Preparation method of ketorolac tromethamine injection with low impurity content
By adding ethanol and sodium chloride in the preparation process of ketorolac tromethamine injection, pH adjustment and filtering of the filter membrane, combined with appropriate sterilization and standstill conditions, the content of impurity E was successfully reduced. The problem of excessive impurity E in ketorolac tromethamine injection was solved, and the product's qualified status was changed.
Patent Information
- Application Number
- CN202411233886.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-04
- Publication Date
- 2024-12-27
AI Technical Summary
In the prior art, the content of impurity E in ketorolac tromethamol injection is often higher than the standard limit, resulting in unqualified products, and the existing methods fail to effectively reduce the impurity content.
When preparing ketorolac tereamyl injection, ethanol and sodium chloride were added, and the pH was adjusted to 6.9-7.9, filtered by 0.22 μm filter membrane and sterilized at 121 ℃, and then avoid light at 30-70 ℃ Leave it in place to control the formation of impurity E and ensure that its content is within the standard regulations.
It significantly reduces the content of impurity E in ketorolac tromethamyl injection, so that it meets factory standards, avoids the product being judged as unqualified, and changes the product to a qualified state within one week, without adding other impurities. Type and content.
Smart Images
Figure BDA0005027137470000011 
Figure BDA0005027137470000021
Abstract
Description
Technical Field
[0001] The invention relates to a preparation method of ketorolac tromethamine injection with low impurity content, belonging to the technical field of medicines. Background Art
[0002] Ketorolac tromethamine injection is a nonsteroidal anti-inflammatory drug for intravenous administration for short-term treatment of acute and severe pain. It was first launched in the United States by Roche Pharmaceuticals (ROCHE PALO ALTO LLC) on November 30, 1989, with the trade name "TORADOL". Ketorolac tromethamine injection is used for short-term treatment of acute and severe pain that requires opioid-level analgesics, usually for postoperative analgesia, and is not suitable for the treatment of mild or chronic pain.
[0003] Ketorolac tromethamine injection is usually prepared by dissolving ketorolac tromethamine raw material in water for injection, adjusting the pH value, and sterilizing. The sterilization condition is sterilization at 121°C for 15 minutes. During the sterilization process, an impurity E will be generated in the ketorolac tromethamine injection. The chemical structure of this impurity is as follows:
[0004]
[0005] Impurity E Chemical name: 5-benzoyl-N-[1,3-dihydroxy-2-(hydroxymethyl)propane-2-yl]-2,3-dihydro-1H-pyrrolazine-1-carboxamide, Molecular formula: C 19 H 22 N2O5 molecular weight: 358.15. Impurity E is produced by the condensation of ketorolac and tromethamine. According to the quality standard of ketorolac tromethamine injection stipulated in my country, its limit shall not exceed 0.1%. However, in actual production, this impurity is often produced 2 to 3 times higher than the limit value. Once the impurity E is detected to exceed the limit, it is usually directly determined as an unqualified product and destroyed. Regarding how to reduce the content of impurity E in ketorolac tromethamine injection, there is no report in the prior art.
[0006] Several other known impurities are mentioned in the national standard for ketorolac tromethamine injection:
[0007]
[0008] After sterilization, the concentrations of impurities A, B, C, D, F, G, H, I, J and ketorolac oxidation products can usually be controlled within the national standard requirements (not exceeding 0.1%). Therefore, solving the problem of impurity E exceeding the standard is the key to reducing the impurity content of ketorolac tromethamine injection. Summary of the invention
[0009] The object of the present invention is to solve the deficiencies of the prior art and provide a method for preparing a ketorolac tromethamine injection with a low impurity content. The method is simple to operate and can significantly reduce the impurity content, especially the content of impurity E, in the ketorolac tromethamine injection.
[0010] To achieve the above object, the present invention adopts the following technical solution:
[0011] A preparation method of ketorolac tromethamine injection with low impurity content:
[0012] Ketorolac tromethamine, ethanol and sodium chloride are added to water for injection, and after being completely dissolved, the pH value is adjusted to 6.9-7.9, and then filtered through a filter membrane, filled, and sterilized at 121° C. for 15 minutes. After cooling, it is placed at 30-70° C. in the dark to obtain ketorolac tromethamine injection.
[0013] Furthermore, the weight ratio of the ketorolac tromethamine to the water for injection is 1:(33.3±1.4).
[0014] Furthermore, the pH value is adjusted using a 0.5 mol / L sodium hydroxide solution.
[0015] Furthermore, the pore size of the filter membrane is 0.22 μm.
[0016] Furthermore, the standing temperature is 40-60°C.
[0017] Furthermore, the standing time is 2-7 days.
[0018] Compared with the prior art, the present invention has the following technical effects:
[0019] The invention provides a method for preparing a ketorolac tromethamine injection with a low impurity content. The method is simple to operate and can significantly reduce the impurity content in the ketorolac tromethamine injection, especially the content of impurity E, so that the content of impurity E is controlled within the limit specified by the standard. In the prior art, when the impurity E exceeds the standard, the product is directly determined as an unqualified product and destroyed. The method of the invention can convert the product into a qualified product within a period of no more than one week without increasing the types and contents of other impurities. DETAILED DESCRIPTION
[0020] The technical scheme of the present invention is described clearly and completely below in conjunction with specific embodiments. In the following embodiments, the ketorolac tromethamine used was purchased from Zhejiang Chetou Pharmaceutical Co., Ltd.
[0021] Comparative Example 1
[0022] Preparation method of ketorolac tromethamine injection:
[0023] Nitrogen was passed through 60L of water for injection (nitrogen flow rate was 8-12L / min). After half an hour, 6 liters of water were released, 1.854kg of ketorolac tromethamine, 6kg of ethanol and 0.261g of sodium chloride were dissolved in water for injection, 0.5mol / L sodium hydroxide solution was used to adjust the pH value of the solution to 7.3-7.5, and then water was added to 60L. Stir for 15 minutes, and after detecting the intermediate, it was filtered with a 0.22μm filter membrane and filled, 1.02-1.06ml per bottle, sterilized at 121℃ for 15min, inspected by light, and packaged in a light-shielding paper box. The relevant substances were detected (according to the method in the CP2020 version of the Pharmacopoeia Ketorolac Tromethamine Injection Standard), of which the impurity E content reached 0.35%, which was in line with the pharmacopoeia except for impurities Ⅰ (impurity A in the manufacturer's standard), Ⅱ (impurity B in the manufacturer's standard) and Ⅲ (impurities in the manufacturer's standard) Not more than 0.5%, but it did not meet the factory standard requirements.
[0024] Example 1
[0025] A preparation method of ketorolac tromethamine injection with low impurity content:
[0026] Nitrogen was passed through 60L of water for injection (nitrogen flow rate was 8-12L / min). Half an hour later, 6L of water for injection was released, 1.854kg of ketorolac tromethamine, 6kg of ethanol and 0.261g of sodium chloride were dissolved in the water for injection, 0.5mol / L sodium hydroxide solution was used to adjust the pH value of the solution to 7.3-7.5, and then water was added to 60L, stirred for 15 minutes, and after detecting the intermediate, filtered with a 0.22μm filter membrane, filled, 1.02-1.06ml per bottle, sterilized at 121°C for 15min, cooled and inspected by light, packaged in a light-shielding paper box, and placed in an oven at 60°C for 2 days in batches with the packaging, and the relevant substances were detected (according to the method in the CP2020 version of the Pharmacopoeia Ketorolac Tromethamine Injection Standard), and the impurity E content was measured to be 0.07%, and the contents of other impurities were also within 0.1%, reaching the factory standard.
[0027] Example 2
[0028] A preparation method of ketorolac tromethamine injection with low impurity content:
[0029] Nitrogen was passed through 60L of water for injection (nitrogen flow rate was 8-12L / min). Half an hour later, 6 liters of water were released, 1.854kg of ketorolac tromethamine, 6kg of ethanol and 0.261g of sodium chloride were dissolved in water for injection, 0.5mol / L sodium hydroxide solution was used to adjust the pH value of the solution to 7.3-7.5, and then water was added to 60L, stirred for 15 minutes, and after detecting the intermediate, it was filtered with a 0.22μm filter membrane, filled, 1.02-1.06ml per bottle, sterilized at 121°C for 15min, light inspected, packed in a light-shielding paper box, and placed in an oven at 40°C for 2 days with the packaging in batches, and the relevant substances were detected (according to the method in the CP2020 version of the Pharmacopoeia Ketorolac Tromethamine Injection Standard), and the impurity E content was measured to be 0.08%, and the contents of other impurities were also within 0.1%, reaching the factory standard.
Claims
1. A method for preparing a ketorolac tromethamine injection with a low impurity content, characterized in that: Ketorolac tromethamine, ethanol and sodium chloride are added to water for injection, and after being completely dissolved, the pH value is adjusted to 6.9-7.9, and then filtered through a filter membrane, filled, and sterilized at 121° C. for 15 minutes. After cooling, it is placed at 30-70° C. in the dark to obtain ketorolac tromethamine injection.
2. The method for preparing the ketorolac tromethamine injection with low impurity content as claimed in claim 1, characterized in that: The weight ratio of the ketorolac tromethamine to the water for injection is 1:(33.3±1.4).
3. The method for preparing the ketorolac tromethamine injection with low impurity content as claimed in claim 1, characterized in that: The pH value is adjusted using a 0.5 mol / L sodium hydroxide solution.
4. The method for preparing the ketorolac tromethamine injection with low impurity content as claimed in claim 1, characterized in that: The standing temperature is 40-60°C.
5. The method for preparing the ketorolac tromethamine injection with low impurity content as claimed in claim 1, characterized in that: The standing time is 2-7 days.