A clindamycin phosphate injection solution and a method of preparing the same
By using Zn-OC bonded activated carbon, the contradiction between impurity removal and drug purity in clindamycin phosphate injection solution was resolved, achieving effective impurity removal and drug content maintenance, thus improving the preparation process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- NANYANG PUKANG HENGWANG PHARM CO LTD
- Filing Date
- 2026-03-30
- Publication Date
- 2026-05-29
AI Technical Summary
In the preparation of existing clindamycin phosphate injection solutions, although increasing the amount of activated carbon can reduce impurities, it also leads to a decrease in the clindamycin phosphate content, making it difficult to effectively remove impurities while ensuring drug purity.
Zn-OC bonded activated carbon is used. The activated carbon is oxidized at low temperature with low concentration of nitric acid and carboxyl/hydroxyl groups are introduced. Combined with ZnO nanoparticles, a stable Zn-OC bonded interface is formed by calcination. This interface adsorbs acidic/neutral impurities and hinders the selective adsorption of clindamycin phosphate.
This effectively reduced the impurity content in clindamycin phosphate injection solution while maintaining or increasing the clindamycin phosphate content, thus achieving high-purity drug preparation.
Smart Images
Figure CN122097259A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of injection technology, specifically relating to a clindamycin phosphate injection solution and its preparation method. Background Technology
[0002] Clindamycin phosphate injection is a colorless or slightly yellow clear liquid whose main component is clindamycin phosphate. Clinically, it is mainly used to treat various infectious diseases caused by Gram-positive bacteria and anaerobic bacteria. It has no antibacterial activity in vitro. Clindamycin phosphate belongs to the lincosamide class of antibiotics and is a semi-synthetic derivative of clindamycin. Currently, clindamycin phosphate injection is receiving widespread attention in clinical applications.
[0003] The quality of clindamycin phosphate injection solution depends primarily on its preparation and production process. Activated carbon added during production serves to adsorb impurities and remove pyrogens. Within a certain range, as the amount of activated carbon added increases, the amount of related substances (impurities) decreases. However, at the same time, because activated carbon also adsorbs clindamycin phosphate, the clindamycin phosphate content in the final clindamycin phosphate injection solution will decrease. Summary of the Invention
[0004] To address the problems existing in the background art, the present invention provides a clindamycin phosphate injection solution and its preparation method, which increases the clindamycin phosphate content by increasing the amount of activated carbon used, thereby reducing related substances (total impurities).
[0005] To achieve the above objectives, in a first aspect, the present invention provides a method for preparing clindamycin phosphate injection solution, comprising the following steps:
[0006] S1. Take 75-85 mL of water for injection, add (0.5-0.6) g of clindamycin phosphate, stir to dissolve, then add the stabilizer, continue stirring to dissolve, and obtain the base solution;
[0007] S2. Add Zn-OC bonded activated carbon to the base solution obtained in S1, adjust the pH to 5.3-5.5, then add 15-25 mL of water for injection, stir, and filter to obtain the clindamycin phosphate injection solution.
[0008] Furthermore, the preparation method of the Zn-OC bonded activated carbon is as follows:
[0009] A1. Immerse activated carbon in a 15-18 wt% nitric acid solution and stir for 2-3 hours to obtain acid-impregnated carbon;
[0010] A2. Add ZnO nanoparticles to the acid-leached carbon obtained in A1. The mass of ZnO nanoparticles is 3% of the mass of activated carbon. Calcine at 600℃ for 40 min in a nitrogen atmosphere to obtain Zn-OC bonded activated carbon.
[0011] Furthermore, in A1, the mass ratio of the activated carbon to the nitric acid solution is 1:(3-5).
[0012] Furthermore, in A2, the mass of the ZnO nanoparticles is 3-5% of the mass of the activated carbon.
[0013] Furthermore, the ratio of the mass of the Zn-OC bonded activated carbon to the total volume of water for injection is (0.14–0.16) g: 100 mL.
[0014] Furthermore, the stabilizer is sodium calcium edetate.
[0015] Furthermore, the ratio of the mass of the stabilizer to the total volume of water for injection is (0.01-0.02) g: 100 mL.
[0016] Furthermore, in S2, the pH is adjusted using sodium hydroxide solution.
[0017] Secondly, the present invention provides a clindamycin phosphate injection solution, which is prepared by the above-described preparation method.
[0018] This application has the following beneficial effects:
[0019] The present invention uses Zn-OC bonded activated carbon in the preparation of clindamycin phosphate injection solution. The activated carbon is oxidized at low temperature with low concentration nitric acid to introduce an appropriate amount of carboxyl / hydroxyl groups; then calcined under inert gas protection to stabilize functional groups and remove strong acid sites. It can retain appropriate polarity to adsorb acidic / neutral impurities (such as degradation products) and can avoid chemical adsorption of clindamycin phosphate due to excessive oxidation, thereby reducing the selective adsorption of clindamycin phosphate.
[0020] Meanwhile, ZnO nanoparticles are introduced for co-calcination to form a Zn-OC bonding interface; ZnO provides Lewis acid sites, preferentially adsorbing phosphorus-containing impurities (such as inorganic phosphates), and its steric hindrance effect prevents clindamycin phosphate from approaching the surface, further reducing the selective adsorption of clindamycin phosphate. Attached Figure Description
[0021] Figure 1 This is a comparative trend chart of related substances (total impurities) data for clindamycin phosphate injection solutions prepared in Examples 1-3 and Comparative Examples 1-3 of the present invention.
[0022] Figure 2This is a comparative trend chart showing the clindamycin phosphate content data of clindamycin phosphate injection solutions prepared in Examples 1-3 and Comparative Examples 1-3 of the present invention. Detailed Implementation
[0023] The present application will be further described in detail below with reference to the embodiments.
[0024] Unless otherwise specified, the raw materials used in the embodiments and comparative examples of this application are all commercially available.
[0025] Example 1: (a) Preparation of Zn-OC bonded activated carbon, the preparation method is as follows:
[0026] A1. Accurately weigh 10g of activated carbon and immerse it in a 16wt% nitric acid solution, with a mass ratio of activated carbon to nitric acid solution of 1:4. At room temperature (approximately 25℃), stir the mixture at 250rpm for 2.5 hours using a mechanical stirrer. During stirring, ensure the activated carbon is evenly dispersed in the nitric acid solution, allowing the activated carbon surface to fully contact the nitric acid and undergo oxidation and other reactions. After the reaction is complete, filter the mixture and wash it repeatedly with deionized water until the washing solution is neutral (pH test paper test). This process removes residual nitric acid and other impurities, yielding acid-impregnated carbon. Place the washed acid-impregnated carbon in a vacuum drying oven and dry it at 60℃ for 12 hours to remove moisture.
[0027] Acid leaching with nitric acid solution increases the number of oxygen-containing functional groups, such as carboxyl and hydroxyl groups, on the surface of activated carbon, thereby improving its surface activity and facilitating subsequent bonding with ZnO nanoparticles. Simultaneously, appropriate stirring and reaction time ensure the uniformity and stability of the treatment effect.
[0028] A2. Add ZnO nanoparticles to the acid-leached carbon obtained in A1, with the mass of ZnO nanoparticles being 3.5% of the mass of the acid-leached carbon; calcine at 600℃ for 45 min in an inert atmosphere. Specifically, place the mixed sample into a tube furnace, introduce inert gas (nitrogen) at a flow rate controlled at 70 mL / min to purge air from the furnace, and then raise the temperature to 600℃ at a rate of 10℃ / min, holding at this temperature for 45 min; after calcine, stop heating, continue to introduce inert gas, and after the tube furnace cools naturally to room temperature, remove the sample to obtain Zn-OC bonded activated carbon.
[0029] Calcination in an inert atmosphere can prevent the oxidation of ZnO nanoparticles and ensure the stability of their chemical properties. Appropriate calcination temperature and time can promote the chemical reaction between ZnO nanoparticles and oxygen-containing functional groups on the surface of activated carbon to form stable Zn-OC bonds, thereby improving the adsorption performance and catalytic activity of activated carbon.
[0030] (II) A method for preparing a clindamycin phosphate injection solution, comprising the following steps:
[0031] S1. Take 80 mL of water for injection and pour it into a clean solution preparation container. Slowly add 0.55 g of clindamycin phosphate to the solution and start stirring. Stir at 220 rpm for 20 min until the clindamycin phosphate is completely dissolved. Then weigh 0.015 g of the stabilizer sodium edetate and add it to the above solution. Continue stirring for 20 min to fully dissolve the sodium edetate and obtain the base solution.
[0032] Dissolving clindamycin phosphate first, followed by adding a stabilizer, helps to ensure uniform dispersion of drug molecules. The stabilizer can then play a stabilizing role in a timely manner, preventing adverse reactions such as drug degradation in subsequent processes and ensuring drug stability.
[0033] S2. Add 0.15g of Zn-OC bonded activated carbon (equivalent to 0.15% under 100mL water for injection) to the base solution obtained in S1. Start stirring again and stir at 300rpm for 10min to ensure that the activated carbon and base solution are fully mixed. Adjust the pH with sodium hydroxide solution (0.2mol / L) by adding it dropwise while stirring. After adjusting the pH to 5.4, add 20mL of water for injection and continue stirring for 5min to ensure that the solution is mixed evenly. Then filter the solution through a 0.22μm microporous membrane and collect the filtrate to obtain clindamycin phosphate injection solution.
[0034] Example 2: The difference between this example and Example 1 is that a method for preparing clindamycin phosphate injection solution includes the following steps:
[0035] S1. Take 75 mL of water for injection, add 0.5 g of clindamycin phosphate, stir to dissolve, then add 0.01 g of the stabilizer sodium edetate, and continue stirring to dissolve to obtain the base solution.
[0036] S2. Add 0.14g of Zn-OC bonded activated carbon (equivalent to 0.14% under 100mL water for injection) to the base solution obtained in S1. Adjust the pH to 5.4 with sodium hydroxide solution, then add 25mL of water for injection, stir, and filter to obtain clindamycin phosphate injection solution.
[0037] Example 3: The difference between this example and Example 1 is that a method for preparing clindamycin phosphate injection solution includes the following steps:
[0038] S1. Take 85 mL of water for injection, add 0.6 g of clindamycin phosphate, stir to dissolve, then add 0.02 g of stabilizer sodium edetate, and continue stirring to dissolve to obtain the base solution.
[0039] S2. Add 0.16g of Zn-OC bonded activated carbon (equivalent to 0.16% under 100mL water for injection) to the base solution obtained in S1. Adjust the pH to 5.4 with sodium hydroxide solution, then add 15mL of water for injection, stir, and filter to obtain clindamycin phosphate injection solution.
[0040] Comparative Example 1: The difference between this comparative example and Example 1 is that 0.15g of Zn-OC bonded activated carbon was replaced with 0.1g of activated carbon (equivalent to 0.1% under 100mL water for injection conditions).
[0041] Specifically, a method for preparing a clindamycin phosphate injection solution includes the following steps:
[0042] S1. Take 80 mL of water for injection, add 0.55 g of clindamycin phosphate, stir to dissolve, then add 0.015 g of stabilizer sodium edetate, and continue stirring to dissolve to obtain the base solution.
[0043] S2. Add 0.1g of activated carbon (equivalent to 0.1% under 100mL water for injection) to the base solution obtained in S1. Adjust the pH to 5.4 with sodium hydroxide solution, then add 20mL of water for injection, stir, and filter to obtain clindamycin phosphate injection solution.
[0044] Comparative Example 2: The difference between this comparative example and Example 1 is that 0.15g of Zn-OC bonded activated carbon was replaced with 0.15g of activated carbon (equivalent to 0.15% under 100mL water for injection conditions).
[0045] Specifically, a method for preparing a clindamycin phosphate injection solution includes the following steps:
[0046] S1. Take 80 mL of water for injection, add 0.55 g of clindamycin phosphate, stir to dissolve, then add 0.015 g of stabilizer sodium edetate, and continue stirring to dissolve to obtain the base solution.
[0047] S2. Add 0.15g of activated carbon (equivalent to 0.15% under 100mL water for injection) to the base solution obtained in S1. Adjust the pH to 5.4 with sodium hydroxide solution, then add 20mL of water for injection, stir, and filter to obtain clindamycin phosphate injection solution.
[0048] Comparative Example 3: The difference between this comparative example and Example 1 is that 0.15g of Zn-OC bonded activated carbon was replaced with 0.1g of Zn-OC bonded activated carbon (equivalent to 0.1% under 100mL water for injection conditions).
[0049] Specifically, a method for preparing a clindamycin phosphate injection solution includes the following steps:
[0050] S1. Take 80 mL of water for injection, add 0.55 g of clindamycin phosphate, stir to dissolve, then add 0.015 g of stabilizer sodium edetate, and continue stirring to dissolve to obtain the base solution.
[0051] S2. Add 0.1g of Zn-OC bonded activated carbon (equivalent to 0.1% under 100mL water for injection) to the base solution obtained in S1. Adjust the pH to 5.4 with sodium hydroxide solution, then add 20mL of water for injection, stir, and filter to obtain clindamycin phosphate injection solution.
[0052] Experimental Example: Experimental Subjects: Clindamycin phosphate injection solutions prepared in Examples 1-3 and Comparative Examples 1-3. Experimental Items: ① Determination of related substances (total impurities): determined by HPLC. ② Determination of clindamycin phosphate content: determined by HPLC, with the content expressed as clindamycin; octadecylsilane-bonded silica gel was used as the packing material; the mobile phase was potassium dihydrogen phosphate solution (10.54 g of potassium dihydrogen phosphate was dissolved in 775 mL of water, and the pH was adjusted to 2.5 with phosphoric acid) - acetonitrile (775:225); the detection wavelength was 210 nm. Experimental Results: See Table 1.
[0053] Table 1. Experimental Data
[0054] Related substances (total impurities) / % Clindamycin phosphate content / % Example 1 3.14 97.5 Example 2 3.15 97.5 Example 3 3.12 97.4 Comparative Example 1 3.36 96.4 Comparative Example 2 3.26 95.6 Comparative Example 3 3.29 97.8
[0055] Results Analysis: Combining the data in Table 1 and... Figures 1-2 Analysis of Examples 1-3 shows that the total impurities (related substances) of the clindamycin phosphate injection solution prepared by the present invention (Examples 1-3) are as low as 3.15%, and the clindamycin phosphate content is as high as 97.4% or more.
[0056] Combining the data in Table 1 and Figures 1-2 The analysis focused on Example 1 and Comparative Examples 1-3:
[0057] Specifically, comparing Comparative Examples 1 and 2, it can be seen that compared to Comparative Example 1 where 0.1% activated carbon was added, Comparative Example 2 increased the amount of activated carbon to 0.15%. As a result, the related substances (total impurities) in the prepared clindamycin phosphate injection solution decreased from 3.36% (Comparative Example 1) to 3.26% (Comparative Example 2). However, at the same time, the clindamycin phosphate content decreased from 96.4% (Comparative Example 1) to 95.6% (Comparative Example 2). This indicates that increasing the amount of activated carbon added from 0.1% to 0.15% can reduce the related substances (total impurities) in the prepared clindamycin phosphate injection solution, but it also leads to a decrease in the clindamycin phosphate content.
[0058] This is mainly because increasing the amount of activated carbon can reduce the amount of related substances (total impurities) through adsorption; however, at the same time, since activated carbon also has an adsorption effect on clindamycin phosphate, it will lead to a decrease in the clindamycin phosphate content in the final clindamycin phosphate injection solution.
[0059] Specifically, comparing Comparative Examples 1 and 3, it was found that compared to Comparative Example 1 which added 0.1% activated carbon, Comparative Example 3 added 0.1% Zn-OC bonded activated carbon. As a result, the related substances (total impurities) in the prepared clindamycin phosphate injection solution decreased from 3.36% (Comparative Example 1) to 3.29% (Comparative Example 3), and the clindamycin phosphate content increased from 96.4% (Comparative Example 1) to 97.8% (Comparative Example 3). This indicates that replacing activated carbon with Zn-OC bonded activated carbon can reduce the related substances (total impurities) in the prepared clindamycin phosphate injection solution and increase its clindamycin phosphate content.
[0060] Comparing with Example 1, it can be seen that further increasing the amount of Zn-OC bonded activated carbon to 0.15% further reduces the related substances (total impurities) in the prepared clindamycin phosphate injection solution to 3.14%, while maintaining the clindamycin phosphate content at 97.5% without significant change. This indicates that at this dosage, Zn-OC bonded activated carbon is more effective in reducing the related substances (total impurities) in the prepared clindamycin phosphate injection solution while simultaneously increasing its clindamycin phosphate content.
[0061] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.
[0062] Furthermore, various different embodiments of the present invention can be combined in any way, as long as they do not violate the spirit of the present invention, they should also be regarded as the content disclosed by the present invention.
Claims
1. A method for preparing clindamycin phosphate injection solution, characterized in that, Includes the following steps: S1. Take 75-85 mL of water for injection, add (0.5-0.6) g of clindamycin phosphate, stir to dissolve, then add the stabilizer, continue stirring to dissolve, and obtain the base solution; S2. Add Zn-OC bonded activated carbon to the base solution obtained in S1, adjust the pH to 5.3-5.5, then add 15-25 mL of water for injection, stir, and filter to obtain the clindamycin phosphate injection solution.
2. The method for preparing clindamycin phosphate injection solution according to claim 1, characterized in that, The preparation method of the Zn-OC bonded activated carbon is as follows: A1. Immerse activated carbon in a 15-18 wt% nitric acid solution and stir for 2-3 hours to obtain acid-impregnated carbon; A2. Add ZnO nanoparticles to the acid-leached carbon obtained in A1, and calcine at 600±10℃ for 30-50 min in an inert atmosphere to obtain the Zn-OC bonded activated carbon.
3. The method for preparing clindamycin phosphate injection solution according to claim 2, characterized in that, In A1, the mass ratio of activated carbon to nitric acid solution is 1:(3-5).
4. The method for preparing clindamycin phosphate injection solution according to claim 1, characterized in that, In A2, the mass of the ZnO nanoparticles is 3-5% of the mass of the activated carbon.
5. The method for preparing clindamycin phosphate injection solution according to claim 1, characterized in that, The ratio of the mass of the Zn-OC bonded activated carbon to the total volume of water for injection is (0.14-0.16) g: 100 mL.
6. The method for preparing clindamycin phosphate injection solution according to claim 1, characterized in that, The stabilizer is sodium calcium edetate.
7. The method for preparing clindamycin phosphate injection solution according to claim 1 or 6, characterized in that, The ratio of the mass of the stabilizer to the total volume of water for injection is (0.01-0.02) g: 100 mL.
8. The method for preparing clindamycin phosphate injection solution according to claim 1, characterized in that, In S2, the pH is adjusted using sodium hydroxide solution.
9. A clindamycin phosphate injection solution, characterized in that, It is prepared by the preparation method described in any one of claims 1 to 8.