Novel method for purifying high-purity clindamycin phosphate
Through the method of combining amide solvent systems and benign solvent systems, the thermal beating of clindamycin phosphate, activated carbon treatment and gradient cooling crystallization of clindamycin phosphate in the prior art has solved the problem of clindamycin phosphate purification in the prior art and achieved high purity Finished clindamycin phosphate.
Patent Information
- Application Number
- CN202311005367.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-08-10
- Publication Date
- 2025-02-18
AI Technical Summary
In the prior art, the crystallization method of clindamycin phosphate is difficult to effectively remove impurity G, resulting in insufficient purity.
The amide solvent system is used to heat beaten, activated carbon treatment in benign solvent systems and gradient cooling and crystallization are gradually improved to gradually improve the purity of clindamycin phosphate.
Through this method, impurity E and other impurities can be effectively removed, the purity of the finished product of clindamycin phosphate can be improved, with a content of more than 98%, and a total miscellaneous content of less than 2.0%.
Smart Images
Figure BDA0004387915170000011 
Figure BDA0004387915170000021 
Figure BDA0004387915170000041
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of raw material drug purification, and particularly relates to a post-processing purification method for clindamycin phosphate. Background Art
[0002] Clindamycin phosphate is a semi-synthetic antibiotic drug. Its chemical name is 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-α-D-pyranosylgalactoside-2-dihydrogen phosphate. Its English name is clindamycin phosphate. Its structural formula is as follows:
[0003]
[0004] Clindamycin phosphate impurity G is referred to as impurity G, and its chemical name is: methyl 6,8-dideoxy-2,4-O-(hydroxyphosphoryl)-6-[[[(2S,4R)-1-methyl-4-propyl-pyrrolidin-2-yl]formyl]amino]-1-thio-D-erythro-α-D-galacto-octanopyranoside, CAS: 1440605-46-8, and its chemical structure is as follows:
[0005]
[0006] Clindamycin phosphate has no antibacterial activity in vitro. It can only exert its pharmacological effect after it is rapidly hydrolyzed into clindamycin after entering the body. Its antibacterial spectrum, antibacterial activity and therapeutic effect are the same as those of clindamycin, but its ester solubility and permeability are 4 to 8 times stronger than those of clindamycin, it is well absorbed, has a high concentration in bone tissue, and has strong antibacterial activity against Gram-positive cocci and anaerobic bacteria.
[0007] The crystallization method of clindamycin phosphate in the prior art is to purify clindamycin phosphate by ethanol crystallization or ethanol / water system recrystallization. Although the above purification method has a good removal effect on most impurities in clindamycin phosphate, it has no good removal effect on impurity G. Therefore, it is necessary to develop a new purification method to obtain high-purity clindamycin phosphate. Summary of the invention
[0008] The invention provides a new method for purifying high-purity clindamycin phosphate, which selectively removes impurities through an amide solvent system and improves the purity of the finished clindamycin phosphate.
[0009] The technical solution adopted to achieve the above invention object is:
[0010] A method for purifying clindamycin phosphate comprises the following steps:
[0011] 1) hot slurrying the crude clindamycin phosphate in an amide solvent system, and performing solid-liquid separation to obtain a wet product of clindamycin phosphate;
[0012] 2) adding the wet clindamycin phosphate obtained in step 1) into a benign solvent system for dissolution, and treating with activated carbon to obtain a clindamycin phosphate decolorized liquid;
[0013] 3) subjecting the clindamycin phosphate decolorizing solution obtained in step 2) to gradient cooling and crystallization to obtain a finished clindamycin phosphate product.
[0014] Wherein, the amide solvent system in step 1) consists of.
[0015] Wherein, the mass ratio of the amide solvent, water and glacial acetic acid is 50-30:1-0.5:0.05-0.025.
[0016] Wherein, the amide solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide and N,N-dimethylbutyramide.
[0017] The hot pulping temperature in step 1 is 70-85°C, preferably 75-82°C.
[0018] Wherein, the hot pulping time in step 1) is 5 to 8 hours, preferably 6 to 7 hours.
[0019] Wherein, the benign solvent system in step 2) consists of a benign solvent and water.
[0020] Wherein, the benign solvent is selected from at least one of methanol, ethanol, acetone, isopropanol and n-butanol.
[0021] Wherein, the volume percentage of the benign solvent system is 65% to 85% aqueous solution.
[0022] Wherein, in step 3), the gradient cooling rate is 0.1-0.3°C / min, and the gradient cooling is to 2-8°C.
[0023] The technical solution of the present invention has at least the following beneficial technical effects:
[0024] The purification method provided by the present invention adopts an amide solvent system. The amide solvent has good solubility for impurity E, but poor solubility for clindamycin phosphate. The purification method provided by the present invention can not only effectively remove impurity E, but also has good removal effect on other impurities. Experimental results show that the content of clindamycin phosphate obtained by the purification method provided by the present invention is more than 98%, the content of impurity E is less than 0.2%, and the total impurity content is less than 2.0%. DETAILED DESCRIPTION
[0025] The present invention will be further described below in conjunction with specific examples. It should be understood that the following examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.
[0026] The crude products used in the following experiments were obtained by the traditional synthesis method: esterification, hydrolysis, adsorption, elution and concentration of clindamycin hydrochloride alcoholate.
[0027] The following experimental high performance liquid chromatography method is tested in accordance with the determination method under the "Content Determination" item of the clindamycin phosphate drug standard in the "Pharmacopoeia 2020 Edition".
[0028] Example 1
[0029] Take 50 g of crude clindamycin phosphate, add it into a three-necked bottle, add 200 g of N,N-dimethylformamide, 5.0 g of deionized water, and 0.25 g of glacial acetic acid, heat and stir, control the temperature at 80-82°C, the speed at 200 rpm, keep warm for 6 hours, cool to room temperature, and filter to obtain the wet product.
[0030] The above wet products were all added to the reaction bottle, 350 ml of 75% ethanol aqueous solution was added, heated to dissolve, and then 1.0 g of activated carbon was added for decolorization for 30 min, filtered while hot, and the filtrate was kept at a gradient temperature of 0.1-0.3 ° C / min to 5 ° C, crystallized, filtered, and vacuum dried at 75 ° C for 6 hours to obtain 43.60 g of the finished product, with a yield of 87.2%
[0031] White crystalline powder, melting point 113.8~114℃ (literature reference 114℃).
[0032] HPLC test results of batch number 20230301 sample:
[0033]
[0034] Example 2
[0035] Take 50 g of crude clindamycin phosphate, add it into a three-necked bottle, add 200 g of ethanol, 5.0 g of deionized water, and 0.25 g of glacial acetic acid, heat and stir at 200 rpm, keep warm and reflux for 8 hours, cool to room temperature, and filter to obtain the wet product.
[0036] All the wet products were added to the reaction bottle, and then 400 ml of 75% acetone aqueous solution was added, heated to dissolve, and then 1.0 g of activated carbon was added for decolorization for 30 min. The filtrate was filtered while hot, and the filtrate was cooled to 5°C at a gradient rate of 0.1-0.3°C / min, crystallized, filtered, and vacuum dried at 75°C for 6 hours to obtain 44.3 g of the finished product with a yield of 88.6%.
[0037] White crystalline powder, melting point 113.5~114℃ (literature reference 114℃).
[0038] HPLC test results of batch number 20230302 sample:
[0039]
[0040] Example 3
[0041] Take 50 g of crude clindamycin phosphate, add it to a three-necked bottle, add 180 g of N, N-dimethylacetamide, 4.5 g of deionized water, and 0.22 g of glacial acetic acid, heat and stir at 200 rpm, control the temperature at 80-82°C, keep warm and stir for 8 hours, cool to room temperature, and filter to obtain the wet product.
[0042] Add all the above wet products into the reaction bottle, add 350 ml of 75% ethanol aqueous solution, heat to dissolve, add 1.0 g of activated carbon to decolorize for 30 minutes, filter while hot, keep the filtrate cooled to 5°C at a gradient of 0.1-0.3°C / min, crystallize, filter, and vacuum dry at 75°C for 6 hours to obtain 44.50 g of the finished product with a yield of 89.0%.
[0043] HPLC test results of batch number 20230303 sample:
[0044]
[0045]
[0046] Comparative Example 1
[0047] Take 50g of crude clindamycin phosphate, add 350ml of 75% ethanol aqueous solution, heat to dissolve, then add 1.0g of activated carbon to decolorize for 30min, filter while hot, cool the filtrate to 5°C, crystallize, filter, and vacuum dry at 75°C for 6 hours to obtain 40.0g of the finished product, with a yield of 80.0%.
[0048] HPLC test results of batch number 20230304 sample:
[0049]
[0050] Note: Impurity index is unqualified.
[0051] Comparative Example 2
[0052] Take 50 g of crude clindamycin phosphate and add it to a three-necked bottle, add 180 g of N,N-dimethylacetamide and 0.22 g of glacial acetic acid, heat and stir at 200 rpm, control the temperature at 80-82°C, keep warm and stir for 8 hours, cool to room temperature, and filter to obtain the wet product.
[0053] Add all the above wet products into the reaction bottle, add 350 ml of 75% ethanol aqueous solution, heat to dissolve, add 1.0 g of activated carbon to decolorize for 30 minutes, filter while hot, keep the filtrate cooled to 5°C at a gradient of 0.1-0.3°C / min, crystallize, filter, and vacuum dry at 75°C for 6 hours to obtain 44.50 g of the finished product with a yield of 89.0%.
[0054] HPLC test results of batch number 20230305 sample:
[0055]
[0056] Note: Impurity index is unqualified.
[0057] Comparative Example 3
[0058] Take 50 g of crude clindamycin phosphate, add it to a three-necked bottle, add 180 g of N, N-dimethylacetamide and 4.5 g of deionized water, heat and stir at 200 rpm, control the temperature at 80-82°C, keep warm and stir for 8 hours, cool to room temperature, and filter to obtain the wet product.
[0059] Add all the above wet products into the reaction bottle, add 350 ml of 85% ethanol aqueous solution, heat to dissolve, add 1.0 g of activated carbon to decolorize for 30 minutes, filter while hot, keep the filtrate cooled to 5°C at a gradient of 0.1-0.3°C / min, crystallize, filter, and vacuum dry at 75°C for 6 hours to obtain 44.50 g of the finished product with a yield of 89.0%.
[0060] HPLC test results of batch number 20230306 sample:
[0061]
[0062]
[0063] Note: Impurity index is unqualified.
Claims
1. A method for purifying clindamycin phosphate, comprising the following steps: 1) hot slurrying the crude clindamycin phosphate in an amide solvent system, and performing solid-liquid separation to obtain a wet product of clindamycin phosphate; 2) adding the wet clindamycin phosphate obtained in step 1) into a benign solvent system for dissolution, and treating with activated carbon to obtain a clindamycin phosphate decolorized liquid; 3) subjecting the clindamycin phosphate decolorizing solution obtained in step 2) to gradient cooling and crystallization to obtain a finished clindamycin phosphate product.
2. The purification method according to claim 1, characterized in that The amide solvent system of step 1) consists of:
3. The purification method according to claim 2, characterized in that The mass ratio of amide solvent, water and glacial acetic acid is 50-30:1-0.5:0.05-0.
025.
4. The purification method according to claim 2, characterized in that The amide solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide and N,N-dimethylbutyramide.
5. The purification method according to claim 1, characterized in that Step 1) The hot pulping temperature is 70-85°C.
6. The purification method according to claim 1, characterized in that The hot beating time of step 1) is 5 to 8 hours.
7. The purification method according to claim 1, characterized in that Step 2) The benign solvent system consists of a benign solvent and water.
8. The purification method according to claim 7, characterized in that The benign solvent is selected from at least one of methanol, ethanol, acetone, isopropanol and n-butanol.
9. The purification method according to claim 7, characterized in that The volume percentage of the benign solvent system is 65% to 85% of aqueous solution.
10. The purification method according to claim 1, characterized in that Step 3) The gradient cooling rate is 0.1-0.3°C / min, and the gradient cooling is to 2-8°C.