 50% to 80%.

[0037] (b) The filtrate obtained in step (a) is slowly stirred and cooled to allow aminopyrine to crystallize and precipitate, resulting in high-density aminopyrine.

[0038] Specifically, in step (a), the present invention uses an ethanol aqueous solution with a specific volume concentration of 50% to 80% (e.g., 50%, 55%, 60%, 65%, 70%, 75%, or 80%) as a solvent. The increased water content in the solvent makes the polarity and solubility of the solvent moderate, and the nucleation rate and growth rate of the aminopyrine crystals are balanced. Therefore, the aminopyrine crystals crystallized at this concentration are solid and have a high density. At the same time, the additives glycerol and Tween 80 can interact with the aminopyrine molecules through hydrogen bonds in the ethanol aqueous solution, changing the crystal habit of aminopyrine and ensuring that aminopyrine grows simultaneously in both the length and width directions, avoiding the needle-like crystal form of traditional processes.

[0039] Furthermore, there are limitations on the amount of additives used, specifically, the mass of the additive should be 0.1% to 0.5% of the crude aminopyrine mass. The mass percentage of the additive should not be too high (e.g., above 0.5%), otherwise it can easily lead to high solvent viscosity, inducing the formation of metastable crystals or solvates in aminopyrine, resulting in a significant decrease in the loose density of aminopyrine (i.e., the powder becomes more fluffy and larger in volume). This change will adversely affect subsequent formulation processes (such as mixing, filling, and tableting) and product quality (such as dosage accuracy, stability, and appearance). The mass percentage of the additive should also not be too low (e.g., below 0.1%), otherwise it can easily lead to irregular and excessively fine aminopyrine crystals. Therefore, typical but non-limiting additive mass percentages of crude aminopyrine are 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5%, etc.

[0040] In step (b), slow cooling and stirring are used to ensure the formation and growth of crystals.

[0041] The aminopyrine prepared by the method of the present invention has a high bulk density and a simple monoclinic crystal shape with a smooth and dense surface structure. As an active pharmaceutical ingredient, it significantly improves the flowability of the drug product compared with commercially available products, while reducing the space volume occupied by the same quality of product and reducing transportation costs.

[0042] This preparation method simplifies the production process and reduces production costs while ensuring product quality, making it suitable for industrial production requirements.

[0043] There are further restrictions on the source or relative amount of each raw material used in the preparation process.

[0044] Crude aminopyrine can be obtained using conventional methods in the art. As an optional embodiment of the technical solution of the present invention, in step (a), the crude aminopyrine is obtained using MAA oil (4-methylaminoantipyrine), formaldehyde, and sodium metabisulfite. Specifically, MAA oil undergoes a condensation reaction with formaldehyde and sodium metabisulfite to generate a liquid; the liquid is then cooled, crystallized, centrifuged, and dried to obtain crude aminopyrine.

[0045] As an optional embodiment of the technical solution of the present invention, in step (a), the purity of the crude aminopyrine is ≥95%, for example, 95%, 95.5%, 96%, 96.5%, 97% or 97.5%.

[0046] As an optional embodiment of the technical solution of the present invention, in step (a), the mass ratio of crude aminopyrine to solvent is 1:1 to 1:2.5, and typical but non-limiting mass ratios are 1:1, 1:1.5, 1:1.8, 1:2, 1:2.2 or 1:2.5, etc.

[0047] By limiting the mass ratio of crude aminopyrine to solvent, it is possible to ensure both complete dissolution of aminopyrine in the solvent and product yield.

[0048] As an optional embodiment of the technical solution of the present invention, in step (a), the mass of activated carbon is 0.1% to 0.5% of the mass of crude aminopyrine. Typical but non-limiting activated carbon accounts for 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5% of the mass of crude aminopyrine.

[0049] By limiting the mass ratio of activated carbon to crude aminopyrine, the purity and color of aminopyrine are improved.

[0050] As an optional embodiment of the technical solution of the present invention, in step (a), the temperature is raised to 60-80°C, for example, 60°C, 65°C, 70°C, 75°C or 80°C, etc.

[0051] And / or, the stirring speed during stirring is 60 to 100 r / min, for example, 60 r / min, 70 r / min, 80 r / min, 90 r / min or 100 r / min, and the stirring time is 20 to 40 min, for example, 20 min, 30 min or 40 min.

[0052] As an optional embodiment of the technical solution of the present invention, in step (b), the stirring rate is 10 to 60 r / min, for example, 10 r / min, 20 r / min, 40 r / min, 50 r / min or 60 r / min.

[0053] As an optional embodiment of the technical solution of the present invention, in step (b), the cooling rate is 1 to 5℃ / h, for example, 1℃ / h, 1.5℃ / h, 2℃ / h, 2.5℃ / h, 3℃ / h, 3.5℃ / h, 4℃ / h, 4.5℃ / h or 5℃ / h, etc.

[0054] In step (b), the filtrate can be slowly stirred and cooled in stages. As an optional embodiment of the technical solution of this invention, step (b), specifically the slow stirring and slow cooling, includes the following steps:

[0055] The filtrate obtained in step (a) is first cooled at a rate of 3–5 °C / h (e.g., 3 °C / h, 3.5 °C / h, 4 °C / h, 4.5 °C / h, or 5 °C / h, etc.) to near the crystallization point (e.g., 55 °C, 58 °C, 60 °C, 62 °C, or 65 °C, etc.) to begin crystal precipitation. During this process, the stirring rate is controlled at 60–100 r / min (e.g., 60 r / min, 70 r / min, 80 r / min, 90 r / min, or 100 r / min, etc.). Then, the filtrate is cooled at a rate of 0.1–1 °C / h (e.g., 0.1 °C / h, 0.2 °C / h, 0.5 °C / h, 0.8 °C / h, or 1.0 °C / h, etc.). The temperature is then lowered to 40–50°C (e.g., 40°C, 42°C, 45°C, 48°C, or 50°C) to increase the crystal yield. During this process, the stirring rate is controlled at 10–20 r / min (e.g., 10 r / min, 15 r / min, or 20 r / min). The temperature is then further lowered to 15–20°C (e.g., 15°C, 18°C, or 20°C) at a rate of 3–5°C / h (e.g., 3°C / h, 3.5°C / h, 4°C / h, 4.5°C / h, or 5°C / h) to further increase the crystal yield. During this process, the stirring rate is controlled at 30–40 r / min (e.g., 30 r / min, 35 r / min, or 40 r / min).

[0056] By controlling the cooling rate and stirring rate, the formation and growth of crystals are ensured.

[0057] As an optional embodiment of the technical solution of the present invention, the bulk density of high-bulk-density aminopyrine ranges from 0.4 g / mL to 0.55 g / mL. For example, it is 0.4 g / mL, 0.45 g / mL, 0.48 g / mL, 0.50 g / mL, 0.52 g / mL, 0.54 g / mL, or 0.55 g / mL, etc. High-bulk-density aminopyrine has good flowability and more uniform particle size, improving the compressibility and consistency of solid tablets.

[0058] According to a second aspect of the present invention, a high-density aminopyrine is provided, which is prepared by the preparation method provided in the first aspect of the present invention, and the high-density aminopyrine has a density range of 0.4 g / mL to 0.55 g / mL.

[0059] The aminopyrine prepared by the method of this invention has a higher bulk density. The high bulk density aminopyrine has a more regular shape, more uniform particle size, and a simple monoclinic crystal shape with a smooth and dense surface structure. As a raw material, it significantly improves the flowability of the drug product compared with commercially available products, while reducing the space volume occupied by the same quality of product and reducing transportation costs.

[0060] The present invention will now be described in further detail with reference to specific embodiments and comparative examples.

[0061] It should be noted that the crude aminopyrine used in the various embodiments and comparative examples was prepared using the following method:

[0062] (1) Add 2400 kg of 95% ethanol to the reactor, start stirring, then add 1222 kg of MAA, 522 kg of sodium metabisulfite and 9 kg of activated carbon. Add 555 kg of 30 wt% formaldehyde solution at room temperature, and add it all within half an hour. Heat the mixture to 80°C and reflux for 50 min at boiling point. During the reflux, adjust the pH of the reaction solution to 7.2 with sodium carbonate.

[0063] (2) After the reaction is completed, the reaction liquid is filtered and pressed into a crystallization tank, cooled to 20°C, crystallized, centrifuged, and dried to obtain 2000 kg of crude aminopyrine. The purity of crude aminopyrine is 97.5%.

[0064] Example 1

[0065] This embodiment provides a method for preparing high-density aminopyrine, including the following steps:

[0066] (a) Mix 2000 kg of crude aminopyrine, 2 kg of activated carbon, 2 kg of glycerol additive, and 4000 kg of 80% (volume concentration) ethanol aqueous solution evenly, heat to 80°C to dissolve, stir for 20 min, filter out the carbon, and obtain the filtrate; wherein, the mass ratio of crude aminopyrine to solvent is 1:2, the mass of activated carbon is 0.1% of the mass of crude aminopyrine, and the mass of glycerol additive is 0.1% of the mass of crude aminopyrine;

[0067] (b) The filtrate obtained in step (a) is slowly stirred and slowly cooled. Specifically, the filtrate is first cooled to near the crystallization point (60°C) at a cooling rate of 5°C / h, and the stirring rate is controlled at 60 r / min during this process, and crystals begin to precipitate. Then, the filtrate is cooled to 50°C at a cooling rate of 1°C / h, and the stirring rate is controlled at 10 r / min during this process, so that more crystals precipitate. Then, the filtrate is cooled to 20°C at a cooling rate of 3°C / h, and the stirring rate is controlled at 30 r / min during this process, to further increase the crystallization yield of aminopyrine and obtain high-density aminopyrine.

[0068] Example 2

[0069] This embodiment provides a method for preparing high-density aminopyrine. Except for adjusting the mass of the additive glycerol in step (a) from 2 kg to 8 kg, i.e., the mass of the additive glycerol is 0.4% of the crude aminopyrine mass, the other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0070] Example 3

[0071] This embodiment provides a method for preparing high-density aminopyrine. Except for changing the type of additive in step (a) from glycerol to Tween 80, the other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0072] Example 4

[0073] This embodiment provides a method for preparing high-density aminopyrine. Except for adjusting the volume concentration of the 80% ethanol aqueous solution in step (a) from 80% to 60%, the other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0074] Example 5

[0075] This embodiment provides a method for preparing high-density aminopyrine. Except for adjusting the mass of the 80% ethanol aqueous solution in step (a) from 4000 kg to 2000 kg, i.e., adjusting the mass ratio of crude aminopyrine to solvent from 1:2 to 1:1, the other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0076] Example 6

[0077] This embodiment provides a method for preparing high-density aminopyrine. Except for adjusting the mass of the 80% ethanol aqueous solution in step (a) from 4000 kg to 6000 kg, i.e., adjusting the mass ratio of crude aminopyrine to solvent from 1:2 to 1:3, the other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0078] Example 7

[0079] This embodiment provides a method for preparing high-density aminopyrine. Except for step (b), which involves slow stirring and slow cooling, the filtrate is first cooled to near the crystallization point (60°C) at a cooling rate of 5°C / h, with the stirring rate controlled at 50 r / min during this process, to induce crystal precipitation. Then, the filtrate is cooled to 50°C at a cooling rate of 2°C / h, with the stirring rate controlled at 30 r / min during this process, to induce more crystal precipitation. Finally, the filtrate is cooled to 20°C at a cooling rate of 1°C / h, with the stirring rate controlled at 50 r / min during this process, to further increase the aminopyrine crystallization yield and obtain high-density aminopyrine. The remaining preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0080] Example 8

[0081] This embodiment provides a method for preparing high-density aminopyrine, including the following steps:

[0082] (a) Mix 2000 kg of crude aminopyrine, 6 kg of activated carbon, 10 kg of glycerol additive, and 2000 kg of 80% (volume concentration) ethanol aqueous solution evenly, heat to 80°C to dissolve, stir for 20 min, filter out the carbon, and obtain the filtrate; wherein, the mass ratio of crude aminopyrine to solvent is 1:1, the mass of activated carbon is 0.3% of the mass of crude aminopyrine, and the mass of glycerol additive is 0.5% of the mass of crude aminopyrine;

[0083] (b) The filtrate obtained in step (a) is slowly stirred and slowly cooled, specifically: the filtrate is first cooled to near the crystallization point (60°C) at a cooling rate of 3°C / h, and the stirring rate is controlled at 80 r / min during this process; then cooled to 50°C at a cooling rate of 0.5°C / h, and the stirring rate is controlled at 20 r / min during this process; then cooled to 20°C at a cooling rate of 5°C / h, and the stirring rate is controlled at 35 r / min during this process, so that aminopyrine crystallizes out and high-density aminopyrine is obtained.

[0084] Comparative Example 1

[0085] This comparative example provides a method for preparing aminopyrine. Except for step (a) where glycerol is not added, the other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0086] Comparative Example 2

[0087] This comparative example provides a method for preparing aminopyrine. Except that in step (a), the mass of the additive glycerol is adjusted from 2 kg to 1 kg, that is, the mass of the additive glycerol is 0.05% of the crude aminopyrine mass. The other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0088] Comparative Example 3

[0089] This comparative example provides a method for preparing aminopyrine. Except that in step (a), the mass of the additive glycerol is adjusted from 2 kg to 12 kg, that is, the mass of the additive glycerol is 0.6% of the crude aminopyrine mass. The other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0090] Comparative Example 4

[0091] This comparative example provides a method for preparing aminopyrine. Except for changing the type of additive in step (a) from glycerol to isopropanol, the other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0092] Comparative Example 5

[0093] This comparative example provides a method for preparing aminopyrine. Except for step (a), in which the volume concentration of the solvent ethanol aqueous solution is adjusted from 80% to 95%, the other preparation steps and process parameters are the same as in Example 1, and will not be repeated here.

[0094] Comparative Example 6

[0095] This comparative example provides a method for preparing aminopyrine, including the following steps:

[0096] (a) Mix 2000 kg of crude aminopyrine, 2 kg of activated carbon and 6000 kg of 95% (volume concentration) ethanol aqueous solution evenly, heat to 80°C to dissolve, stir for 20 min, filter the carbon, and obtain the filtrate; wherein, the mass ratio of crude aminopyrine to solvent is 1:3, and the mass of activated carbon is 0.1% of the mass of crude aminopyrine;

[0097] (b) The filtrate obtained in step (a) is slowly stirred and slowly cooled. Specifically, the filtrate is first cooled to near the crystallization point (72°C) at a cooling rate of 5°C / h. The higher the alcohol concentration of the ethanol aqueous solution, the lower the solubility of aminopyrine, so the crystallization point temperature is higher than that in Example 1. During this process, the stirring rate is controlled at 60 r / min. Then, the filtrate is cooled to 50°C at a cooling rate of 1°C / h. During this process, the stirring rate is controlled at 10 r / min. Then, the filtrate is cooled to 20°C at a cooling rate of 3°C / h. During this process, the stirring rate is controlled at 30 r / min, so that aminopyrine crystallizes out and is obtained.

[0098] To further illustrate the technical effects of the above embodiments and comparative examples, the following experimental examples are provided.

[0099] Experimental Example 1

[0100] (1) The morphology of the aminopyrine prepared in Example 1 and Comparative Example 6 of the present invention was examined using a microscope, specifically as follows: Figure 1 and Figure 2 .

[0101] from Figure 1 As can be seen from the above, the aminopyrine prepared in Example 1 is mostly rectangular flakes with regular grains, good dispersibility, little agglomeration, strong particle independence, and tighter stacking. Figure 1 Its high bulk density and uniform particle size facilitate powder flow, making it suitable for tableting or filling.

[0102] from Figure 2 As can be seen from the results, the overall grains of the aminopyrine prepared in Comparative Example 6 are small and irregular, and the grains are prone to adhesion and agglomeration, forming loose aggregates with poor uniformity.

[0103] (2) The bulk density, liquid phase purity, and yield of the aminopyrine prepared in each example and comparative example were detected or calculated. The bulk density was determined according to Method I of Determination of Bulk Density and Tap Density in Chinese Pharmacopoeia 0993. Liquid phase purity was determined using liquid chromatography, and the detection method was based on the first supplement of the 2010 edition of the Chinese Pharmacopoeia. Specific results are shown in Table 1.

[0104] Table 1

[0105]

[0106] As can be seen from the data in Table 1, the higher the density of aminopyrine, the higher its purity. Whether the additive is added little or no, the density of aminopyrine will not be ≥0.4 g / mL. Furthermore, the inventors discovered that while glycerol and / or Tween 80 can inhibit excessive growth of aminopyrine crystals in a certain direction, excessive additives alter the crystal form, causing the crystals to become small spherical, thus resulting in a lower density. Only by using an appropriate amount of additive can the growth of aminopyrine be effectively inhibited along its length while also allowing it to grow wider, thus improving the density. When the alcohol concentration in the ethanol-water solution is >80%, the resulting aminopyrine density is also lower. The yield of aminopyrine varies significantly with alcohol concentration; the lower the ethanol concentration, the lower the yield. This is because ethanol solutions contain more water, and aminopyrine dissolves in water. Conversely, higher ethanol concentrations result in higher yields.

[0107] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing high-density aminopyrine, characterized in that, Includes the following steps: (a) Mix crude aminopyrine with activated carbon, additives and solvent evenly, heat until crude aminopyrine dissolves, stir, filter carbon to obtain filtrate; The additives include glycerol and / or Tween 80, and the mass of the additives is 0.1% to 0.5% of the crude mass of aminopyrine; the solvent is an aqueous ethanol solution with a volume concentration of 50% to 80%. (b) The filtrate obtained in step (a) is slowly stirred and cooled to allow aminopyrine to crystallize out, resulting in high-density aminopyrine; Step (b), which involves slow stirring and slow cooling, specifically includes the following steps: The filtrate obtained in step (a) is first cooled to near the crystallization point of 55-65℃ at a cooling rate of 3-5℃ / h, with the stirring rate controlled at 60-100r / min during this process; then cooled to 40-50℃ at a cooling rate of 0.1-1℃ / h, with the stirring rate controlled at 10-20r / min during this process; and then cooled to 15-20℃ at a cooling rate of 3-5℃ / h, with the stirring rate controlled at 30-40r / min during this process.

2. The method for preparing high-density aminopyrine according to claim 1, characterized in that, In step (a), the mass ratio of crude aminopyrine to solvent is 1:1 to 1:2.

5.

3. The method for preparing high-density aminopyrine according to claim 1, characterized in that, In step (a), the mass of the activated carbon is 0.1% to 0.5% of the crude mass of aminopyrine.

4. The method for preparing high-density aminopyrine according to claim 1, characterized in that, In step (a), the method for preparing the crude aminopyrine includes: 4-Methylaminoantipyrine was condensed with formaldehyde and sodium metabisulfite to produce a liquid. After cooling, crystallizing, centrifuging, and drying, crude aminopyrine was obtained.

5. The method for preparing high-density aminopyrine according to claim 1, characterized in that, In step (a), the purity of the crude aminopyrine is ≥95%.

6. The method for preparing high-density aminopyrine according to claim 1, characterized in that, In step (a), the temperature is raised to 60~80℃; And / or, the stirring speed is 60~100r / min and the stirring time is 20~40min.

7. The method for preparing high-density aminopyrine according to any one of claims 1-6, characterized in that, The high-density aminopyrine has a density range of 0.4 g / mL to 0.55 g / mL.

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