A method for preparing a high-purity gentisic acid excipient for injection

Abstract

The present invention relates to a method for preparing a high-purity gentisic acid excipient for injection, and belongs to the field of medical technology. The present invention adopts a method for adding a crude gentisic acid product to an ethanol solution for heating and dissolving, and recrystallizing after passing through a 0.22 μm filter material, suction filtering, washing the filter cake with a certain concentration of ethanol, collecting the filter cake, vacuum drying, and sieving to obtain a high-purity gentisic acid excipient for injection. The quality inspection items such as the content, related substances, solvent residues, heavy metals, moisture, and microbial limits of the obtained product are all very high-quality and meet the quality requirements of injection excipients. Through the invention, the preparation of a high-purity gentisic acid excipient for injection from a crude gentisic acid product can be realized. The refining method of gentisic acid described in the present invention is simple to operate, has high product quality and a short production cycle, and the solvent ethanol solution used is low-toxic and economical, and the HPLC purity of the obtained product is as high as 99.7% or more (maximum single impurity content <0.02%).

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a method for preparing a high-purity gentisic acid auxiliary material for injection. Background Art

[0002] Gentisic acid, chemically known as 2,5-dihydroxybenzoic acid, referred to as DBH, is a polyhydroxycarboxylic acid, a white to light yellow powder, soluble in hot water, ethanol and ether, and poorly soluble in chloroform, benzene and carbon disulfide. Gentisic acid belongs to the hydroquinone class of compounds, which is easily oxidized. It is often used as an antioxidant excipient in the pharmaceutical industry, has antipyretic and analgesic effects, and is also an important pharmaceutical intermediate. With the development of radiopharmaceuticals, gentisic acid is used as an important anti-radiolysis agent (antioxidant) in nuclear drugs that have been marketed and are under development, such as 68 Ga-DOTATATE, 177 Lu-DOTATATE, 68 Ga-PSMA-11, 177 Lu-PSMA-617 and other injections all use gentisic acid as an excipient. Although four domestic companies have completed CDE registration, none of them have passed the associated approval and are in the "I" state. Therefore, the importance of developing high-purity gentisic acid excipients for injection has become more prominent.

[0003] Through the search of Chinese invention patents, the patent: A method for preparing high-purity gentisic acid (CN102766042B), hydrochloric acid is used to adjust the pH during recrystallization, and oxalic acid and activated carbon are heated to reflux for acidification and decolorization. First of all, the use of hydrochloric acid is not environmentally friendly; secondly, according to the "Technical Requirements for Injection Consistency Evaluation" of the State Food and Drug Administration, it is not recommended to use activated carbon in the production of injections; oxalic acid may remain in the product as a solvent; and the final gentisic acid purity is >99%, which is difficult to meet the requirements for injection use. Patent: A method for refining high-purity gentisic acid and its application (CN114716308A), also uses ethylenediamine, activated carbon, hydrochloric acid, etc. during recrystallization. First, the process also uses activated carbon for decolorization; secondly, toxic and harmful organic solvents such as acetone, isopropanol and tetrahydrofuran (Class II solvent) are used when filtering and washing the filter cake. These steps may lead to unqualified solvent residues, making the quality of gentisic acid fail to meet the quality requirements of injection excipients. The above patents all use acid during recrystallization, which places high demands on equipment. Acid corrosion may cause quality items such as heavy metals, chlorides, and ignition residues to be insufficient to meet the quality requirements for injectable excipients.

[0004] In view of this, the present invention aims to propose a method for preparing a high-purity gentisic acid excipient for injection, so as to supplement and solve the problems and shortcomings that may exist in the existing gentisic acid preparation process, such as the use of hydrochloric acid, oxalic acid, toxic and harmful organic solvents, insufficient purity (greater than 99%), solvent residues, related substances, ignition residues, insoluble matter, microbial limits, etc., which are difficult to meet the quality requirements of injection excipients, and develop a high-purity gentisic acid excipient for injection. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing a high-purity gentisic acid excipient for injection, which specifically comprises adding ethanol solution to a crude gentisic acid product for heating and dissolving, filtering through a 0.22 μm filter material, recrystallizing, filtering by suction, washing the filter cake with ethanol of a certain concentration, collecting the filter cake, drying, and sieving to obtain a high-purity gentisic acid excipient for injection. To solve the above technical problems, the present invention is implemented by the following technical solutions:

[0006] The invention discloses a method for preparing a high-purity gentisic acid excipient for injection, characterized in that the method comprises the following steps: heating and dissolving a crude gentisic acid product with an ethanol solution, continuing to raise the temperature by 5 to 20°C after the solution becomes clear, passing the solution through a 0.22 μm filter material while hot, slowly cooling the filtrate for crystallization, suction filtering, washing the filter cake with an ethanol solution, vacuum drying the filter cake, and sieving to obtain a high-purity gentisic acid excipient for injection.

[0007] Preferably, the crude gentisic acid is heated and dissolved with an ethanol solution, and the mass volume ratio (w / v) of the crude gentisic acid to the ethanol solution is 1g:1.2~2.0ml, specifically 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0.

[0008] If the amount of ethanol is too much, the yield will be reduced; if the amount of ethanol is too little, it will lead to rapid crystallization, which is not conducive to the removal of impurities and the purification effect is poor. At the same time, the heating time should not be too long. If the heating, stirring and dissolving time is too long, more impurities such as ethyl gentisate may be generated.

[0009] Preferably, the crude gentisic acid is dissolved by heating with an ethanol solution, and the concentration of the ethanol solution is 40-60%.

[0010] Recrystallization is based on the principle of similar compatibility, using the difference in solubility between the refined product and the impurities in the solvent. If the ethanol concentration is too low, it is not conducive to the removal of fat-soluble impurities; if the ethanol concentration is too high, the yield is low or the removal effect of water-soluble impurities is poor.

[0011] Preferably, the filtration temperature during hot filtration is 50-90° C., which is 5-20° C. higher than the dissolution temperature. The filtration temperature is appropriately increased to prevent rapid precipitation of gentisic acid during or after filtration, thereby preventing clogging of the filtration equipment or insufficient removal of impurities due to excessive crystallization.

[0012] Preferably, the 0.22 μm filter material includes one or two of polytetrafluoroethylene filter membrane, nylon filter membrane, polycarbonate filter membrane, mixed fiber membrane, polyethersulfone membrane, polypropylene membrane, and titanium rod filter, and performs positive pressure filtration.

[0013] The use of 0.22μm filter material can intercept insoluble particles, microorganisms and bacterial endotoxins, so that the product's ignition residue, chlorides, heavy metals, solution clarity, microorganisms, bacterial endotoxins, etc. meet the quality standards; positive pressure filtration is used during filtration. If negative pressure filtration will cause the filtrate to volatilize and cool down, resulting in rapid precipitation of gentisic acid, causing the filter membrane / device to be blocked or insufficient impurity removal.

[0014] Preferably, after the crystals are precipitated, the temperature is continued to be lowered to 30-0°C and stirred for crystallization.

[0015] The solubility of most solid substances increases with increasing temperature, and this is also true for gentisic acid and its impurities. If the final crystallization temperature is too high, the yield will be reduced, resulting in material waste; if the temperature is too low, impurities may precipitate together, reducing the purity of the product, and low temperature often means increased energy consumption.

[0016] Preferably, the concentration of the ethanol solution used for washing the filter cake is 5-30%, and the amount used is a mass volume ratio of crude gentisic acid to ethanol solution of 1 g: 0.1-0.3 ml.

[0017] If the concentration of ethanol used for washing is too high or the amount used is too much, the filter cake will dissolve and the product yield will be reduced; if the amount of ethanol used is too little or the concentration is too low, it will not be conducive to the washing and removal of impurities.

[0018] Preferably, the vacuum drying temperature is 50-70° C., the vacuum degree is ≥0.07 MPa, and the drying time is 4-12 h.

[0019] Preferably, the commercially available crude gentisic acid has a purity of ≥97.0%.

[0020] By studying the impurities in the recrystallization mother liquor, a new compound was obtained, which is impurity C. This impurity can be detected in both the product before and after refining. The structure is: .

[0021] Compared with the prior art, a method for preparing a high-purity gentisic acid excipient for injection uses an economical and low-toxic ethanol solution to recrystallize and purify the crude gentisic acid of commercially available chemical raw materials or chemical reagents, and the ethanol solution has the function of disinfection and sterilization; no toxic and harmful organic solvents such as hydrochloric acid, oxalic acid, and tetrahydrofuran are used; the purity of the obtained product is greater than 99.7% (maximum single impurity content <0.02%), and the appearance is good; the quality items such as solvent residue, related substances, ignition residue, insoluble matter, and microbial limit meet or even exceed the basic requirements of injection excipients, and a high-purity gentisic acid excipient for injection is obtained, which provides high-quality excipients for the development of injections, especially radiopharmaceuticals. At the same time, it has the advantages of simple operation method, low equipment requirements, mild conditions, short production cycle, etc., and is suitable for mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is a representative HPLC spectrum of crude gentisic acid;

[0023] Figure 2 The figure is a representative HPLC spectrum of gentisic acid prepared in the present invention. DETAILED DESCRIPTION

[0024] The present invention is further described in detail below by examples, and those skilled in the art can refer to the contents of this article and appropriately improve the process parameters according to specific actual equipment. The method of the present invention has been described in more detail for the preparation method of high-purity gentian excipients for injection, and relevant personnel can change or appropriately change and combine the method described herein without departing from the content, spirit and scope of the present invention to realize and apply the method of the present invention. However, the protection scope of the present invention is not limited to the content, and the methods in the embodiments are conventional methods unless otherwise specified, and the reagents used are conventional commercially available reagents or reagents configured according to conventional methods unless otherwise specified.

[0025] Example 1

[0026] (1) Dissolution: Add 1 kg of crude gentisic acid with a purity of 97.6% into a 5L glass reactor, heat and stir with 1600 ml of 50% ethanol to dissolve, the dissolution temperature is 52°C, and continue to heat to 57°C after dissolution;

[0027] (2) Filtration: The solution in (1) was filtered through a double-layer 0.22 μm polytetrafluoroethylene filter membrane under positive pressure while hot;

[0028] (3) Recrystallization: The filtrate obtained in the above (2) is slowly cooled down while stirring to crystallize. After the crystals are precipitated, the temperature is continuously lowered to 20-30°C and stirred to crystallize for 8 hours;

[0029] (4) Filtration: The solid-liquid mixture obtained in (3) above was filtered, and the filter cake was washed with 200 ml of 20% ethanol solution, and the filter cake was collected after being nearly dried.

[0030] (5) The filter cake obtained in (4) was dried under reduced pressure (temperature 50°C, vacuum degree 0.08 MPa) for 12 h. The moisture content was 0.32% as detected by a rapid moisture meter. The material was collected.

[0031] (6) Screening and packaging: The solid obtained in the above (5) is screened through a 65-mesh sieve. The product is packaged in a medicinal low-density polyethylene bag as the inner layer and in a composite aluminum-plastic bag as the outer layer, thereby obtaining a high-purity gentisic acid excipient for injection.

[0032] Example 2

[0033] (1) Dissolution: Add 1 kg of crude gentisic acid with a purity of 98.0% into a 5L glass reactor, heat and stir with 2000 ml of 40% ethanol to dissolve, the dissolution temperature is 50°C, and continue to heat to 70°C after dissolution;

[0034] (2) Filtration: The solution in (1) was filtered through a double-layer 0.22 μm nylon filter membrane under positive pressure while hot;

[0035] (3) Recrystallization: The filtrate obtained in the above (2) is slowly cooled down while stirring to crystallize. After the crystals are precipitated, the temperature is continuously lowered to 10-15°C and stirred for crystallization for 10 hours;

[0036] (4) Filtration: The solid-liquid mixture obtained in (3) above was filtered, and the filter cake was washed with 100 ml of 30% ethanol solution, and the filter cake was collected after being filtrated until it was nearly dry.

[0037] (5) The filter cake obtained in (4) was dried under reduced pressure (temperature 70°C, vacuum degree 0.08 MPa) for 4 h. The moisture content was 0.41% as detected by a rapid moisture meter. The material was collected.

[0038] (6) Screening and packaging: The solid obtained in the above (5) is screened through a 65-mesh sieve and the product is packaged in pharmaceutical brown vials to obtain a high-purity gentisic acid excipient for injection.

[0039] Example 3

[0040] (1) Dissolution: Add 1 kg of crude gentisic acid with a purity of 97.0% into a 5L glass reactor, heat and stir with 1200 ml of 60% ethanol to dissolve, the dissolution temperature is 58°C, and continue to heat to 69°C after dissolution;

[0041] (2) Filtration: The solution in (1) was filtered through a double-layer 0.22 μm polytetrafluoroethylene filter membrane under positive pressure while hot;

[0042] (3) Recrystallization: The filtrate obtained in the above (2) is slowly cooled down while stirring to crystallize. After the crystals are precipitated, the temperature is continuously lowered to 0-5°C and stirred to crystallize for 2 hours;

[0043] (4) Filtration: The solid-liquid mixed system obtained in the above (3) was filtered, and the filter cake was washed with 300 ml of 5% ethanol solution, and the filter cake was collected after being filtrated until it was nearly dry;

[0044] (5) The filter cake obtained in (4) was dried under reduced pressure (temperature 65°C, vacuum degree 0.08 MPa) for 6 h. The moisture content was 0.28% as detected by a rapid moisture meter. The material was collected.

[0045] (6) Screening and packaging: The solid obtained in the above (5) is screened through a 65-mesh sieve and the product is packaged in a pharmaceutical polyester / aluminum / polyethylene composite bag to obtain a high-purity gentisic acid excipient for injection.

[0046]

[0047] Example 4

[0048] After the mother liquor obtained in step 4 of the above embodiment was concentrated to dryness, acetonitrile was used for multiple recrystallization to remove excess gentisic acid, and the remaining mother liquor was recovered and concentrated. When the obtained solid was less than 50 g, it was purified by silica gel column chromatography-dichloromethane / methanol system elution and enrichment of impurity C component segment. After the impurity C component segment was concentrated, preparative liquid phase separation (mobile phase: acetonitrile / 0.1% formic acid aqueous solution = 70 / 30) was obtained to obtain 65 mg of impurity C, and the structural confirmation information is as follows: .

[0049] 1 H NMR (600 MHz, DMSO- d 6) δ 11.15 (s, 1H), 10.62 (br, 1H), 9.89 (br,1H), 8.77 (d, J = 3.0 Hz, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 3.0 Hz,1H), 7.03 (d, J = 9.0 Hz, 1H).

[0050] 13 C NMR (150 MHz, DMSO- d 6) δ 166.01, 164.72, 154.56, 153.08, 147.46,140.34, 126.28, 119.86, 118.49, 117.43, 116.82, 116.80, 105.34.

[0051] MS(+ESI): m / z [M+H]+ : 289.12.

Claims

1. A method for preparing a high-purity gentisic acid excipient for injection, characterized in that: The preparation method comprises the following steps: heating and dissolving a crude gentisic acid product with an ethanol solution, continuing to raise the temperature by 5 to 20°C after the solution becomes clear, passing the solution through a 0.22-mu m filter material while hot, slowly cooling the filtrate to crystallize, suction filtering, washing the filter cake with an ethanol solution, vacuum drying the filter cake, and sieving to obtain a high-purity gentisic acid auxiliary material for injection; the crude gentisic acid product is heated and dissolved with an ethanol solution, the mass volume ratio (w / v) of the crude gentisic acid product to the ethanol solution is 1 g: 1.2 to 2.0 ml, and the concentration of the ethanol solution used is 40 to 60%; the concentration of the ethanol solution used for washing the filter cake is 5 to 30%, and the amount used is the mass volume ratio (w / v) of the crude gentisic acid product to the ethanol is 1 g: 0.1 to 0.3 ml.

2. A method for preparing a high-purity gentisic acid excipient for injection according to claim 1, characterized in that: The 0.22 μm filter material is one or two of polytetrafluoroethylene filter membrane, nylon filter membrane, polycarbonate filter membrane, mixed fiber membrane, polyethersulfone membrane, polypropylene membrane, and titanium rod filter, and is positive pressure filtered.

3. A method for preparing a high-purity gentisic acid excipient for injection according to claim 1, characterized in that: The slow cooling and crystallization, after the crystals are precipitated, continue to cool to 30-0°C and stir to crystallize.

4. A method for preparing a high-purity gentisic acid excipient for injection according to claim 1, characterized in that: The vacuum drying temperature is 50-70° C., the vacuum degree is ≥0.07 MPa, and the drying time is 4-12 hours.

5. A method for preparing a high-purity gentisic acid excipient for injection according to any one of claims 1 to 4, characterized in that: The crude gentisic acid has a purity of ≥97.0%.

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