Preparation method of clindamycin phosphate external solution

Abstract

According to the clindamycin phosphate external solution and the preparation method thereof, sodium hydroxide and triethanolamine are added in the solution preparation process, meanwhile, a filter membrane is made of polyvinylidene fluoride (PVDF), the prepared clindamycin phosphate external solution has good stability, the preparation process is simple, and large-scale production can be achieved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a clindamycin phosphate external solution and a preparation method thereof. Background Art

[0002] Clindamycin, also known as chloramphenicol, was first synthesized by the American company Upjohn in 1966 and patented in the United States in 1969. Clindamycin phosphate is commonly used in clinical practice. The chemical formula of clindamycin phosphate is C 18 H 34 ClN2O8PS is an antibiotic drug with no antibacterial activity in vitro. It is rapidly hydrolyzed into clindamycin after entering the body and shows its pharmacological activity. Therefore, its antibacterial spectrum, antibacterial activity and therapeutic effect are the same as those of clindamycin, but its fat solubility and permeability are better than those of clindamycin. It can be taken orally, or by intramuscular injection or intravenous drip. Its structural formula is as follows:

[0003]

[0004] Clindamycin phosphate contains active groups such as ester bond, thiomethyl, halogen, etc., which are prone to hydrolysis, oxidation, substitution, elimination, and rearrangement reactions. The molecule contains a sulfur atom, which is easily oxidized to produce high-valent sulfur, or the phosphate bond and thiomethyl are easily hydrolyzed under acidic conditions, and the compound is prone to halogen hydrolysis and elimination reactions when alkaline or heated, and isomerization reactions also occur in addition. The solubility of clindamycin phosphate bulk drug has pH dependence, and a large amount of sodium hydroxide is required to adjust the pH of the drug solution during the liquid preparation process so that the bulk drug can be fully dissolved. In addition, as can be seen from the structural formula, it is unstable to heat and cannot tolerate terminal sterilization, and can only adopt a filtration and sterilization process. Therefore, the stability problem of the clindamycin phosphate aqueous solution has always been a problem that needs to be solved for a long time. Summary of the invention

[0005] In order to overcome the above technical problems, the present invention provides a method for preparing a clindamycin phosphate topical solution, which solves the stability problem of the clindamycin phosphate topical solution by adding sodium hydroxide and triethanolamine during the solution preparation process and using polyvinylidene fluoride (PVDF) as the filter membrane material.

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

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

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

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

[0010] Add 70-90% injection water to a liquid preparation 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, make up to volume with injection water, measure the pH value, filter through 0.45 μm and 0.22 μm PVDF filter membranes respectively, and fill to obtain a clindamycin phosphate external solution.

[0011] The invention adds sodium hydroxide and triethanolamine in the process of preparing the solution, and adopts polyvinylidene fluoride (PVDF) as the filtering membrane material, so as to prepare the clindamycin phosphate external-use solution, which has good stability, simple preparation process and can be scaled up for production. DETAILED DESCRIPTION

[0012] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is further described in detail below in conjunction with specific embodiments.

[0013] Example 1

[0014] Name of raw materials 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 into a liquid preparation 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, make up to volume with water for injection, determine the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill to obtain clindamycin phosphate external solution.

[0016] Example 2

[0017] Name of raw materials 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 into a liquid preparation 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, make up to volume with water for injection, determine the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill to obtain clindamycin phosphate external solution.

[0019] Example 3

[0020] Name of raw materials 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 into a liquid preparation 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, make up to volume with water for injection, determine the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill to obtain clindamycin phosphate external solution.

[0022] Comparative Example 1

[0023] Name of raw materials Prescription dosage Clindamycin phosphate 170g Sodium hydroxide 3.46g Water for injection Add to 1000ml

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

[0025] Comparative Example 2

[0026] Name of raw materials 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 into a liquid preparation tank, add the prescribed amount of ammonia water and sodium hydroxide, stir to dissolve, then add the prescribed amount of clindamycin phosphate, stir until completely dissolved, make up to volume with water for injection, determine the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill to obtain clindamycin phosphate external solution.

[0028] Comparative Example 3

[0029]

[0030]

[0031] Preparation method: Add 85% water for injection into a liquid preparation 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, make up to volume with water for injection, determine the pH value, filter through 0.45μm and 0.22μm PVDF filter membranes respectively, and fill to obtain clindamycin phosphate external solution.

[0032] Comparative Example 4

[0033] Name of raw materials 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 into a liquid preparation 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, make up to volume with water for injection, measure the pH value, filter through 0.45μm and 0.22μm polyethersulfone (PES) filter membranes respectively, and fill to obtain a clindamycin phosphate external solution.

[0035] Comparative Example 5

[0036] Name of raw materials 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 into a liquid preparation 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, make up to volume with water for injection, determine the pH value, filter through 0.45μm and 0.22μm polytetrafluoroethylene (PTFE) filter membranes respectively, and fill to obtain a clindamycin phosphate external solution.

[0038] Accelerated stability test

[0039] The clindamycin phosphate external-use 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 external-use 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 as follows:

[0043]

[0044]

[0045] As can be seen from the above results, Comparative Example 1 only adopts sodium hydroxide to prepare Clindamycin Phosphate External Use Solution, and the product prepared therefrom has a faster increase of impurities, a lower content, and unstable quality under the conditions of acceleration and long-term stability test. Comparative Example 2 adds ammonia and sodium hydroxide in the solution preparation process, and Comparative Example 3 adds diethylamine and sodium hydroxide in the solution preparation process, and the product prepared therefrom has an increase of impurities, a lower content, and unstable quality under the conditions of acceleration and long-term stability test. Comparative Examples 4-5 adopt PES and PTFE filter membranes to filter the solution respectively, which has an impact on the product content, and the product prepared therefrom has an increase of impurities, and unstable quality under the conditions of acceleration and long-term stability test. While Embodiments 1-3 add sodium hydroxide and triethanolamine in the solution preparation process, and the filtration membrane adopts PVDF at the same time, and the Clindamycin Phosphate External Use Solution prepared therefrom has stable quality under the conditions of acceleration and long-term stability test.

[0046] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any equivalent substitutions or changes made by those skilled in the art on the basis of the present invention without departing from the essential content 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 in that: The method comprises the following preparation steps: adding 70-90% injection water into a liquid preparation tank, adding a prescribed amount of triethanolamine and sodium hydroxide, stirring to dissolve, then adding a prescribed amount of clindamycin phosphate, stirring until completely dissolved, fixing the volume with injection water, measuring the pH value, filtering with a PVDF filter membrane, and filling to obtain a clindamycin phosphate external solution; each 1000 ml external solution comprises 170 g of clindamycin phosphate, 5-12 g of triethanolamine, 1.5-3 g of sodium hydroxide, and the remainder of injection water, and the pH value is 6.0-6.

5.

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

4.

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

4. The method for preparing the clindamycin phosphate topical solution according to any one of claims 1 to 3, characterized in that: The filtration is performed through 0.45 μm and 0.22 μm PVDF filter membranes respectively.

5. The method for preparing the clindamycin phosphate topical solution according to any one of claims 1 to 3, characterized in that: Add 85% water for injection into the preparation tank.

6. The method for preparing the clindamycin phosphate topical solution according to any one of claims 1 to 3, characterized in that: The temperature of the water for injection is 10-30°C.

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

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