Ephedrine hydrochloride injection and its preparation process

Abstract

The present invention belongs to the field of pharmaceutical preparations, and specifically relates to an ephedrine hydrochloride injection and a preparation process thereof. The ephedrine hydrochloride injection comprises ephedrine hydrochloride, sodium chloride, an antioxidant, a pH regulator, and water for injection, wherein the antioxidant is one of ascorbic acid or monothioglycerol. Combined with an optimized preparation process, the ephedrine hydrochloride injection is characterized by minimal harm to the human body, low impurity content, stable quality, and safety.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to an ephedrine hydrochloride injection and a preparation process thereof. Background Art

[0002] Ephedrine hydrochloride injection is a sympathomimetic drug with vasoconstriction, hypertension, and bronchial dilation effects. It is primarily used clinically to correct hypotension during anesthesia, as an adjunctive treatment for bronchial asthma, and to relieve nasal congestion (e.g., rhinitis). Due to its rapid onset and clear effects, ephedrine hydrochloride injection holds significant value in settings such as operating rooms and emergency departments. However, existing formulations still suffer from issues such as poor stability, susceptibility to oxidation, and high injection irritation, impacting their safety and effectiveness in clinical use.

[0003] The phenolic hydroxyl groups in the ephedrine hydrochloride molecule are susceptible to oxidation and degradation under light, high temperature, or metal ion catalysis, leading to decreased efficacy and even the production of harmful impurities (such as quinone compounds). Existing formulations lack antioxidants, and long-term storage may cause discoloration (yellow to brown) in the solution, affecting drug safety and shelf life. Furthermore, the traditional preparation process (e.g., dissolution → filtration → potting) fails to consider oxygen isolation and metal ion control, leading to the potential for oxidation risks during production. Simply relying on low pH (hydrochloric acid adjustment) to inhibit oxidation has limited effectiveness and may increase injection irritation.

[0004] To address the above problems, the present invention proposes to introduce a highly effective, low-toxic antioxidant into the basic formula of the existing ephedrine hydrochloride injection, and further optimize the process to inhibit the oxidative degradation of the product, making the product more stable during production and storage, thereby improving the safety of medication. Summary of the Invention

[0005] The first object of the present invention is to provide a formula of ephedrine hydrochloride injection with better antioxidant effect and better long-term storage performance.

[0006] The second object of the present invention is to provide a preparation process for the ephedrine hydrochloride injection having better antioxidant effect and better long-term storage performance.

[0007] To solve the above technical problems, the present invention discloses the following ephedrine hydrochloride injection, comprising the following ingredients: ephedrine hydrochloride, sodium chloride, an antioxidant, a pH regulator, and water for injection, wherein the antioxidant is one of ascorbic acid or thioglycerol.

[0008] In some preferred embodiments, the contents of the ingredients are 4.7 mg / ml of ephedrine hydrochloride, 7.5 mg / ml of sodium chloride, 0.4-0.6 mg / ml of ascorbic acid or 0.5-1.0 mg / ml of thioglycerol, and the pH value of the injection is 4.6-6.0.

[0009] The present invention also provides a preparation process for the above-mentioned ephedrine hydrochloride injection, which specifically comprises the following steps:

[0010] (1) Add sodium chloride, antioxidant, and ephedrine hydrochloride to an appropriate amount of water for injection, mix well, and adjust the pH value of the solution to 4.6-6.0; (2) Filter the solution using a filter membrane, fill with nitrogen before filling, fill, fill with nitrogen after filling, and seal; (3) Sterilize.

[0011] In some preferred embodiments, the antioxidant in step (1) is one of ascorbic acid or thioglycerol.

[0012] In some preferred embodiments, the ascorbic acid is 0.4-0.6 mg / ml, and the thioglycerol is 0.5-1.0 mg / ml.

[0013] In some preferred embodiments, the pre-filling nitrogen flow rate in step (2) is 10-15 L / min, and the post-filling nitrogen flow rate is 8-15 L / min.

[0014] Positive effects of the present invention:

[0015] 1. Oxidative degradation problem: By optimizing the type and concentration of antioxidants, the shelf life of the preparation can be significantly extended;

[0016] 2. Process compatibility: Ensure that the injection solution remains active during sterilization (such as autoclaving at 121°C) and long-term storage;

[0017] 3. Safety: Avoid the allergic risk of traditional antioxidants (such as sulfites) and improve clinical applicability; inhibit the production of impurities caused by product oxidation degradation and improve product safety. DETAILED DESCRIPTION

[0018] The sources of reagents are shown in Table 1:

[0019] Table 1 Sources of reagents

[0020]

[0021] The present invention is described in detail below with reference to the embodiments, which are intended to explain but not to limit the technical solutions of the present invention.

[0022] Example 1 Screening of Antioxidant Types

[0023] Table 2 Antioxidant screening prescription

[0024]

[0025] The above samples were prepared according to the following preparation method and then tested: 360 ml of water for injection was measured and put into a container, 3 g of sodium chloride was added, and the corresponding antioxidant was added and stirred to dissolve. 1.88 g of ephedrine hydrochloride was added thereto, stirred to dissolve, and the pH value of the solution was adjusted to 4.5-7.0 with hydrochloric acid / sodium hydroxide solution. Water for injection was added to obtain 400 ml of preparation, and the pH value was checked and adjusted to 4.5-7.0. The obtained solution was filtered using an appropriate filter membrane, divided into containers and sterilized. The samples were subjected to stability testing, and the test results are shown in Table 3:

[0026] Table 3 Antioxidant screening sample test results

[0027]

[0028] As can be seen from the table, the relevant substances of the prescriptions with added thioglycerol or ascorbic acid are better than those without antioxidants or with other antioxidants.

[0029] Example 2 Screening of Antioxidant Dosage

[0030] Table 4 Antioxidant dosage formulation

[0031]

[0032] The above samples were prepared according to the following preparation method and then tested. 360 ml of water for injection was measured and put into a beaker. 3 g of sodium chloride was added, and the corresponding antioxidant was added and stirred to dissolve. 1.88 g of ephedrine hydrochloride was added thereto, stirred to dissolve, and the pH value of the solution was adjusted to 4.5-7.0 with hydrochloric acid / sodium hydroxide solution. Water for injection was added to obtain 400 ml of preparation, and the pH value was checked and adjusted to 4.5-7.0. The resulting solution was filtered using an appropriate filter membrane and sterilized after being dispensed in containers. The samples were subjected to stability testing, and the test results are shown in Table 5:

[0033] Table 5 Antioxidant dosage test results of samples

[0034]

[0035] As can be seen from the table, among samples 9 to 13, the impurities in the 0.5-1.0 mg / ml thioglycerol formulation (samples 10 to 12) were relatively low and the growth rate was small. The impurities in the 0.3 mg / ml thioglycerol formulation (sample 9) and the 1.5 mg / ml thioglycerol formulation (sample 13) increased significantly after 12 days of illumination, indicating that the optimal thioglycerol dosage is 0.5-1.0 mg / ml.

[0036] Among samples 14 to 18, the impurities in the formulations with ascorbic acid at 0.4 to 0.6 mg / ml (samples 15 and 16) were low and the increase was small. The methcathinone hydrochloride content in the formulation with ascorbic acid at 0.2 mg / ml (sample 14) increased significantly after 12 days of light exposure. The unknown single impurities and total impurities in the formulations with ascorbic acid at 0.8 mg / ml (sample 17) and 1.2 mg / ml (sample 18) increased significantly after 12 days of light exposure, indicating that the optimal ascorbic acid dosage is 0.4 to 0.6 mg / ml.

[0037] Example 3 Process Optimization

[0038] Process 1: According to the recipe for Sample 10, measure 360 ​​ml of water for injection into a beaker, add 3 g of sodium chloride and 0.2 g of monothioglycerol, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride and stir to dissolve. Adjust the pH of the solution to 3.5-4.5 with hydrochloric acid or sodium hydroxide solution. Add more water for injection to obtain 400 ml of preparation. Check the pH again and adjust it to 3.5-4.5. Filter the resulting solution using an appropriate filter membrane, aliquot into containers, and sterilize to obtain the Process 1 sample.

[0039] Process 2: Following the recipe for Sample 10, measure 360 ​​ml of water for injection into a beaker, add 3 g of sodium chloride and 0.2 g of monothioglycerol, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride and stir to dissolve. Adjust the pH of the solution to 4.6–6.0 with hydrochloric acid or sodium hydroxide solution. Add additional water for injection to obtain 400 ml of the preparation. Check the pH again and adjust it to 4.6–6.0. ​​Filter the resulting solution using an appropriate filter membrane, aliquot into containers, and sterilize to obtain the Process 2 sample.

[0040] Process 3: Following the recipe for Sample 10, measure 360 ​​ml of water for injection into a beaker, add 3 g of sodium chloride and 0.2 g of monothioglycerol, and stir to dissolve. Add 1.88 g of ephedrine hydrochloride and stir to dissolve. Adjust the pH of the solution to 6.1–7.5 with hydrochloric acid or sodium hydroxide solution. Add additional water for injection to obtain 400 ml of the preparation. Check the pH again and adjust it to 6.1–7.5. Filter the resulting solution using an appropriate filter membrane, aliquot into containers, and sterilize to obtain the Process 3 sample.

[0041] Process 4: According to the prescription of sample 10, measure 360ml of water for injection into a beaker, add 3g of sodium chloride and 0.2g of monothioglycerol, and stir to dissolve. Add 1.88g of ephedrine hydrochloride, stir to dissolve, adjust the pH value of the solution to 4.6-6.0 with hydrochloric acid or sodium hydroxide solution, add water for injection to obtain 400ml of preparation, and then check the pH value / adjust to 4.6-6.0. The resulting solution is filtered using an appropriate filter membrane and packaged in containers. Before filling the liquid, the container is filled with nitrogen at a nitrogen flow rate of 0-9L / min. After filling, the container is filled with nitrogen above the liquid level at a nitrogen flow rate of 0-7L / min. After filling and nitrogen filling, the container is immediately sealed and the prepared sample is sterilized to obtain the process 4 sample.

[0042] Process 5: According to the prescription of sample 10, measure 360ml of water for injection into a beaker, add 3g of sodium chloride and 0.2g of monothioglycerol, and stir to dissolve. Add 1.88g of ephedrine hydrochloride, stir to dissolve, adjust the pH value of the solution to 4.6-6.0 with hydrochloric acid or sodium hydroxide solution, add more water for injection to obtain 400ml of preparation, and then check the pH value / adjust it to 4.6-6.0. The resulting solution is filtered using an appropriate filter membrane and divided into containers. Before filling the liquid, the container is filled with nitrogen at a nitrogen flow rate of 10-15L / min. After filling, the container is filled with nitrogen above the liquid level at a nitrogen flow rate of 8-15L / min. After filling and nitrogen filling, the container is immediately sealed and the prepared sample is sterilized to obtain the process 5 sample.

[0043] The samples prepared by the above process were tested and stability investigated. The test and investigation results are shown in Tables 6 and 7:

[0044] Table 6 Comparison of test results of process 1 / 2 / 3 samples

[0045]

[0046] As can be seen from the table, the impurities and impurity growth rates of process 1 and process 3 samples are significantly higher than those of process 2 samples, indicating that the product stability is best when the pH value of the solution is between 4.6 and 6.0.

[0047] Table 7 Comparison of test results of process 2 / 4 / 5 samples

[0048]

[0049] As can be seen from the table, the sample from Process 5 shows almost no growth in impurities, and its stability is superior to that of the samples from Processes 2 and 4. This suggests that pre-filling with nitrogen at 10-15 L / min and post-filling with nitrogen at 8-15 L / min can make the sample more stable. Furthermore, based on actual commercial production practices, further increasing the nitrogen flow rate will increase the impact of nitrogen on the drug solution, causing splashing, increasing the risk of contamination, and potentially causing sample quality issues. Furthermore, while maintaining the same sample quality and stability, using excessively high nitrogen flow rates results in a certain waste of resources. Therefore, the optimal nitrogen flow rate range is 10-15 L / min for pre-filling and 8-15 L / min for post-filling.

[0050] Stability studies:

[0051] The following samples were tested for stability under high temperature and light conditions, and the pH, related substances, and content were tested. The related substances included methcathinone hydrochloride, pseudoephedrine hydrochloride, other largest single impurities, and other total impurities. The stability of each ephedrine hydrochloride injection was investigated.

[0052] Table 8 pH value test results

[0053]

[0054] Table 9 Test results of methcathinone hydrochloride content (%)

[0055]

[0056] Table 10 Test results of other maximum single impurity contents (%)

[0057]

[0058] Table 11 Test results of other total impurities (%)

[0059]

[0060] The remaining indicators (content, pseudoephedrine hydrochloride) of all samples were stable and had comparable stability.

[0061] The results in Tables 8-11 show that the purchased reference preparation and the homemade reference preparation showed significant increases in impurities during the stability study. The optimal sample (Sample 10) showed some increase in impurities, but was significantly superior to the purchased reference preparation or the homemade reference preparation. The optimal process sample (Process 5) prepared using the optimized process showed almost no increase in impurities during the stability study, further improving the impurity stability of the optimal sample. Furthermore, when comparing the pH values ​​of the different samples during the stability study, the optimal process sample showed a smaller change than the purchased reference preparation or the homemade reference preparation, indicating that the optimal process sample had a more stable pH index. This demonstrates that the optimal process sample has significant advantages in quality and stability.

Claims

1. An ephedrine hydrochloride injection, characterized in that: The invention comprises the following ingredients: ephedrine hydrochloride, sodium chloride, antioxidant, pH regulator, and water for injection; wherein the antioxidant is one of ascorbic acid or thioglycerol, and the contents of the ingredients are 4.7 mg / ml of ephedrine hydrochloride, 7.5 mg / ml of sodium chloride, 0.4-0.6 mg / ml of ascorbic acid or 0.5-1.0 mg / ml of thioglycerol, respectively, and the pH value of the injection is 4.6-6.0; the preparation process of the ephedrine hydrochloride injection comprises the following steps: (1) adding sodium chloride, antioxidant, and ephedrine hydrochloride to an appropriate amount of water for injection, mixing, and adjusting the pH value of the solution to 4.6-6.0; (2) filtering the solution using a filter membrane, filling with nitrogen before filling, filling, filling with nitrogen after filling, and sealing; (3) sterilizing.

2. An ephedrine hydrochloride injection according to claim 1, characterized in that: In step (2), the front nitrogen filling flow rate is 10-15 L / min, and the rear nitrogen filling flow rate is 8-15 L / min.

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