Preparation process of high-stability dipyridamole sodium chloride injection

Abstract

The invention discloses a preparation process of a high-stability dipyridamole sodium chloride injection. The preparation process comprises the following steps: S1, weighing raw materials and auxiliary materials: weighing 1g of dipyridamole, 90g of sodium chloride, 10-30g of sodium citrate and 30-70g of propylene glycol; s2, adding water for injection accounting for 70% of the prescription dosage into a liquid preparation tank, then adding sodium chloride, sodium citrate and propylene glycol accounting for the prescription dosage, and completely dissolving in a stirring state; s3, adding a proper amount of a hydrochloric acid solution, adjusting the pH value to 2.5, adding dipyridamole according to the prescription amount, and dissolving dipyridamole in a stirring state; s4, adding a proper amount of a sodium hydroxide solution, adjusting the pH value to 4.0, and fixing the volume to the prescription dosage by using the water for injection; s5, filtering the prepared solution, filling the filtered liquid medicine into a glass bottle, filling nitrogen into the bottle, plugging and capping; s6, sterilizing the filled sample; the stability of the prepared sample is obviously higher than that of a commercially available preparation, DP-II degradation impurities are avoided, obvious advantages are achieved, and the safety risk in the use process of the product can be obviously reduced.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation process of high-stability dipyridamole sodium chloride injection. BACKGROUND

[0002] Dipyridamole, English name is Dipyridamole, chemical name is 2,2',2'',2'''-[(4,8-dipiperidylpyrimido[5,4-d]pyrimidine-2,6-diyl)]dinitrilo]-tetraethanol. The CAS number is 58-32-2, and the structural formula is as follows:

[0003]

[0004] Dipyridamole was developed by F.G.Fischer and J.Roch in 1951, and was introduced by Dr. Karl Tome of Germany in 1959 as a treatment for coronary artery disease. PR Emmons et al. reported in 1965 that dipyridamole has anti-platelet activity. This effect has been studied from both basic and clinical perspectives in countries around the world, and the effectiveness of clinical application has been recognized. At present, it is widely used as a treatment for thrombosis and embolism after heart valve replacement based on anti-platelet effect, or for the treatment of glomerulonephritis, nephrotic syndrome, etc. As a treatment for coronary artery disease, the main products on the market are dipyridamole tablets, dipyridamole injection, etc.

[0005] Because the existing dipyridamole injection prescription contains tartaric acid, tartaric acid and dipyridamole will produce DP-II degradation impurities (DP-II in the figure below) under the conditions of acid, high temperature and oxygen, especially under high temperature conditions, the content of the degradation impurity DP-II of tartaric acid and dipyridamole is the highest, far exceeding the quality standard limit requirement (degradation product DP-II side chain source auxiliary material tartaric acid).

[0006] In order to improve the stability of dipyridamole injection and the convenience of clinical use, and to avoid the generation of DP-II degradation impurities, the application designs a preparation process of high-stability dipyridamole sodium chloride injection. SUMMARY

[0007] The purpose of the application is to provide a preparation process of high-stability dipyridamole sodium chloride injection to solve the problems in the background art.

[0008] To achieve the above purpose, the application provides the following technical scheme: a preparation process of high-stability dipyridamole sodium chloride injection, S1: weighing of raw and auxiliary materials: weighing 1g of dipyridamole, 90g of sodium chloride, 10-30g of sodium citrate, and 30-70g of propylene glycol, for standby;

[0009] S2: In the liquid preparation tank, 70% of the prescription amount of water for injection is added, and then the prescription amount of sodium chloride, sodium citrate and propylene glycol is added, and it is completely dissolved under stirring, and nitrogen protection should be continued during the dissolution process, and the residual oxygen content is controlled to be less than 3 ppm;

[0010] S3: Add an appropriate amount of hydrochloric acid solution to adjust the pH value to 2.5, and add the prescription amount of dipyridamole, and dissolve it under stirring, and the nitrogen protection should be continued during the dissolution process, and the residual oxygen content is controlled to be less than 3 ppm;

[0011] S4: Add an appropriate amount of sodium hydroxide solution to adjust the pH value to 4.0, and then use water for injection to constant volume to the prescription amount;

[0012] S5: The prepared solution is filtered, and then the filtered liquid is filled into a glass bottle, the filling amount is 100ml / bottle, the bottle is filled with nitrogen, and the plug is rolled;

[0013] S6: The filled sample is placed in a sterilization pot for sterilization.

[0014] Preferably, in S1, the dipyridamole is weighed under the condition of red light, and in S2, the liquid preparation process also needs to be carried out under the condition of red light.

[0015] Preferably, the amount of propylene glycol is 30-70g.

[0016] Preferably, the amount of propylene glycol is 500g.

[0017] Preferably, in S5, the filtration adopts a 0.45μm polyether sulfone filter membrane, and the filling environment needs to be light-proof, and the filling container is a brown borosilicate glass bottle.

[0018] Preferably, the sterilization temperature is 121℃, and the sterilization time is 12min, and the sterilization temperature rise and fall time is not more than 30min.

[0019] Compared with the prior art, the beneficial effects of the present application are:

[0020] The sample prepared by the dipyridamole sodium chloride injection preparation process has significantly higher stability than the commercial preparation, avoids the generation of DP-II degradation impurities, has obvious advantages, and can significantly reduce the safety risk in the use process. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 It is the HPLC graph of example 1 of the present application;

[0022] Figure 2 It is the TIC graph of example 1 of the present application;

[0023] Figure 3A mass spectrum of Example 1 of the present application; DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all the other embodiments obtained by a person of ordinary skill in the art without creative effort belong to the scope of protection of the present application.

[0025] Example 1

[0026] A preparation process of a high-stability dipyridamole sodium chloride injection solution, and the specific steps are as follows:

[0027] Raw and auxiliary materials are weighed: 1 g of dipyridamole (weighed under red light conditions), 90 g of sodium chloride, 22.5 g of sodium citrate, and 50 g of propylene glycol are weighed and prepared.

[0028] Preparation process: In a liquid preparation tank, 70% of the prescription amount of water for injection is added, and then the prescription amount of sodium chloride, sodium citrate, and propylene glycol is added. Under stirring, they are completely dissolved. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled to be below 3 ppm. An appropriate amount of hydrochloric acid solution is added to adjust the pH value to 2.5. The prescription amount of dipyridamole is added, and it is dissolved under stirring. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled to be below 3 ppm. An appropriate amount of sodium hydroxide solution is added to adjust the pH value to 4.0. Then, the water for injection is used to make up to the prescription amount. The prepared solution is filtered through a 0.45 μm polyether sulfone filter membrane. The filtered liquid is filled into brown borosilicate glass bottles (filled under red light conditions), and the filling amount is 100 ml / bottle. Nitrogen is filled in the bottle, and the bottle is capped. The filled sample is placed in a sterilization pot for sterilization. The sterilization temperature is set to 121℃, the sterilization time is set to 12 minutes, and the temperature rising and falling time is controlled to be not more than 30 minutes.

[0029] Example 2

[0030] Raw and auxiliary materials are weighed: 1 g of dipyridamole, 90 g of sodium chloride, 22.5 g of sodium citrate, and 50 g of propylene glycol are weighed and prepared.

[0031] Preparation process: in the container, add 70% of the prescription amount of water for injection, and then add the prescription amount of sodium chloride, sodium citrate, propylene glycol, and make it completely dissolved under stirring. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled below 3 ppm. Add an appropriate amount of hydrochloric acid solution to adjust the pH value to 2.5, add the prescription amount of dipyridamole, and make it dissolved under stirring. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled below 3 ppm. Add an appropriate amount of sodium hydroxide solution to adjust the pH value to 4.0, and then use water for injection to constant volume to the prescription amount. The prepared solution is filtered through a 0.45 μm polyether sulfone filter membrane, and then the filtered liquid is filled into a brown borosilicate glass bottle (which needs to be filled under red light conditions), with a filling capacity of 100 ml / bottle. Nitrogen is filled in the bottle, and the bottle is capped and rolled. The filled sample is placed in a sterilization pot for sterilization, with a sterilization temperature of 121°C, a sterilization time of 12 minutes, and a control of the temperature rising and falling time not exceeding 30 minutes.

[0032] Example 3

[0033] Raw material weighing: weigh 1 g of dipyridamole (which needs to be weighed under red light conditions), 90 g of sodium chloride, 22.5 g of sodium citrate, and 50 g of propylene glycol, and prepare for use.

[0034] Preparation process: in the preparation tank, add 70% of the prescription amount of water for injection, and then add the prescription amount of sodium chloride, sodium citrate, and propylene glycol, and make it completely dissolved under stirring. Add an appropriate amount of hydrochloric acid solution to adjust the pH value to 2.5, add the prescription amount of dipyridamole, and make it dissolved under stirring. Add an appropriate amount of sodium hydroxide solution to adjust the pH value to 4.0, and then use water for injection to constant volume to the prescription amount. The prepared solution is filtered through a 0.45 μm polyether sulfone filter membrane, and then the filtered liquid is filled into a brown borosilicate glass bottle (which needs to be filled under red light conditions), with a filling capacity of 100 ml / bottle. Nitrogen is filled in the bottle, and the bottle is capped and rolled. The filled sample is placed in a sterilization pot for sterilization, with a sterilization temperature of 121°C, a sterilization time of 12 minutes, and a control of the temperature rising and falling time not exceeding 30 minutes.

[0035] Example 4

[0036] Raw material weighing: weigh 1 g of dipyridamole (which needs to be weighed under red light conditions), 90 g of sodium chloride, 22.5 g of sodium citrate, and 50 g of propylene glycol, and prepare for use.

[0037] Preparation process: in the liquid preparation tank, add 70% of the prescription amount of water for injection, then add the prescription amount of sodium chloride, sodium citrate, propylene glycol, and make it completely dissolved under stirring. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled below 3 ppm. Add an appropriate amount of hydrochloric acid solution to adjust the pH value to 2.5, add the prescription amount of dipyridamole, and make it dissolved under stirring. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled below 3 ppm. Add an appropriate amount of sodium hydroxide solution to adjust the pH value to 4.0, and then use water for injection to make up to the prescription amount. The prepared solution is filtered through a 0.45 μm polyether sulfone filter membrane, and then the filtered liquid is filled into a brown borosilicate glass bottle (which needs to be filled under red light). The filling amount is 100 ml / bottle, the bottle is filled with nitrogen, and the bottle is capped and rolled. The filled sample is placed in a sterilization pot for sterilization, the sterilization temperature is set to 121°C, the sterilization time is 12 minutes, and the heating and cooling time is about 1 hour.

[0038] Example 5

[0039] Raw material weighing: weigh 1 g of dipyridamole (which needs to be weighed under red light), 90 g of sodium chloride, 22.5 g of sodium citrate, and 50 g of propylene glycol.

[0040] Preparation process: in the liquid preparation tank, add 70% of the prescription amount of water for injection, then add the prescription amount of sodium chloride, sodium citrate, propylene glycol, and make it completely dissolved under stirring. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled below 3 ppm. Add an appropriate amount of hydrochloric acid solution to adjust the pH value to 2.5, add the prescription amount of dipyridamole, and make it dissolved under stirring. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled below 3 ppm. Add an appropriate amount of sodium hydroxide solution to adjust the pH value to 4.0, and then use water for injection to make up to the prescription amount. The prepared solution is filtered through a 0.45 μm polyether sulfone filter membrane, and then the filtered liquid is filled into a transparent borosilicate glass bottle (which needs to be filled under red light). The filling amount is 100 ml / bottle, the bottle is filled with nitrogen, and the bottle is capped and rolled. The filled sample is placed in a sterilization pot for sterilization, the sterilization temperature is set to 121°C, the sterilization time is 12 minutes, and the heating and cooling time is controlled not to exceed 30 minutes.

[0041] Comparative Example 1

[0042] Raw material weighing: weigh 1 g of dipyridamole, 0.4 g of tartaric acid, and 10 g of polyethylene glycol 600.

[0043] Preparation process: In the liquid preparation tank, add 70% of the prescription amount of water for injection, then add the prescription amount of tartaric acid and polyethylene glycol 600, and dissolve completely under stirring. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled below 3 ppm. Add an appropriate amount of hydrochloric acid solution to adjust the pH value to 2.5. Add the prescription amount of dipyridamole and dissolve under stirring. Nitrogen protection should be continued during the dissolution process, and the residual oxygen content should be controlled below 3 ppm. Then use water for injection to make up to the prescription amount. The prepared solution is filtered through a 0.45 μm polyether sulfone filter membrane, and then the filtered liquid is filled into transparent borosilicate glass ampoules with a filling capacity of 2 ml per bottle. Nitrogen is filled in the bottle, and the bottle is capped. The filled sample is placed in a sterilization pot for sterilization, with a sterilization temperature of 121°C, a sterilization time of 12 minutes, and a control of the temperature rise and fall time not exceeding 30 minutes.

[0044] The related substances of the stability samples of Example 1, Example 2, Example 3, Example 4, Example 5, Comparative Example 1 and commercially available injection were checked by HPLC method.

[0045] Related substance test method:

[0046] Perform the operation in the dark. Determine the content of dipyridamole in dipyridamole and sodium chloride injection by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Test 0512)

[0047] The chromatographic conditions are as follows: Welch Ultimate XB-C18 4.6x150mm, 5μm is used as the chromatographic column; potassium dihydrogen phosphate buffer (1.0g of potassium dihydrogen phosphate is dissolved in 900mL of water, 0.5mol / L sodium hydroxide is used to adjust the pH to 7.0, and water is used to dilute to 1000ml) is used as the mobile phase A; methanol is used as the mobile phase B; the flow rate is 1.2ml / min; the column temperature is 45℃; the wavelength is 295nm; the injection volume is 5μl. The content of a single impurity should not exceed 2.0%, and the total amount of impurities should not exceed 4.0%.

[0048] The main degradation unknown impurities of dipyridamole and sodium chloride injection are RRT 0.18 and RRT 0.64, and the main degradation product is identified by mass spectrometry as an oxidative degradation impurity.

[0049] Table 1 summarizes the results of related substance tests

[0050]

[0051]

[0052] From the comparison of the related substance data of Example 1 and Example 2, it can be seen that when the weighing, liquid preparation and filling process are not carried out in the dark (i.e. the process of Example 2), the related substance of the prepared sample is significantly worse than that of the sample prepared in the dark throughout the process. The single impurity and total impurity of the sample not stored in the dark exceed the limit after being placed under accelerated conditions for 1 month and 3 months. It is shown that the dipyridamole sodium chloride injection needs to be prepared in the dark.

[0053] From the comparison of the related substance data of Example 1 and Example 3, it can be seen that when the liquid preparation and filling process are not carried out in nitrogen (i.e. the process of Example 3), the related substance of the prepared sample is significantly worse than that of the sample prepared in nitrogen throughout the process. The total impurity of the sample not prepared in nitrogen exceeds the limit at 0 day. The single impurity and total impurity of the sample not prepared in nitrogen exceed the limit after being placed under accelerated conditions for 1 month and 3 months. It is shown that the dipyridamole sodium chloride injection needs to be prepared in nitrogen.

[0054] From the comparison of the related substance data of Example 1 and Example 4, it can be seen that when the temperature rising and falling time during the moist heat sterilization process is prolonged (i.e. the process of Example 4), the related substance of the prepared sample is worse than that of the sample with shortened temperature rising and falling time. The single impurity and total impurity of the sample with prolonged temperature rising and falling time are significantly increased after being placed under accelerated conditions for 1 month and 3 months. It is shown that the dipyridamole sodium chloride injection needs to control the temperature rising and falling time during the sterilization process.

[0055] From the comparison of the related substance data of Example 1 and Example 5, it can be seen that when the transparent borosilicate glass bottle is used for packaging during the filling process (i.e. the process of Example 5), the related substance of the prepared sample is worse than that of the sample using the brown borosilicate glass bottle. The single impurity and total impurity of the sample using the transparent borosilicate glass bottle exceed the limit after being placed under accelerated conditions for 1 month and 3 months. It is shown that the dipyridamole sodium chloride injection is sensitive to light, and needs to be packaged using the brown borosilicate glass bottle.

[0056] From the comparison of the related substance data of Example 1, Comparative Example 1 (a sample prepared according to the original research process) and the commercially available dipyridamole injection, it can be seen that the sample prepared by the process of the present application (Example 1) is superior to Comparative Example 1 and the commercially available dipyridamole injection in terms of the related substance, single impurity and total impurity at 0 day. After being placed under accelerated conditions for 1 month and 3 months, the single impurity and total impurity of Example 1 are significantly superior to those of Comparative Example 1 and the commercially available dipyridamole injection in terms of the degradation trend.

[0057] In summary of the above investigation results, the stability of the sample prepared by the present application is significantly higher than that of the commercially available preparation, and has obvious advantages, which can significantly reduce the safety risk in the use of the product.

[0058] While embodiments of the application have been shown and described in detail, those skilled in the art will readily appreciate that many modifications and variations can be made thereto without departing from the principles and spirit of the application, and the scope of the application is to be interpreted only in the light of the accompanying claims and their equivalents.

Claims

1. A process for the preparation of a dipyridamole sodium chloride injection solution of high stability, characterized by: S1: raw and auxiliary materials weighing: take 1g dipyridamole, 90g sodium chloride, 10-30g sodium citrate, 30-70g propylene glycol, ready for use; S2: in the liquid preparation tank, add 70% of the prescription amount of water for injection, then add the prescription amount of sodium chloride, sodium citrate and propylene glycol, and make it completely dissolved under stirring. During the dissolution process, nitrogen protection should be continued, and the residual oxygen content should be controlled below 3ppm; S3: add appropriate amount of hydrochloric acid solution to adjust the pH value to 2.5, add the prescription amount of dipyridamole, and make it dissolve under stirring. During the dissolution process, nitrogen protection should be continued, and the residual oxygen content should be controlled below 3ppm; S4: add appropriate amount of sodium hydroxide solution to adjust the pH value to 4.0, and then use water for injection to make up to the prescription amount; S5: filter the prepared solution, then fill the filtered liquid into glass bottles, with a filling amount of 100ml / bottle, nitrogen filling in the bottle, and capping; S6: place the filled sample in a sterilization pot for sterilization.

2. A process for the preparation of a high stability dipyridamole sodium chloride injection as claimed in claim 1, wherein: In S1, dipyridamole needs to be weighed under red light conditions, and in S2, the liquid preparation process also needs to be carried out under red light conditions.

3. The preparation process of a highly stable dipyridamole sodium chloride injection according to claim 1, characterized in that: The amount of propylene glycol used is 30-70g.

4. A process for the preparation of a high stability dipyridamole sodium chloride injection as claimed in claim 3, wherein the process comprises of the steps of: The amount of propylene glycol used is 500g.

5. A process for the preparation of a high stability dipyridamole sodium chloride injection as claimed in claim 1, wherein: In S5, 0.45μm polyether sulfone filter membrane is used for filtration, and the filling environment needs to be light-proof, and the filling container is a brown borosilicate glass bottle.

6. A process for the preparation of a high stability dipyridamole sodium chloride injection as claimed in claim 1, wherein: The sterilization temperature is 121℃, and the sterilization time is 12min, and the sterilization temperature rise and fall time is not more than 30min.

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