Novel purification method for obtaining high-purity clindamycin phosphate

Abstract

The present application relates to a novel purification method for obtaining high-purity clindamycin phosphate, which comprises the steps of: first carrying out hot pulping and impurity removal on a clindamycin phosphate crude product in an amide solvent system, then adding a benign solvent system for dissolving, carrying out decolorization by using activated carbon, and finally carrying out gradient cooling crystallization to obtain a clindamycin phosphate finished product. The purification method provided in the present application relates to the use of the amide solvent system, which has a good impurity removal effect, but has poor solubility for clindamycin phosphate. The content of clindamycin phosphate obtained by using the purification method provided in the present application is higher than 98%, the content of impurity G is lower than 0.2%, and the total impurity content is lower than 2.0%.

Description

A new method for purifying high-purity clindamycin phosphate

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application number 202311005367.8, filed with the State Intellectual Property Office of China on August 10, 2023, entitled “A New Method for Purifying High-Purity Clindamycin Phosphate,” the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the technical field of raw material drug purification, and in particular to a post-processing purification method for clindamycin phosphate. Background Art

[0004] 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-galactopyranoside-2-dihydrogen phosphate. Its English name is clindamycin phosphate. Its structural formula is as follows:

[0005] Clindamycin phosphate impurity G is referred to as impurity G. 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-octopyranoside, CAS: 1440605-46-8, and its chemical structure is as follows:

[0006] Clindamycin phosphate has no antibacterial activity in vitro and rapidly hydrolyzes into clindamycin upon entry into the body to exert its pharmacological effects. Its antimicrobial spectrum, antimicrobial activity, and therapeutic efficacy are similar to those of clindamycin, but its ester solubility and permeability are 4-8 times greater than those of clindamycin, resulting in better absorption and high bone tissue concentrations. It exhibits strong antibacterial activity against both Gram-positive cocci and anaerobic bacteria.

[0007] The prior art crystallization method for clindamycin phosphate involves purifying clindamycin phosphate using ethanol crystallization or recrystallization in an ethanol / water system. Although these purification methods have a good removal effect on most impurities in clindamycin phosphate, they have no good removal effect on impurity G. Therefore, it is necessary to develop a new purification method to obtain high-purity clindamycin phosphate.

[0008] Summary of the Invention

[0009] The present application provides a new method for purifying high-purity clindamycin phosphate, which selectively removes impurities through an amide solvent system while improving the purity of the finished clindamycin phosphate product.

[0010] The technical solutions adopted to achieve the above-mentioned invention objects are:

[0011] A method for purifying clindamycin phosphate comprises the following steps:

[0012] 1) hot beating the crude clindamycin phosphate in an amide solvent system, and performing solid-liquid separation to obtain a wet product of clindamycin phosphate;

[0013] 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 decolorized clindamycin phosphate solution;

[0014] 3) subjecting the clindamycin phosphate decolorant obtained in step 2) to gradient cooling and crystallization to obtain a finished clindamycin phosphate product.

[0015] Wherein, the amide solvent system in step 1) consists of.

[0016] The mass ratio of the amide solvent, water and glacial acetic acid is 50-30:1-0.5:0.05-0.025.

[0017] Wherein, the amide solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide and N,N-dimethylbutanamide.

[0018] The hot beating temperature in step 1 is 70-85°C, preferably 75-82°C.

[0019] Wherein, the hot beating time in step 1) is 5 to 8 hours, preferably 6 to 7 hours.

[0020] Wherein, the benign solvent system in step 2) consists of a benign solvent and water.

[0021] Wherein, the benign solvent is selected from at least one of methanol, ethanol, acetone, isopropanol and n-butanol.

[0022] Wherein, the volume percentage of the benign solvent system is 65% to 85% aqueous solution.

[0023] Wherein, in step 3), the gradient cooling rate is 0.1-0.3°C / min, and the gradient cooling is to 2-8°C.

[0024] The technical solution of this application has at least the following beneficial technical effects:

[0025] The purification method provided herein utilizes an amide solvent system. Amide solvents have good solubility for impurity G but poor solubility for clindamycin phosphate. This purification method not only effectively removes impurity G but also effectively removes other impurities. Experimental results demonstrate that the clindamycin phosphate content obtained by the purification method provided herein is above 98%, the impurity G content is less than 0.2%, and the total impurity content is less than 2.0%. DETAILED DESCRIPTION

[0026] In order to achieve the purpose of the embodiment of this application,

[0027] The present invention will be further described below with reference to specific examples. It should be understood that the following examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0028] 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.

[0029] The following experimental high-performance liquid chromatography method is tested in accordance with the determination method under the "Determination of Content" of the clindamycin phosphate drug standard in the "Pharmacopoeia 2020 Edition".

[0030] Example 1

[0031] Take 50 g of crude clindamycin phosphate, add it to a three-necked flask, 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.

[0032] All the wet products were added to the reaction flask, 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 minutes. The mixture was filtered while hot, and the filtrate was cooled to 5 ° C at a gradient of 0.1-0.3 ° C / min, 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%.

[0033] White crystalline powder, melting point 113.8~114℃ (referenced in literature: 114℃).

[0034] HPLC test results of sample batch number 20230301:

[0035] Example 2

[0036] Take 50 g of crude clindamycin phosphate, add it to a three-necked flask, 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 reflux for 8 hours, cool to room temperature, and filter to obtain the wet product.

[0037] All the above wet products were added to the reaction flask, and then 400 ml of 75% acetone aqueous solution was added and heated to dissolve. Then 1.0 g of activated carbon was added for decolorization for 30 min, and the mixture was filtered while hot. The filtrate was cooled to 5°C at a gradient rate of 0.1-0.3°C / min, crystallized, filtered, and dried in vacuo at 75°C for 6 hours to obtain 44.3 g of the finished product with a yield of 88.6%.

[0038] White crystalline powder, melting point 113.5-114°C (referenced in literature at 114°C).

[0039] HPLC test results of sample batch number 20230302:

[0040] Example 3

[0041] Take 50 g of crude clindamycin phosphate, add it to a three-necked flask, 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 stirring for 8 hours, cool to room temperature, and filter to obtain the wet product.

[0042] All the above wet products were added to the reaction flask, and then 350 ml of 75% ethanol aqueous solution was added and heated to dissolve. Then 1.0 g of activated carbon was added for decolorization for 30 min, and the mixture was filtered while hot. The filtrate was cooled to 5 ° C at a gradient of 0.1-0.3 ° C / min, crystallized, filtered, and vacuum dried 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 sample batch number 20230303:

[0044] Comparative Example 1

[0045] 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%.

[0046] HPLC test results of sample batch number 20230304:

[0047] Note: Impurity index is unqualified.

[0048] Comparative Example 2

[0049] Take 50 g of crude clindamycin phosphate and add it to a three-necked flask. 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. After keeping warm and stirring for 8 hours, cool to room temperature and filter to obtain the wet product.

[0050] All the above wet products were added to the reaction flask, and then 350 ml of 75% ethanol aqueous solution was added and heated to dissolve. Then 1.0 g of activated carbon was added for decolorization for 30 min, and the mixture was filtered while hot. The filtrate was cooled to 5 ° C at a gradient of 0.1-0.3 ° C / min, crystallized, filtered, and vacuum dried at 75 ° C for 6 hours to obtain 44.50 g of the finished product with a yield of 89.0%.

[0051] HPLC test results of sample batch number 20230305:

[0052] Note: Impurity index is unqualified.

[0053] Comparative Example 3

[0054] Take 50g of crude clindamycin phosphate, add it to a three-necked flask, add 180g of N,N-dimethylacetamide and 4.5g of deionized water, heat and stir at 200 rpm, control the temperature at 80-82°C, keep stirring for 8 hours, cool to room temperature, and filter to obtain the wet product.

[0055] All the above wet products were added to the reaction flask, and then 350 ml of 85% ethanol aqueous solution was added, heated to dissolve, and then 1.0 g of activated carbon was added for decolorization for 30 minutes. The mixture was filtered while hot, and the filtrate was cooled to 5°C at a gradient of 0.1-0.3°C / min. Crystallization was performed, filtration was performed, and vacuum drying was performed at 75°C for 6 hours to obtain 44.50 g of the finished product with a yield of 89.0%.

[0056] HPLC test results of sample batch number 20230306:

[0057] 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.

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