Preparation method of digoxin injection

Abstract

The invention discloses a preparation method of a digoxin injection. The preparation method comprises the following steps: dissolving anhydrous citric acid and anhydrous disodium hydrogen phosphate by using about 30% of water for injection, then adding absolute ethyl alcohol and propylene glycol (for injection), stirring and uniformly mixing until no obvious layering exists, and finally adding digoxin, and stirring and dissolving to obtain the digoxin injection. According to the preparation process provided by the invention, the water for injection and the absolute ethyl alcohol can form a latent solvent, so that the solubility of the digoxin in a single auxiliary material is greatly improved, and the subsequent preparation of the digoxin injection is facilitated.

Description

Technical Field

[0001] The invention belongs to the pharmaceutical field, and more specifically, relates to a preparation method of digoxin injection. Background Art

[0002] Digoxin, chemical name: 3β-[[O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl(1→4)-2,6-dideoxy-β-D-ribo-hexopyranosyl]oxy]-12β,14β-dihydroxy-5β-cardiosteroid-20(22)enolactone, molecular formula: C 41 H 64 O 14 , molecular weight: 780.94. Digoxin can effectively strengthen myocardial contractility, slow heart rate, and inhibit cardiac conduction. It is widely used in the clinic to treat various acute and chronic heart failures, and to control the ventricular rate and supraventricular tachycardia of patients with atrial fibrillation and atrial flutter accompanied by rapid ventricular rate.

[0003] Digoxin is a white crystal or crystalline powder, which is easily soluble in pyridine, slightly soluble in dilute alcohol, very slightly soluble in chloroform, and insoluble in water or ether. Rapid dissolution of digoxin is beneficial to improving production efficiency. Since ethanol contains hydroxyl groups, which are polar groups and are similar to water in solubility, especially hydroxyl groups can form hydrogen bonds with water molecules, which greatly increases the solubility of ethanol and water. Therefore, a certain proportion of injection water is mixed with anhydrous ethanol to reduce the dissolution time of digoxin and reduce the risk of ethanol volatilization during the production process. Summary of the invention

[0004] The object of the present invention is to overcome at least one disadvantage of the prior art and provide a method for preparing digoxin injection.

[0005] The technical solution adopted by the present invention is: The invention provides a preparation method of digoxin injection: firstly, about 30% injection water is used to dissolve anhydrous citric acid and anhydrous disodium hydrogen phosphate, then anhydrous ethanol and propylene glycol (for injection) are added and stirred until no obvious stratification occurs, and finally digoxin is added and stirred to dissolve to obtain digoxin injection.

[0006] The preparation method of digoxin injection provided by the present invention specifically comprises the following steps: 1) First, dissolve anhydrous citric acid and anhydrous disodium hydrogen phosphate in 30% water for injection to obtain a pH regulator solution; 2) Then add anhydrous ethanol and propylene glycol (for injection) and stir until no obvious stratification occurs; 3) Finally, add digoxin and stir to dissolve to obtain digoxin solution. 4) Add water to the digoxin solution in step 3 to make up the volume, then filter, fill and sterilize to obtain digoxin injection.

[0007] In some examples, the amount of water used for about 30% of the injection solution in step 1) is 150 g / L.

[0008] In some examples, the amount of anhydrous citric acid used in step 1) is 0.8 g / L, and the amount of anhydrous disodium hydrogen phosphate used is 1.7 g / L.

[0009] In some examples, the amount of anhydrous ethanol used in step 2) is 79.1 g / L, and the amount of propylene glycol (for injection) used is 414.4 g / L.

[0010] In some examples, the amount of digoxin used in step 3) is 0.28 g / L.

[0011] In some examples, the pH adjuster in step 1) is anhydrous citric acid and anhydrous disodium hydrogen phosphate.

[0012] In some examples, the dissolving temperature in step 1) is 20-30°C.

[0013] In some examples, the Chinese medicine liquid in step 3) is sterile filtered through 0.45 μm and 0.22 μm cartridge PES filter elements into a storage tank, and then sterile filtered through 0.22 μm cartridge PES filter element into a buffer tank, and the material filtration cycle is performed 4 times between the storage tank and the buffer tank.

[0014] In some examples, the sterilization temperature in step 3) is 121°C.

[0015] The beneficial effects of the present invention are: The present invention provides a preparation process of digoxin injection, which can quickly dissolve digoxin. Since ethanol contains hydroxyl groups, which are polar groups and are similar to water in solubility, especially hydroxyl groups can form hydrogen bonds with water molecules, which greatly improves the mutual solubility of ethanol and water. Therefore, a certain proportion of injection water and anhydrous ethanol are mixed, thereby reducing the dissolution time of digoxin and reducing the risk of ethanol volatilization in the production process. DETAILED DESCRIPTION

[0016] The present invention provides a production process example to illustrate

[0017] Example 1

[0018] Weighing: According to the prescribed amount, weigh the prescribed amount of anhydrous citric acid, anhydrous disodium hydrogen phosphate, anhydrous ethanol, propylene glycol (for injection), and digoxin respectively.

[0019] Inject about 30% of the total water volume into the preparation tank, turn on the upper mechanical stirrer to stir at 42rpm, the lower magnetic stirrer to stir at 200rpm, and control the temperature of the water for injection at 20-30℃. Add anhydrous citric acid and anhydrous disodium hydrogen phosphate into the preparation tank and stir until they are completely dissolved visually. Then add anhydrous ethanol and propylene glycol (for injection) into the preparation tank, close the preparation tank and the feed port, and stir until there is no obvious stratification visually. Finally, add digoxin into the preparation tank and stir for 50 minutes. After stirring, add 20℃-30℃ water for injection to the preparation tank to the full amount and stir for 10 minutes.

[0020] The liquid medicine was sterilized and filtered through the 0.45μm and 0.22μm cartridge PES filter elements to the storage tank. The magnetic stirrer was turned on and stirred at a speed of 250rpm until the liquid level was lower than the magnetic stirrer and the stirring was stopped. The liquid medicine was sterilized and filtered through the 0.22μm cartridge PES filter element to the buffer tank, and the material filtration cycle was performed 4 times between the liquid storage tank and the buffer tank.

[0021] The product is finally sterilized, water bath sterilization temperature: 121°C, sterilization time: 15 minutes, Fo value ≥ 12.0.

[0022] The above is a further detailed description of the present invention, which should not be regarded as a limitation on the specific implementation of the present invention. For ordinary technicians in the technical field of the present invention, simple deduction or replacement without departing from the concept of the present invention is within the protection scope of the present invention.

Claims

1. A method for preparing digoxin injection, characterized in that: First, use about 30% injection water to dissolve anhydrous citric acid and anhydrous disodium hydrogen phosphate, then add anhydrous ethanol and propylene glycol (for injection solution) and stir until no obvious stratification occurs. Finally, add digoxin and stir to dissolve to obtain digoxin injection.

2. The preparation method according to claim 1, characterized in that: The following steps are involved: 1) First, dissolve anhydrous citric acid and anhydrous disodium hydrogen phosphate in 30% water for injection to obtain a pH regulator solution; 2) Then add anhydrous ethanol and propylene glycol (for injection) and stir until no obvious stratification occurs; 3) Finally, add digoxin and stir to dissolve to obtain digoxin solution. 4) Add water to the digoxin solution in step 3 to make up the volume, then filter, fill and sterilize to obtain digoxin injection.

3. The preparation method according to claim 2, characterized in that: In the step 1), the water consumption of about 30% injection solution is 150 g / L.

4. The preparation method according to claim 2, characterized in that: In the step 1), the amount of anhydrous citric acid used is 0.8 g / L, and the amount of anhydrous disodium hydrogen phosphate used is 1.7 g / L.

5. The preparation method according to claim 2, characterized in that: In the step 2), the amount of anhydrous ethanol used is 79.1 g / L, and the amount of propylene glycol (for injection) used is 414.4 g / L.

6. The preparation method according to claim 2, characterized in that: The digoxin dosage in step 3) is 0.28 g / L.

7. The preparation method according to any one of claims 2 to 6, characterized in that: The pH regulator in step 1) is anhydrous citric acid and anhydrous disodium hydrogen phosphate.

8. The preparation method according to any one of claims 2 to 6, characterized in that: The dissolving temperature in step 1) is 20-30°C.

9. The preparation method according to any one of claims 2 to 6, characterized in that: In the step 3), the Chinese medicine liquid is sterilized and filtered through 0.45 μm and 0.22 μm cylindrical PES filter elements to a storage tank, and then sterilized and filtered through 0.22 μm cylindrical PES filter element to a buffer tank, and the material filtration cycle is performed 4 times between the liquid storage tank and the buffer tank.

10. The preparation method according to any one of claims 2 to 6, characterized in that: The sterilization temperature in step 3) is 121°C.