Method for reducing impurity content in clindamycin hydrochloride alcoholate

Abstract

The invention discloses a method for reducing impurity content in clindamycin hydrochloride alcoholate, which comprises the following steps: 1) preparing a clindamycin free alkali solution by using lincomycin hydrochloride, adding water into the clindamycin free alkali solution, then dropwise adding hydrochloric acid to adjust the pH value, and layering to obtain a clindamycin hydrochloride aqueous solution; 2) adjusting the pH value of the obtained clindamycin hydrochloride aqueous solution to 5-7; then adding monopotassium phosphate and dipotassium phosphate, stirring, dissolving and clarifying, heating, and cooling; and 3) adding ethanol and sodium salt, heating, stirring, dissolving, cooling, preserving heat, crystallizing, cooling to below 10 DEG C, and centrifuging to obtain the clindamycin hydrochloride alcoholate. According to the method, the content of 7-clindamycin is remarkably reduced, meanwhile, the problem that clindamycin hydrochloride is degraded to generate lincomycin, 7-epilincomycin impurities and the like can be effectively inhibited, and the content of related impurities is effectively controlled and remarkably reduced; and the related treatment method is simple, convenient to operate and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a method for reducing the impurity content in clindamycin hydrochloride alcoholate. Background Art

[0002] Clindamycin hydrochloride alcoholate is an intermediate that must be experienced in the preparation process of lincosamide raw material products clindamycin hydrochloride, clindamycin phosphate, and clindamycin palmitate. The level of its impurity content directly affects the quality of downstream products. The industrial production method of clindamycin hydrochloride alcoholate usually uses lincomycin hydrochloride as a raw material, undergoes a chlorination reaction with a Vilsmeier reagent, and then completes a hydrolysis reaction, stratifies and extracts to obtain a chloroform solution of clindamycin free base; then the chloroform is completely evaporated, and hydrochloric acid is acidified and crystallized in an ethanol system to obtain clindamycin hydrochloride alcoholate. The primary alcoholate produced by this method has a high content of related impurities, especially 7-difference clindamycin impurities, which remain at 0.8-1.0%, and lincomycin and 7-epilcomycin are also at 0.15-0.25%, respectively. In order to obtain clindamycin hydrochloride alcoholate with a low 7-difference clindamycin content, it is usually necessary to perform 1-2 recrystallization treatments, which sacrifices the product yield and also increases other consumption.

[0003] Patent application CN102702279A discloses a method for preparing clindamycin hydrochloride, wherein a chloroform solution of clindamycin free base is added with water, acidified and phase-transferred to obtain a clindamycin hydrochloride aqueous solution, then adsorbed by a macroporous resin, washed with water, desorbed with methanol, and concentrated with methanol, and finally acidified and crystallized with hydrochloric acid in an acetone system to obtain clindamycin hydrochloride, wherein the impurity 7-diffaclin can be controlled to be 0.3%. This solution mainly utilizes macroporous resin to separate impurities and purify products, but the equipment process is greatly increased, and unit operations such as adsorption, water washing, methanol desorption, and methanol concentration are added, which will further increase the operation process and increase the raw material and labor costs. Patent application CN103172683A discloses a method for preparing clindamycin hydrochloride, wherein the chloroform solution of clindamycin free base is evaporated to remove chloroform, and the clindamycin free base compound monomer is directly kept at 90-120°C for 20-120 minutes, and then acidified and crystallized with hydrochloric acid in an ethanol system to obtain clindamycin hydrochloride alcoholate, and the content of 7-differential clindamycin can be controlled below 0.1%; the main purpose of this scheme is to reduce the content of 7-differential clindamycin, but clindamycin will degrade during the corresponding treatment process, and lincomycin and 7-epilcomycin impurities will be produced at the same time. The obtained clindamycin hydrochloride alcoholate needs to further add a process to remove impurities such as lincomycin and 7-epilcomycin, which will sacrifice a certain yield and increase the time consumption. Further exploration of a simple and efficient preparation method for clindamycin hydrochloride alcoholate that can simultaneously remove related impurities such as 7-differential clindamycin, lincomycin, and 7-epilcomycin has important research and application significance. Summary of the invention

[0004] The main purpose of the present invention is to provide a method for reducing the content of impurities such as 7-dicalcin, lincomycin, 7-epi-lincomycin and the like in clindamycin hydrochloride alcoholate under the premise of basically retaining the existing preparation process and equipment, so as to provide high-quality intermediates for preparing high-quality clindamycin hydrochloride, clindamycin phosphate, clindamycin hydrochloride palmitate and the like; and the preparation method involved is relatively simple and has a short cycle, which is suitable for popularization and application.

[0005] To achieve the above object, the technical solution adopted by the present invention is:

[0006] A method for reducing the impurity content in clindamycin hydrochloride alcoholate comprises the following steps:

[0007] 1) preparing a clindamycin free base solution using lincomycin hydrochloride, adding water thereto, then dropping hydrochloric acid to adjust the pH value to 2-3, and layering to obtain a clindamycin hydrochloride aqueous solution;

[0008] 2) adding liquid alkali to the obtained clindamycin hydrochloride aqueous solution to adjust the pH value to 5-7; then adding potassium dihydrogen phosphate and dipotassium hydrogen phosphate, stirring to dissolve, heating and cooling;

[0009] 3) Add ethanol and sodium salt to the solution obtained in step 2), heat up, stir to dissolve, cool down and then keep warm to crystallize, cool down to below 10° C., centrifuge to obtain clindamycin hydrochloride alcoholate.

[0010] In the above scheme, the preparation method of the clindamycin free base solution comprises the following steps: subjecting lincomycin hydrochloride to a chlorination reaction with a Vilsmeier reagent to obtain a reaction solution containing clindamycin hydrochloride, and then subjecting the reaction solution to a hydrolysis reaction, extraction and stratification to obtain a clindamycin free base chloroform solution.

[0011] In the above scheme, the concentration of clindamycin free base in the clindamycin free base chloroform solution is 8-9wt%.

[0012] In the above scheme, the mass ratio of water introduced in step 1) to lincomycin hydrochloride is 3 to 6:1.

[0013] In the above scheme, the concentration of hydrochloric acid used in step 1) is 10-30wt%.

[0014] Preferably, in step 1), the pH value is controlled to be 5.0-5.5 by adding liquid alkali.

[0015] In the above scheme, the concentration of the liquid alkali is 10 to 30 wt%.

[0016] In the above scheme, the mass ratio of water introduced in step 1) to potassium dihydrogen phosphate introduced in step 2) is 1:0.005-0.01, and the mass ratio of water introduced in step 1) to dipotassium hydrogen phosphate introduced in step 2) is 1:0.0005-0.001.

[0017] In the above scheme, the temperature used in the heating treatment step in step 2) is 90-100° C., preferably 98-99° C.; the insulation time is 30-60 minutes.

[0018] In the above scheme, the temperature is lowered to 60-70°C in step 2).

[0019] In the above scheme, the mass ratio of lincomycin hydrochloride introduced in step 1) to ethanol introduced in step 3) is 1:0.8-1.2.

[0020] In the above scheme, the mass ratio of lincomycin hydrochloride introduced in step 1) to sodium chloride introduced in step 3) is 1:1.0-1.5.

[0021] In the above scheme, in step 3), after adding ethanol and sodium chloride, the temperature is first raised to 75-80°C.

[0022] In the above scheme, the temperature used in the heat preservation crystallization step in step 3) is 50-60° C. and the time is 1-3 hours.

[0023] Furthermore, in step 3), the temperature below 10°C is 0-10°C.

[0024] In the above scheme, the impurities include 7-dicalcin, lincomycin and 7-epilcomycin.

[0025] Furthermore, the impurities also include clindamycin B.

[0026] The clindamycin hydrochloride alcoholate prepared according to the above scheme contains lincomycin <0.1%, 7-epilcomycin <0.1% and 7-epilcomycin <0.1%.

[0027] The invention regulates the pH value of the aqueous solution of clindamycin hydrochloride, then introduces potassium dihydrogen phosphate and dipotassium hydrogen phosphate, regulates the reaction concentration and temperature and maintains a stable pH value condition, effectively promoting the configuration inversion of the main impurity 7-difference clindamycin and other impurities to convert them into clindamycin hydrochloride, and significantly improving the purity of the obtained clindamycin hydrochloride alcoholate product.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1) The method of the present invention can significantly reduce the content of 7-clindamycin while effectively inhibiting the degradation of clindamycin hydrochloride itself and the resulting impurities such as lincomycin and 7-epilcomycin, thereby effectively controlling and significantly reducing the content of related impurities;

[0030] 2) The treatment method involved in the present invention is simple, easy to operate, and suitable for industrial production. DETAILED DESCRIPTION

[0031] The following will be a clear and specific description of the technical solutions used in the present invention through examples and comparative examples. The examples and comparative examples are only examples of the present invention, do not represent all examples, and do not limit the scope of the present invention. The embodiments of the present invention, as well as various changes or modifications made by those skilled in the art according to the present invention, these equivalent forms also belong to the scope of protection of the present invention.

[0032] In the following examples, the method of using clindamycin free base chloroform solution comprises the following steps:

[0033] 1) 200 kg of chloroform and 45 kg of DMF were sequentially pumped into a reaction kettle, cooled to 0°C, and then a solution prepared by 40 kg of solid light and 100 kg of chloroform was slowly added thereto, the dropping time was controlled within 1 hour, and the temperature in the kettle was controlled not to exceed 10°C; after the dropping was completed, the temperature was controlled below 10°C and stirred for 0.5 hours; then 34 kg of lincomycin hydrochloride (B0.6%) was added in batches, the addition time was controlled within 1.0 hour, and the temperature during the addition process was controlled not to exceed 15°C; after the addition was completed, the temperature was raised and controlled at 25°C, 35°C, 45°C, and 55°C for 1 hour each, and then stabilized at 55-57°C and kept for reaction for 24 hours; after the reaction was completed, the temperature was lowered to below 20°C for hydrolysis;

[0034] 2) In a hydrolysis kettle, 160 kg of water and 100 kg of liquid alkali (30 wt%) were added successively, and the chlorination reaction solution obtained in step 1) was added dropwise under stirring. The dropping time was controlled to be 1.0 h, and the temperature was controlled not to exceed 35° C. During the dropping process, the pH value was controlled to be 12-13, and the temperature was controlled to be 35-40° C. and stirred for 3 h. After the hydrolysis was completed, the mixture was allowed to stand and the layers were separated. The aqueous phase was extracted once with 25 kg of chloroform; the chloroform layers were combined to obtain 370 kg of clindamycin free base chloroform solution with a concentration of 8-9 wt%.

[0035] Example 1

[0036] A method for reducing the impurity content in clindamycin hydrochloride alcoholate comprises the following steps:

[0037] 1) Weigh 37 kg of clindamycin free base chloroform solution, pump it into a reaction kettle, add 17 kg of water thereto, dropwise add 30 wt % hydrochloric acid, adjust the pH value to 2.0 (stir for 10 min, repeat measurement and remain unchanged), stand for stratification, and obtain a clindamycin hydrochloride acid aqueous solution;

[0038] 2) Add 30 wt% of liquid alkali to the obtained clindamycin hydrochloride aqueous solution to adjust the pH value to 6.5; then add 140 g of potassium dihydrogen phosphate and 15 g of dipotassium hydrogen phosphate, stir and dissolve; then heat to 98-100° C. and keep warm for 60 min, then cool to 60° C.;

[0039] 3) Add 3 kg of 95 vol% ethanol solution and 4.25 kg of sodium chloride to the solution obtained in step 2), heat to 80°C, stir to dissolve, then cool to 58°C, add 3 g of clindamycin hydrochloride alcoholate as seed crystals, control the temperature at 58-60°C to crystallize for 2 h; then cool to 8°C, discharge the material, filter it, drain it, wash it with a little ethanol, drain it, and dry it to obtain 3.35 kg of clindamycin hydrochloride alcoholate.

[0040] After testing, the product obtained in this embodiment has a clindamycin content (excluding the content of hydrogen chloride and alcohol components; the same below) of 83.6%, of which water content is 4.30% and residue is 0.15%; impurities and their contents include: lincomycin 0.04%, epilincomycin 0.06%, clindamycin B 0.43%, 7-diffaclindamycin 0.10%, and a total impurity content of 0.82%.

[0041] Example 2

[0042] A method for reducing the impurity content in clindamycin hydrochloride alcoholate comprises the following steps:

[0043] 1) Weigh 74 kg of clindamycin free base chloroform solution, pump it into a reaction kettle, add 30 kg of water thereto, dropwise add 30 wt % hydrochloric acid, adjust the pH value to 2.0 (stir for 10 min, repeat measurement and remain unchanged), stand for stratification, and obtain a clindamycin hydrochloride acid aqueous solution;

[0044] 2) Add 30 wt% of liquid alkali to the obtained clindamycin hydrochloride aqueous solution to adjust the pH value to 6.5; then add 250 g of potassium dihydrogen phosphate and 25 g of dipotassium hydrogen phosphate, stir and dissolve; then heat to 98-99° C. for 90 min, and then cool to 60° C.;

[0045] 3) Add 7 kg of 95 vol% ethanol solution and 8 kg of sodium chloride to the solution obtained in step 2), heat to 80°C, stir to dissolve, then cool to 55°C, add 5 g of clindamycin hydrochloride alcoholate as seed crystals, and keep the temperature at 55-58°C for 2 h; then cool to 7°C, drain and filter, drain, wash with a little ethanol, drain, and dry to obtain 6.60 kg of clindamycin hydrochloride alcoholate.

[0046] After testing, the product obtained in this embodiment has a clindamycin content of 83.1%, including 4.46% water and 0.28% residue; impurities and their contents include: lincomycin not detected, 7-epilcomycin 0.03%, clindamycin B 0.46%, 7-diffaclincomycin 0.06%, and a total impurity content of 0.68%.

[0047] Example 3

[0048] A method for reducing the impurity content in clindamycin hydrochloride alcoholate comprises the following steps:

[0049] 1) Weigh 37 kg of clindamycin free base chloroform solution, pump it into a reaction kettle, add 20 kg of water thereto, dropwise add 30 wt % hydrochloric acid, adjust the pH value to 2.0 (after stirring for 10 min, the pH value remains unchanged after repeated measurement), stand for stratification, and obtain a clindamycin hydrochloride acid aqueous solution;

[0050] 2) Add 30 wt% of liquid caustic soda to the obtained clindamycin hydrochloride aqueous solution, adjust the pH value to 6.0; then add 160 g of potassium dihydrogen phosphate and 17 g of dipotassium hydrogen phosphate, stir and dissolve; then heat to 97° C., control to stabilize at 98-99° C., keep warm for 60 min, and then cool to 60° C.;

[0051] 3) Add 3.5 kg of 95 vol% ethanol solution and 4.5 kg of sodium chloride to the solution obtained in step 2), heat to 80°C, stir to dissolve, then cool to 60°C, add 2 g of clindamycin hydrochloride alcoholate as a seed, control the temperature at 58-60°C, and keep warm for crystallization for 2 hours; then cool to 10°C, discharge the material, filter it, drain it, wash it with a little ethanol, drain it, and dry it to obtain 3.50 kg of clindamycin hydrochloride alcoholate.

[0052] After testing, the product obtained in this embodiment has a clindamycin content of 84.2%, including 4.01% water and 0.11% residue; impurities and their contents include: 0.02% lincomycin, 0.05% 7-epilcomycin, 0.45% clindamycin B, 0.08% 7-diffaclindamycin, and a total impurity content of 0.76%.

[0053] Comparative Example 1

[0054] A method for preparing clindamycin hydrochloride alcoholate comprises the following steps:

[0055] 1) Weigh 37 kg of clindamycin free base chloroform solution, pump it into a reaction kettle, first distill it under normal pressure, then distill it under reduced pressure, control the internal temperature below 60° C., and distill the chloroform completely;

[0056] 2) Add 20 kg of 95 vol% ethanol, stir to dissolve, cool to 10°C, drop 30 wt% hydrochloric acid, adjust pH to 2, stir for 10 min, repeat measurement until unchanged; keep warm at 0-5°C for 1 h for crystallization;

[0057] 3) The material was filtered and dried, washed with a little ethanol, dried, and dried to obtain 3.40 kg of clindamycin hydrochloride alcoholate.

[0058] After testing, the obtained product has a clindamycin content of 81.0%, a moisture content of 3.50%, and a residue content of 0.06%; the impurity content includes: lincomycin 0.15%, 7-epilcomycin 0.23%, clindamycin B 0.44%, 7-epilcomycin 1.0%, and the total impurity content is 1.85%.

[0059] Comparative Example 2

[0060] A method for preparing clindamycin hydrochloride alcoholate comprises the following steps:

[0061] 1) 37 kg of clindamycin free base chloroform solution was pumped into a reaction kettle and distilled at normal pressure, with the internal temperature controlled below 60° C. to distill 20 kg of chloroform;

[0062] 2) Cool down to below 40°C, add 4kg of 95vol% ethanol solution, stir to dissolve, continue to cool to 10°C, drop 30wt% hydrochloric acid, adjust pH to 2, stir for 10min, repeat measurement until unchanged; keep warm at 0-5°C for 1h for crystallization;

[0063] 3) The material was filtered and dried, washed with a little ethanol, dried, and dried to obtain 3.60 kg of clindamycin hydrochloride alcoholate.

[0064] After testing, the obtained product has a clindamycin content of 82.0%, a moisture content of 3.20%, and a residue content of 0.04%; the impurity content includes: lincomycin 0.12%, 7-epilcomycin 0.18%, clindamycin B 0.43%, 7-epilcomycin 0.96%, and the total impurity content is 1.75%.

[0065] Comparative Example 3

[0066] A method for preparing clindamycin hydrochloride alcoholate comprises the following steps:

[0067] 1) Weigh 37 kg of clindamycin free base chloroform solution, pump it into a reaction kettle, add 17 kg of water thereto, dropwise add 30 wt % hydrochloric acid, adjust the pH value to 2.0 (stir for 10 min, repeat measurement and remain unchanged), stand for stratification, and obtain a clindamycin hydrochloride acid aqueous solution;

[0068] 2) Add 30 wt% of liquid alkali to the obtained clindamycin hydrochloride aqueous solution to adjust the pH value to 6.5; then add 140 g of potassium dihydrogen phosphate, 15 g of dipotassium hydrogen phosphate, 95 vol% ethanol solution, and 4.25 kg of sodium chloride in sequence, heat to 80°C, and stir to dissolve.

[0069] 3) Stir and cool to 58°C, add 3g of clindamycin hydrochloride alcoholate as seed crystals, control the temperature at 58-60°C and keep warm for crystallization for 2h; then cool to 8°C, discharge the material and filter it, drain it, wash it with a little ethanol, drain it, take the material and dry it to obtain 3.35kg of clindamycin hydrochloride alcoholate.

[0070] After testing, the product obtained in this embodiment has a clindamycin content of 81.6%, including 3.85% water and 0.18% residue; impurities and their contents include: 0.03% lincomycin, 0.07% epilincomycin, 0.41% clindamycin B, 0.92% 7-diffaclindamycin, and a total impurity content of 1.62%.

[0071] Comparative Example 4

[0072] A method for preparing clindamycin hydrochloride alcoholate comprises the following steps:

[0073] 1) Weigh 37 kg of clindamycin free base chloroform solution, pump it into a reaction kettle, add 7 kg of water thereto, dropwise add 30 wt % hydrochloric acid, adjust the pH value to 2.0 (stir for 10 min, repeat measurement and remain unchanged), stand for stratification, and obtain a clindamycin hydrochloride acid aqueous solution;

[0074] 2) Add 30 wt% of liquid caustic soda to the obtained clindamycin hydrochloride aqueous solution, adjust the pH value to 6.0; then add 55 g of potassium dihydrogen phosphate and 5.5 g of dipotassium hydrogen phosphate, stir and dissolve; then heat to 97° C., control to stabilize at 98-99° C., keep warm for 60 min, and then cool to 60° C.;

[0075] 3) Add 3.5 kg of 95 vol% ethanol solution and 1.6 kg of sodium chloride to the solution obtained in step 2), heat to 80°C, stir to dissolve, then cool to 60°C, add 2 g of clindamycin hydrochloride alcoholate as a seed, control the temperature at 58-60°C, and keep warm for crystallization for 2 hours; then cool to 10°C, discharge the material, filter it, drain it, wash it with a little ethanol, drain it, and dry it to obtain 3.46 kg of clindamycin hydrochloride alcoholate.

[0076] After testing, the product obtained in this embodiment has a clindamycin content of 82.6%, including 4.15% water and 0.26% residue; impurities and their contents include: 0.06% lincomycin, 0.08% epilincomycin, 0.42% clindamycin B, 0.88% 7-diffaclindamycin, and a total impurity content of 1.58%.

[0077] Comparative Example 5

[0078] A method for preparing clindamycin hydrochloride alcoholate comprises the following steps:

[0079] 1) Weigh 37 kg of clindamycin free base chloroform solution, pump it into a reaction kettle, add 7 kg of water thereto, dropwise add 30 wt % hydrochloric acid, adjust the pH value to 2.0 (stir for 10 min, repeat measurement and remain unchanged), stand for stratification, and obtain a clindamycin hydrochloride acid aqueous solution;

[0080] 2) adding 30 wt % of liquid caustic soda to the obtained clindamycin hydrochloride aqueous solution, adjusting the pH value to 6.0; then heating to 97° C., controlling the temperature to be stable at 97-99° C., keeping the temperature for 60 min, and then cooling to 60° C.;

[0081] 3) Add 3.5 kg of 95 vol% ethanol solution and 1.6 kg of sodium chloride to the solution obtained in step 2), heat to 80°C, stir to dissolve, then cool to 60°C, add 2 g of clindamycin hydrochloride alcoholate as a seed, control the temperature at 58-60°C, and keep warm for crystallization for 2 hours; then cool to 10°C, discharge the material, filter it, drain it, wash it with a little ethanol, drain it, and dry it to obtain 3.10 kg of clindamycin hydrochloride alcoholate.

[0082] After testing, the product obtained in this embodiment has a clindamycin content of 81.8%, including 4.25% water and 0.30% residue; impurities and their contents include: 0.24% lincomycin, 0.26% epilincomycin, 0.41% clindamycin B, 0.09% 7-diffaclindamycin, and a total impurity content of 1.25%.

[0083] The above is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solution and its improved conception within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for reducing the impurity content in clindamycin hydrochloride alcoholate, characterized in that: The steps include: 1) preparing a clindamycin free base solution using lincomycin hydrochloride, adding water thereto, then dripping hydrochloric acid to adjust the pH value to 2-3, and layering to obtain a clindamycin hydrochloride aqueous solution; 2) adding liquid alkali to the obtained clindamycin hydrochloride aqueous solution to adjust the pH value to 5-7; then adding potassium dihydrogen phosphate and dipotassium hydrogen phosphate, stirring to dissolve, heating and cooling; 3) Add ethanol and sodium salt to the solution obtained in step 2), heat up, stir to dissolve, cool down and then keep warm to crystallize, cool down to below 10° C., centrifuge to obtain clindamycin hydrochloride alcoholate.

2. The method according to claim 1, characterized in that The mass ratio of water introduced in step 1) to lincomycin hydrochloride is 3 to 6:

1.

3. The method according to claim 1, characterized in that: The mass ratio of the water introduced in step 1) to the potassium dihydrogen phosphate introduced in step 2) is 1:0.005-0.01, and the mass ratio of the water introduced in step 1) to the dipotassium hydrogen phosphate introduced in step 2) is 1:0.0005-0.

001.

4. The method according to claim 1, characterized in that: The temperature used in the heating treatment step in step 2) is 90-100° C. and the insulation time is 30-60 minutes.

5. The method according to claim 1, characterized in that In step 2), the temperature is lowered to 60-70°C.

6. The method according to claim 1, characterized in that The mass ratio of lincomycin hydrochloride introduced in step 1) to ethanol introduced in step 3) is 1:0.8-1.

2.

7. The method according to claim 1, characterized in that The mass ratio of lincomycin hydrochloride introduced in step 1) to sodium chloride introduced in step 3) is 1:1.0-1.

5.

8. The method according to claim 1, characterized in that: In step 3), after adding ethanol and sodium chloride, the temperature is first raised to 75-80°C.

9. The method according to claim 1, characterized in that: The temperature of the heat preservation crystallization step in step 3) is 50-60° C. and the time is 1-3 hours.

10. The method according to claim 1, characterized in that The impurities include 7-epilcomycin, lincomycin and 7-epilcomycin.