Process for reducing the content of heavy metal element impurities in glucocorticoid bulk drug

Abstract

The application belongs to the technical field of medicine refining, and particularly relates to a process for reducing the content of heavy metal element impurities in glucocorticoid bulk drug, which comprises the following steps: S1, glucocorticoid bulk drug is added into a solvent, heated and stirred, and after the solution is clarified, the temperature of the system is controlled at 40-70 DEG C and a complexing agent aqueous solution is added, the temperature of the system is continuously controlled at 40-70 DEG C, the whole system is still controlled in a clarified state, stirred, and a mixed solution I is obtained; S2, an anti-solvent is added dropwise into the mixed solution I obtained in step S1, cooled, and then after a period of incubation, the system is filtered and dried, and the glucocorticoid bulk drug is obtained. The process provided by the application is simple in operation, the product yield can reach more than 92%, the cost is low, and the process is very suitable for large-scale industrial application. The refined glucocorticoid bulk drug can meet the quality requirements of the current Chinese, American and European pharmacopoeias for heavy metal element impurities.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical refining, and particularly relates to a process for reducing the content of heavy metal element impurities in glucocorticoid bulk drug. BACKGROUND

[0002] The state has increasingly strict requirements for the content of heavy metal element impurities in drugs, and continues to increase the detection efforts of heavy metal element impurities in drugs, especially bulk drugs. Bulk drugs, especially those that need fluorine addition reaction in chemical synthesis, have many stainless steel equipment in their production equipment. Many enterprises use 304 and below standard stainless steel equipment to save costs. High-concentration hydrofluoric acid used in fluorine addition reaction can easily corrode production equipment, resulting in excessive heavy metal elements in the product, especially chromium, nickel and molybdenum, which are generally higher than the industry-recognized standard. China is a large country in bulk drug production. Many drug products are destroyed at the end due to excessive heavy metal element impurities, which not only wastes resources but also increases enterprise costs and defect rates.

[0003] There are few reports on methods for reducing the content of heavy metal element impurities in the glucocorticoid bulk drug industry. In view of the chemical properties of glucocorticoids, such as intolerance to acid and alkali and easy oxidation, the commonly used alkali neutralization method, oxidation-reduction method and coagulation breaking method can easily affect the quality of glucocorticoids. Therefore, there is an urgent need to develop a method for removing heavy metal element impurities suitable for glucocorticoids. SUMMARY

[0004] In order to solve the problems in the prior art, the purpose of the present application is to provide a process for reducing the content of heavy metal element impurities in glucocorticoid bulk drug. The process provided by the present application is simple to operate, the product yield can reach more than 92%, the cost is low, and it is very suitable for large-scale industrial application. The refined glucocorticoid bulk drug meets the requirements of the ICH Q3D Element Impurities Guideline for element impurities in human drugs.

[0005] The technical scheme of the present application is:

[0006] A process for reducing the content of heavy metal element impurities in glucocorticoid bulk drug, comprising the following steps:

[0007] S1, adding glucocorticoid bulk drug into a solvent, heating and stirring, controlling the system temperature at 40-70 DEG C and adding a complexing agent aqueous solution, continuing to control the system temperature at 40-70 DEG C, and the whole system is still controlled in a clear state, stirring to obtain a mixed solution I;

[0008] S2, control system temperature is 40~70℃, to the mixed solution I obtained in step S1 dropwise adding anti-solvent, cooling, then incubated for a period of time, the system is filtered, dried, to obtain the reduced heavy metal element impurity content after the glucocorticoid raw material;

[0009] The solute of the complexing agent aqueous solution is composed of disodium EDTA and gluconic acid.

[0010] Further, the concentration of the complexing agent aqueous solution in step S1 is 5~20mg / mL; the weight ratio of disodium EDTA and gluconic acid added in the complexing agent aqueous solution is 7~10:1.

[0011] Further, the weight ratio of disodium EDTA and gluconic acid added in the complexing agent aqueous solution is 9:1.

[0012] Further, the volume of the complexing agent aqueous solution added is 1~3 times the weight of the glucocorticoid raw material, the volume is measured in milliliters, and the weight is measured in grams.

[0013] Further, the concentration of the complexing agent aqueous solution in step S1 is 5~10mg / mL.

[0014] Further, the complexing agent aqueous solution in step S1 is added in one time.

[0015] Further, the volume of the solvent added in step S1 is 10~15 times the weight of the glucocorticoid raw material sample; the volume is measured in milliliters, and the weight is measured in grams.

[0016] Further, the solvent in step S1 is selected from one or more of aliphatic hydrocarbons, ketones, and alcohols; the solubility of the mixed solution I system in step S1 is greater than 150mg / mL at a temperature of 40~70℃.

[0017] Further, the glucocorticoid raw material in step S1 is one or more of flumethasone, triamcinolone acetonide, fluticasone, and triamcinolone.

[0018] Further, the stirring speed in step S1 is 60~200r / min, and the stirring time is 10~120min.

[0019] Further, the volume of the anti-solvent added in step S2 is 6~10 times the weight of the glucocorticoid raw material sample; the volume is measured in milliliters, and the weight is measured in grams; and the anti-solvent is deionized water.

[0020] Further, the dropwise adding speed of the anti-solvent in step S2 is 2.0~4.0mL / min.

[0021] Further, the cooling mode after adding the anti-solvent in the step S2 is gradient cooling, the speed of the gradient cooling is 3-7 ℃ / h, and the temperature is cooled to 10-20 ℃, and the temperature is kept for 1-3 h.

[0022] Further, the solubility of the glucocorticoid raw material in the anti-solvent in the step S2 is less than 10 mg / mL at 40-70 ℃; and the solubility of the disodium EDTA in the anti-solvent is greater than 100 mg / mL at room temperature.

[0023] In the process for reducing the content of heavy metal element impurities in the glucocorticoid raw material provided by the application, by controlling the adding amount and concentration of the complexing agent aqueous solution, the reaction temperature, the reaction time and the dropping speed of the anti-solvent, the content of the heavy metal element in the glucocorticoid raw material is effectively reduced, and the yield of the raw material is also improved.

[0024] Firstly, in the step S1, the temperature of the system is controlled to be 40-70 ℃, the complexing agent aqueous solution with a volume of 1-3 times of the glucocorticoid raw material and a concentration of 5-20 mg / mL is added to the organic solvent system containing the glucocorticoid raw material sample and being clear, and the temperature of the system is continuously controlled to be 40-70 ℃.

[0025] In the above steps, the EDTA complexing agent aqueous solution is added to the clear system containing the glucocorticoid raw material in the organic solvent at a specific temperature of 40-70 ℃, the disodium EDTA and gluconic acid are prepared into the complexing agent aqueous solution with a concentration of 5-20 mg / mL in a weight ratio of 7-10:1, and the complexing agent aqueous solution with this concentration and the adding amount can keep the system clear after the adding of the complexing agent aqueous solution, which is very beneficial to the complexing of the heavy metal element impurities in the glucocorticoid raw material and has a very obvious effect on the removal of the heavy metal.

[0026] Then, the anti-solvent with a volume of 6-10 times of the glucocorticoid raw material in the step S1 is added at a speed of 2.0-4.0 mL / min, and then the system is gradient cooled to 10-20 ℃ at a speed of 3-7 ℃ / h per hour, and kept for 1-3 h.

[0027] Further, in the above steps, the anti-solvent is dropped at a dropping speed of 2.0-4.0 mL / min, and the slow gradient cooling mode is very beneficial to the precipitation of the glucocorticoid raw material sample, thereby improving the yield; in addition, the deionized water is used as the anti-solvent, which has a small solubility to the glucocorticoid raw material and a large solubility to the disodium EDTA, and when the temperature is cooled to 10-20℃, the disodium EDTA complex system can effectively ensure the dissolution of the mother liquor and as much as possible promote the precipitation of the glucocorticoid raw material, thereby reducing the heavy metal element impurity content and effectively improving the yield.

[0028] Through experimental verification, the content of the heavy metal elements (Mo, Ni, Cr) in the glucocorticoid raw material refined by the process of the present application is less than the inhalation PDE value in the ICH Q3D element impurity guideline, which can meet the quality requirements of the current Chinese, American and European pharmacopoeias for heavy metal element impurities, and the yield can reach more than 92%.

[0029] Compared with the prior art, the process for reducing the heavy metal element impurity content of the glucocorticoid raw material provided by the present application has the following advantages:

[0030] (1) The process for reducing the heavy metal element impurity content of the glucocorticoid raw material can effectively reduce the heavy metal content in the glucocorticoid raw material, so that the refined glucocorticoid raw material meets the requirements of the ICH Q3D element impurity guideline for element impurities of human drugs.

[0031] (2) The process for reducing the heavy metal element impurity content is simple to operate, low in production cost, and has a product yield of more than 92%, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0032] The present application is further described below through the description of specific embodiments, but this is not a limitation on the present application. Those skilled in the art can make various modifications or improvements according to the basic idea of the present application, as long as they do not deviate from the basic idea of the present application, and they are within the protection scope of the present application.

[0033] In the following examples and comparative examples, the reagents not specifically mentioned are conventional reagents, which can be purchased from conventional reagent production and sales companies, and the methods used are the prior art unless otherwise specified.

[0034] Example 1: A process for reducing the heavy metal element impurity content of a glucocorticoid raw material

[0035] The process for reducing the heavy metal element impurity content of the glucocorticoid raw material comprises the following steps:

[0036] S1, add 20g triamcinolone, 240mL anhydrous ethanol into a four-necked flask, heat and stir, after the solution is clear, control the system temperature at 60-70℃, add 30mL complexing agent aqueous solution with a concentration of 15mg / mL (the weight ratio of disodium EDTA and gluconic acid added in the complexing agent aqueous solution is 7:1), continue to control the system temperature at 60-70℃, and stir at a speed of 80r / min for 20min, to obtain a mixed solution I.

[0037] S2, control the system temperature at 60-70℃, add 160mL deionized water into the mixed solution I of step S1 at a flow rate of 2.0mL / min, then reduce the temperature to 10℃ at a speed gradient of 7℃ / h, keep the system at 10℃ for 1h, filter and dry the system, to obtain the product.

[0038] Example 2: A process for reducing the content of heavy metal element impurities in glucocorticoid raw material drugs

[0039] The process for reducing the content of heavy metal element impurities in glucocorticoid raw material drugs comprises the following steps:

[0040] S1, add 20g triamcinolone, 240mL anhydrous ethanol into a four-necked flask, heat and stir, after the solution is clear, control the system temperature at 60-70℃, add 30mL complexing agent aqueous solution with a concentration of 15mg / mL (the weight ratio of disodium EDTA and gluconic acid added in the complexing agent aqueous solution is 7:1), continue to control the system temperature at 60-70℃, and stir at a speed of 80r / min for 20min, to obtain a mixed solution I.

[0041] S2, control the system temperature at 60-70℃, add 160mL deionized water into the mixed solution I of step S1 at a flow rate of 2.0mL / min, then reduce the temperature to 10℃ at a speed gradient of 7℃ / h, keep the system at 10℃ for 1h, filter and dry the system, to obtain the product.

[0042] Example 3: A process for reducing the content of heavy metal element impurities in glucocorticoid raw material drugs

[0043] The process for reducing the content of heavy metal element impurities in glucocorticoid raw material drugs comprises the following steps:

[0044] S1, add 20g triamcinolone, 240mL anhydrous ethanol into a four-necked flask, heat and stir, after the solution is clear, control the system temperature at 60-70℃, add 30mL complexing agent aqueous solution with a concentration of 15mg / mL (the weight ratio of disodium EDTA and gluconic acid added in the complexing agent aqueous solution is 7:1), continue to control the system temperature at 60-70℃, and stir at a speed of 80r / min for 20min, to obtain a mixed solution I.

[0045] S2, control system temperature is 50~60℃, to step S1 with flow rate of 4.0mL / min drop 140mL deionized water, then with 6℃ / h speed gradient cooling to 20℃, keep 3h, filter, dry, namely the system is obtained.

[0046] Example 4 a process for reducing the content of heavy metal element impurities in glucocorticoid raw material drugs

[0047] The process for reducing the content of heavy metal element impurities in glucocorticoid raw material drugs, comprising the following steps:

[0048] S1, to the four opening bottle is added 20g flumethasone, 300mL butanone, heating stirring, after the solution is clear, control system temperature is 50~60℃, add 40mL concentration of 5mg / mL complexing agent aqueous solution (the complexing agent aqueous solution is added EDTA disodium and gluconic acid weight ratio is 8:1), continue to control system temperature is 50~60℃, and at 150r / min speed stirring 20min, get mixed solution I.

[0049] S2, control system temperature is 50~60℃, to step S1 with flow rate of 3.0mL / min drop 160mL deionized water, then with 4℃ / h speed gradient cooling to 12℃, keep 2h, filter, dry, namely the system is obtained.

[0050] Example 5 a process for reducing the content of heavy metal element impurities in glucocorticoid raw material drugs

[0051] The process for reducing the content of heavy metal element impurities in glucocorticoid raw material drugs, comprising the following steps:

[0052] S1, to the four opening bottle is added 20g flumethasone, 300mL butanone, heating stirring, after the solution is clear, control system temperature is 50~60℃, add 40mL concentration of 5mg / mL complexing agent aqueous solution (the complexing agent aqueous solution is added EDTA disodium and gluconic acid weight ratio is 8:1), continue to control system temperature is 50~60℃, and at 150r / min speed stirring 20min, get mixed solution I.

[0053] S2, control system temperature is 50~60℃, to step S1 with flow rate of 3.5mL / min drop 200mL deionized water, then with 5℃ / h speed gradient cooling to 17℃, keep 3h, filter, dry, namely the system is obtained.

[0054] Example 4 a process for reducing the content of heavy metal element impurities in glucocorticoid raw material drugs

[0055] The difference between Comparative Example 1 and Example 2 is that the disodium EDTA in the aqueous solution of complexing agent in step S1 is replaced by EDTA, and other parameters and operations are the same as those in Example 2.

[0056] A process for reducing the content of heavy metal element impurities in glucocorticoid raw materials

[0057] The difference between Comparative Example 2 and Example 2 is that the gluconic acid in the aqueous solution of complexing agent in step S1 is replaced by citric acid, and other parameters and operations are the same as those in Example 2.

[0058] A process for reducing the content of heavy metal element impurities in glucocorticoid raw materials

[0059] The difference between Comparative Example 3 and Example 2 is that the temperature of the system in steps S1 and S2 is maintained at 80-90°C, and other parameters and operations are the same as those in Example 2.

[0060] A process for reducing the content of heavy metal element impurities in glucocorticoid raw materials

[0061] The difference between Comparative Example 4 and Example 2 is that the dropping speed of deionized water in step S2 is 5 mL / min, and other parameters and operations are the same as those in Example 2.

[0062] A process for reducing the content of heavy metal element impurities in glucocorticoid raw materials

[0063] The difference between Comparative Example 5 and Example 2 is that the cooling method in step S2 does not use gradient cooling, but directly cools to 15°C, and other parameters and operations are the same as those in Example 2.

[0064] Test Example 1, Effect of the process of the present application on reducing the content of heavy metals in glucocorticoid drugs

[0065] 1. Test materials: glucocorticoid raw material samples: triamcinolone, triamcinolone acetonide, fluticasone, and flumethasone; glucocorticoid raw materials refined by the processes of Examples 1-5 and Comparative Examples 1-5.

[0066] 2. Test method:

[0067] (1) The contents of Mo, Ni, and Cr, which are some noble metal element impurities prone to exceed the standard in commercially available triamcinolone, triamcinolone acetonide, fluticasone, and flumethasone, were detected by ICP-MS, and the minimum standard of Mo, Ni, and Cr in the raw materials was calculated according to the maximum dose of 1 g per day and the PDE value of the most stringent inhalation dosage form in the ICH Q3D Element Impurities Guideline, and the test results are shown in Table 1.

[0068] Table 1

[0069]

[0070] (2) The refined glucocorticoid raw materials in Examples 1-5 and Comparative Examples 1-5 were detected for heavy metal elements Mo, Ni and Cr by ICP-MS, and the results are shown in Table 2.

[0071] Table 2

[0072]

[0073]

[0074] As shown in Table 2, the metal elements Mo, Ni and Cr in the glucocorticoid raw materials refined by the methods provided in Examples 1-5 are all less than the most stringent standard of the most stringent dosage form (inhalation type) of ICH Q3D, and have a high yield level; the whole refining process is simple to operate, the raw and auxiliary materials are easy to obtain, the complexing agent is safe and low in price, the results are stable, and it is very suitable for industrial application.

[0075] Compared with the examples, in the processes of Comparative Examples 1-5, when the components of the added complexing agent and the parameter conditions in the process are changed, the contents of the metal elements Mo, Ni and Cr are all increased to different degrees.

[0076] The above examples only illustratively explain the principles and effects of the present application, and are not used to limit the present application. Any person skilled in the art can modify or change the above examples without departing from the spirit and scope of the present application. Therefore, all equivalent modifications or changes completed by those skilled in the art without departing from the spirit and technical thought disclosed by the present application should still be covered by the claims of the present application.

Claims

1. A process for reducing the heavy metal impurity content of glucocorticoid raw materials, characterized in that, Includes the following steps: S1. Add the glucocorticoid raw material to the solvent, heat and stir. After the solution becomes clear, control the system temperature at 50~70℃ and add the complexing agent aqueous solution. Continue to control the system temperature at 50~70℃ and stir to obtain mixture I. S2. Control the system temperature to 50~70℃, add antisolvent dropwise to the mixture I obtained in step S1, cool down, and then keep warm for a period of time. Filter and dry the system to obtain glucocorticoid raw material with reduced heavy metal impurity content. In step S1, the concentration of the complexing agent aqueous solution is 5~20 mg / mL; the solute of the complexing agent aqueous solution is composed of disodium EDTA and gluconic acid; the weight ratio of disodium EDTA and gluconic acid is 7~10:

1. The glucocorticoid raw material in step S1 is one or more of flumethasone, triamcinolone acetonide, fluticasone, and triamcinolone. The solvent in step S1 is selected from anhydrous ethanol, acetone, butanone, and methanol. The antisolvent in step S2 is deionized water; the dropping rate of the antisolvent is 2.0~4.0 mL / min; In step S2, the cooling method after adding the antisolvent is gradient cooling, with a cooling rate of 3~7℃ / h, cooling down to 10~20℃, and holding at that temperature for 1~3 h.

2. The process for reducing the heavy metal impurity content of glucocorticoid raw materials according to claim 1, characterized in that, The volume of the complexing agent aqueous solution added in step S1 is 1 to 3 times the weight of the glucocorticoid raw material, wherein the volume is in milliliters and the weight is in grams.

3. The process for reducing the heavy metal impurity content of glucocorticoid raw materials according to claim 1, characterized in that, In step S1, the volume of solvent added is 10 to 15 times the weight of the glucocorticoid raw material sample; the volume is in milliliters and the weight is in grams.

4. The process for reducing the heavy metal impurity content of glucocorticoid raw materials according to claim 1, characterized in that, In step S1, the solubility of mixture I is greater than 150 mg / mL at a temperature of 50~70℃.

5. The process for reducing the heavy metal impurity content of glucocorticoid raw materials according to claim 1, characterized in that, The stirring speed in step S1 is 60~200 r / min, and the stirring time is 10~120 min.

6. The process for reducing the heavy metal impurity content of glucocorticoid raw materials according to claim 1, characterized in that, In step S2, the volume of the antisolvent added is 6 to 10 times the weight of the glucocorticoid raw material sample; the volume is in milliliters and the weight is in grams.

7. The process for reducing the heavy metal impurity content of glucocorticoid raw materials according to claim 1, characterized in that, The solubility of the glucocorticoid raw material in the antisolvent of step S2 is less than 10 mg / mL at 50~70℃; the solubility of disodium EDTA in the antisolvent of step S2 is greater than 100 mg / mL at room temperature.

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