A method for preparing a clindamycin phosphate topical solution

Abstract

The application provides a clindamycin phosphate external solution and a preparation method thereof. The clindamycin phosphate external solution has good stability and simple preparation process, and can be mass-produced by adding sodium hydroxide and triethanolamine in the solution preparation process and using polyvinylidene fluoride (PVDF) as a filter membrane material.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a clindamycin phosphate external solution and its preparation method. Background Technology

[0002] Clindamycin, also known as clindamycin, was first synthesized by Upjohn in 1966 and patented in the United States in 1969. Clindamycin phosphate is commonly used clinically; its chemical formula is C10. 18 H 34 ClN2O8PS is an antibiotic. It has no antibacterial activity in vitro, but it rapidly hydrolyzes into clindamycin in the body, thus exhibiting its pharmacological activity. Therefore, its antibacterial spectrum, antibacterial activity, and therapeutic effect are the same as clindamycin, but its lipid solubility and permeability are superior to clindamycin. It can be administered orally, intramuscularly, or intravenously. Its structural formula is as follows:

[0003]

[0004] Clindamycin phosphate contains ester bonds, thiomethyl groups, and halogenated groups, making it prone to hydrolysis, oxidation, substitution, elimination, and rearrangement reactions. The presence of sulfur atoms in the molecule makes it susceptible to oxidation to produce high-valence sulfur, or to hydrolysis of the phosphate ester bonds and thiomethyl groups under acidic conditions. Under alkaline conditions or when heated, the compound readily undergoes halogen hydrolysis and elimination reactions, and isomerization reactions also occur. The solubility of clindamycin phosphate active pharmaceutical ingredient (API) is pH-dependent, requiring a large amount of sodium hydroxide to adjust the pH of the solution during preparation for complete dissolution. Furthermore, its structural formula reveals thermal instability; it cannot withstand terminal sterilization and can only be sterilized by filtration. Therefore, the stability of clindamycin phosphate aqueous solutions has been a long-standing problem requiring resolution. Summary of the Invention

[0005] To overcome the above technical problems, the present invention provides a method for preparing clindamycin phosphate external solution. By adding sodium hydroxide and triethanolamine during the solution preparation process, and using polyvinylidene fluoride (PVDF) as the filter membrane material, the stability problem of clindamycin phosphate external solution is solved.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: a clindamycin phosphate external solution, wherein each 1000ml of solution contains 170g of clindamycin phosphate, 5-12g of triethanolamine, 1.5-3g of sodium hydroxide, and the remainder is water for injection, with a pH value of 6.0-6.5.

[0007] Preferably, the clindamycin phosphate external solution contains, per 1000 ml, 170 g of clindamycin phosphate, 7-10 g of triethanolamine, 2-2.8 g of sodium hydroxide, with the remainder being water for injection, and a pH value of 6.1-6.4.

[0008] More preferably, each 1000 ml of the clindamycin phosphate external solution contains 170 g of clindamycin phosphate, 8.6 g of triethanolamine, 2.5 g of sodium hydroxide, and the remainder is water for injection.

[0009] This invention also relates to a method for preparing clindamycin phosphate topical solution, comprising the following preparation steps:

[0010] Add 70-90% water for injection to the mixing tank, add the prescribed amount of triethanolamine and sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, dilute to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm PVDF membranes respectively, and fill into bottles to obtain clindamycin phosphate external solution.

[0011] This invention provides a clindamycin phosphate external solution with good stability by adding sodium hydroxide and triethanolamine during solution preparation and using polyvinylidene fluoride (PVDF) as the filter membrane material. The preparation process is simple and can be scaled up for production. Detailed Implementation

[0012] To enable those skilled in the art to better understand the technical solution of the present invention, the present invention will be further described in detail below with reference to specific embodiments.

[0013] Example 1

[0014] Raw material names Prescription dosage Clindamycin phosphate 170g Triethanolamine 7.5g Sodium hydroxide 2.8g Water for Injection Add to 1000ml

[0015] Preparation method: Add 90% water for injection to the mixing tank, add the prescribed amount of triethanolamine and sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, dilute to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill into bottles to obtain clindamycin phosphate external solution.

[0016] Example 2

[0017] Raw material names Prescription dosage Clindamycin phosphate 170g Triethanolamine 8.6g Sodium hydroxide 2.5g Water for Injection Add to 1000ml

[0018] Preparation method: Add 85% water for injection to a mixing tank, add the prescribed amount of triethanolamine and sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, dilute to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill into bottles to obtain clindamycin phosphate external solution.

[0019] Example 3

[0020] Raw material names Prescription dosage Clindamycin phosphate 170g Triethanolamine 9.2g Sodium hydroxide 2.3g Water for Injection Add to 1000ml

[0021] Preparation method: Add 80% water for injection to the mixing tank, add the prescribed amount of triethanolamine and sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, dilute to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill into bottles to obtain clindamycin phosphate external solution.

[0022] Comparative Example 1

[0023] Raw material names Prescription dosage Clindamycin phosphate 170g Sodium hydroxide 3.46g Water for Injection Add to 1000ml

[0024] Preparation method: Add 85% water for injection to the mixing tank, add the prescribed amount of sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, dilute to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill into bottles to obtain clindamycin phosphate external solution.

[0025] Comparative Example 2

[0026] Raw material names Prescription dosage Clindamycin phosphate 170g ammonia 2.7g Sodium hydroxide 2.5g Water for Injection Add to 1000ml

[0027] Preparation method: Add 85% water for injection to a mixing tank, add the prescribed amount of ammonia and sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, dilute to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm PVDF membranes respectively, and fill into bottles to obtain clindamycin phosphate external solution.

[0028] Comparative Example 3

[0029]

[0030]

[0031] Preparation method: Add 85% water for injection to a mixing tank, add the prescribed amount of diethylamine and sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, dilute to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill into bottles to obtain clindamycin phosphate external solution.

[0032] Comparative Example 4

[0033] Raw material names Prescription dosage Clindamycin phosphate 170g Triethanolamine 8.6g Sodium hydroxide 2.5g Water for Injection Add to 1000ml

[0034] Preparation method: Add 85% water for injection to the mixing tank, add the prescribed amount of triethanolamine and sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, dilute to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm polyethersulfone (PES) filter membranes respectively, and fill into bottles to obtain clindamycin phosphate external solution.

[0035] Comparative Example 5

[0036] Raw material names Prescription dosage Clindamycin phosphate 170g Triethanolamine 8.6g Sodium hydroxide 2.5g Water for Injection Add to 1000ml

[0037] Preparation method: Add 85% water for injection to a mixing tank, add the prescribed amount of triethanolamine and sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, dilute to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm polytetrafluoroethylene (PTFE) filter membranes respectively, and fill into bottles to obtain clindamycin phosphate external solution.

[0038] Accelerated stability test

[0039] The clindamycin phosphate external solutions of Examples 1-3 and Comparative Examples 1-5 were placed at 40°C, and samples were taken at 0, 5, and 10 days to test relevant items.

[0040] Long-term stability test

[0041] The clindamycin phosphate topical solutions of Examples 1-3 and Comparative Examples 1-5 were placed at 25°C, and samples were taken at 0, 12, and 24 months to test relevant items.

[0042] The results are shown in the table below:

[0043]

[0044]

[0045] The results show that Comparative Example 1, which used only sodium hydroxide to prepare the clindamycin phosphate external solution, exhibited rapid impurity growth, decreased content, and unstable quality under accelerated and long-term stability test conditions. Comparative Example 2, which added ammonia and sodium hydroxide during solution preparation, and Comparative Example 3, which added diethylamine and sodium hydroxide, showed increased impurities, decreased content, and unstable quality under accelerated and long-term stability test conditions. Comparative Examples 4-5, which used PES and PTFE membranes respectively, affected the product content, and showed increased impurities and unstable quality under accelerated and long-term stability test conditions. In contrast, Examples 1-3, which added sodium hydroxide and triethanolamine during solution preparation and used PVDF membranes, produced clindamycin phosphate external solutions that showed stable quality under accelerated and long-term stability test conditions.

[0046] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Equivalent substitutions or modifications made by those skilled in the art based on the present invention without departing from the essence of the present invention are all within the protection scope of the present invention.

Claims

1. A method for preparing a clindamycin phosphate topical solution, characterized by, The preparation steps include: adding 70-90% water for injection to a mixing tank, adding the prescribed amount of triethanolamine and sodium hydroxide, stirring to dissolve, then adding the prescribed amount of clindamycin phosphate, stirring until completely dissolved, making up to volume with water for injection, measuring the pH value, filtering through 0.45μm and 0.22μm PVDF membranes respectively, and filling to obtain clindamycin phosphate external solution; each 1000ml external solution contains 170g of clindamycin phosphate, 5-12g of triethanolamine, 1.5-3g of sodium hydroxide, and the balance being water for injection, with a pH value of 6.0-6.

5.

2. The method of preparing clindamycin phosphate topical solution according to claim 1, wherein Each 1000ml external solution contains 170g clindamycin phosphate, 7-10g triethanolamine, 2-2.8g sodium hydroxide, and the remainder is water for injection with a pH of 6.1-6.

4.

3. The method of preparing clindamycin phosphate topical solution according to claim 2, wherein Each 1000ml external solution contains 170g clindamycin phosphate, 8.6g triethanolamine, 2.5g sodium hydroxide, and the remainder is water for injection.

4. The method of preparing clindamycin phosphate topical solution according to any one of claims 1 to 3, wherein Add 85% water for injection to the solution preparation tank.

5. The method of preparing clindamycin phosphate topical solution according to any one of claims 1 to 3, wherein The temperature of the water for injection is 10-30℃.

6. The clindamycin phosphate external solution prepared by the preparation method according to any one of claims 1-5.

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