A process for the preparation of an injection grade oxytetracycline hydrochloride

Abstract

The application discloses a preparation method of injection-grade oxytetracycline hydrochloride and belongs to the technical field of pharmaceutical chemical industry. 2+ The method comprises the following steps: mixing oxytetracycline, isopropanol containing Ca 2+ , and pretreated activated carbon, stirring, filtering, adding acid alcohol dropwise after the filtrate is cooled, stirring and crystallizing, filtering and washing, and drying to obtain injection-grade oxytetracycline hydrochloride. The content of bacterial endotoxin in the injection-grade oxytetracycline hydrochloride prepared by the method is far lower than the United States Pharmacopeia and European standards, all indexes are qualified, the low-temperature salting method is adopted to reduce the generation of degradation impurities, and the standard of injection-grade oxytetracycline hydrochloride is reached.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical technology, specifically relating to a method for preparing injectable oxytetracycline hydrochloride. Background Technology

[0002] Oxytetracycline hydrochloride, chemically named 6-methyl-4-(dimethylamino)-3,5,10,12,12a-hexahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-benzotetrabenzamide hydrochloride, has the following structural formula:

[0003]

[0004] Oxytetracycline hydrochloride, also known as oxytetracycline hydrochloride, is a widely used antibiotic in humans and animals. Clinically, it is used to treat a variety of diseases, such as rickettsia (including epidemic typhus, endemic typhus, and scrub typhus); infections caused by Mycoplasma pneumoniae; chlamydia infections (including psittacosis, lymphogranuloma venereum, nonspecific urethritis, salpingitis, trachoma, relapsing fever, brucellosis, cholera, plague, and tularemia. Oxytetracycline hydrochloride is available in various dosage forms, including tablets, capsules, powders, eye drops, ointments, and injections. Injectable formulations have stricter requirements regarding related substances, microorganisms, and bacterial endotoxins in the active pharmaceutical ingredient. The United States Pharmacopeia and the European Pharmacopoeia both require that the bacterial endotoxin content of oxytetracycline hydrochloride not exceed 0.4 EU / mg. However, current processes have high requirements for the endotoxin content in oxytetracycline. When the endotoxin content in oxytetracycline exceeds 50 EU / mg, the endotoxin content in oxytetracycline hydrochloride produced by existing technologies cannot meet the pharmacopoeia requirements.

[0005] Therefore, it is urgent to provide a method to reduce the bacterial endotoxin content in oxytetracycline hydrochloride to meet the standards of injectable oxytetracycline hydrochloride, thereby ensuring the efficacy of clinical applications and reducing side effects. Summary of the Invention

[0006] To address the aforementioned problems in the existing technology, the first technical problem to be solved by the present invention is to provide a method for preparing injectable oxytetracycline hydrochloride, using a high concentration of Ca... 2+ The combination of solution and activated carbon adsorption helps reduce bacterial endotoxins, and the low-temperature salt formation method reduces the generation of degradation impurities, effectively removing bacterial endotoxins and reducing the formation of degradation products. The second technical problem this invention aims to solve is to provide an injectable grade oxytetracycline hydrochloride with a bacterial endotoxin content far below the pharmacopoeia standards of various countries, meeting the standards for injectable oxytetracycline hydrochloride.

[0007] To solve the above problems, the technical solution adopted by the present invention is as follows:

[0008] A method for preparing injectable grade oxytetracycline hydrochloride, comprising: oxytetracycline, Ca... 2+ Isopropanol and pretreated activated carbon were mixed, stirred and filtered. After the filtrate was cooled, acid alcohol was added dropwise, stirred and crystallized, filtered, washed and dried to obtain injectable grade oxytetracycline hydrochloride.

[0009] Furthermore, the Ca 2+ The concentration is 0.5–0.8 mol / L.

[0010] Furthermore, the mass-to-volume ratio of oxytetracycline to isopropanol is 1:10.

[0011] Furthermore, the amount of activated carbon used is 2-3% of oxytetracycline.

[0012] Furthermore, the acid alcohol is a 22% (w / w) hydrogen chloride-isopropanol solution.

[0013] Furthermore, the mass ratio of oxytetracycline to acid alcohol is 1:0.4 to 0.5.

[0014] Furthermore, the filtrate is cooled to -5°C to 0°C.

[0015] Furthermore, the specific steps are as follows:

[0016] 1) Soak activated carbon in a 2 mol / L sodium hydroxide solution for 2 hours, then wash with purified water, and bake the wet activated carbon at 300℃ for 1 hour to obtain pretreated activated carbon.

[0017] 2) Dissolve oxytetracycline in a solution containing Ca 2+ In isopropanol, the temperature is raised to 50–53°C, the pretreated activated carbon obtained in step 1) is added, and the mixture is stirred for 30 min. The mixture is then filtered, and the filtrate is collected. The filtrate contains Ca... 2+ The concentration is 0.5–0.8 mol / L; the mass-to-volume ratio of oxytetracycline and isopropanol is 1:10; the amount of activated carbon used is 2–3% of the amount of oxytetracycline.

[0018] 3) Cool the filtrate collected in step 2) to -5℃~0℃, add acid alcohol dropwise, stir and crystallize at 0℃, keep warm for 2h, filter, wash with frozen isopropanol, and vacuum dry to obtain injectable grade oxytetracycline hydrochloride; wherein, the acid alcohol is a 22% hydrogen chloride-isopropanol solution; the mass ratio of oxytetracycline to acid alcohol is 1:0.4~0.5.

[0019] Furthermore, in step 1), the mass-to-volume ratio of activated carbon to sodium hydroxide solution is 1:3 to 4.

[0020] Furthermore, the method produces injectable grade oxytetracycline hydrochloride.

[0021] Beneficial effects: Compared with the prior art, the advantages of this invention are:

[0022] (1) This invention uses high concentration Ca 2+ The combination of solution and activated carbon adsorption can effectively reduce the bacterial endotoxin content in oxytetracycline hydrochloride to meet the standard of injectable oxytetracycline hydrochloride, with a bacterial endotoxin content of less than 0.4 EU / mg.

[0023] (2) The present invention reduces the amount of degradation impurities by using low-temperature salt formation.

[0024] (3) The bacterial endotoxin content in the injectable grade oxytetracycline hydrochloride prepared by this invention can reach as low as 0.05 EU / mg, which is far below the standards of the United States Pharmacopeia and the European Pharmacopeia. Moreover, all indicators are qualified, and the purity of oxytetracycline hydrochloride can reach more than 97%. The related substances are superior to the above-mentioned versions of the pharmacopoeia. Attached Figure Description

[0025] Figure 1 This is a high-performance liquid chromatogram of the injectable grade oxytetracycline hydrochloride prepared in Example 2 of the present invention;

[0026] Figure 2 The high-performance liquid chromatogram of oxytetracycline hydrochloride prepared in Example 10 of this invention;

[0027] Figure 3 The image shows the high-performance liquid chromatogram of injectable grade oxytetracycline hydrochloride prepared in Example 11 of this invention. Detailed Implementation

[0028] The present invention will be further described below with reference to specific embodiments.

[0029] Unless otherwise specified, the techniques used in the following examples are all conventional methods well-known to those skilled in the art. Where specific conditions are not specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0030] The bacterial endotoxin content in the oxytetracycline hydrochloride prepared in the following examples was determined using the dynamic turbidimetric method. The horseshoe crab reagent and water used for bacterial endotoxin testing were purchased from Zhanjiang Andus Biotechnology Co., Ltd.; the bacterial endotoxin standard was obtained from the China National Institutes for Food and Drug Control; the detection range of the horseshoe crab reagent was 0.03–10.00 EU / mL; and the endotoxin content of the water used for bacterial endotoxin testing was <0.003 EU / mL. The specific testing procedure is as follows:

[0031] Preparation of the bacterial endotoxin standard curve: Under a clean bench, take one vial of national endotoxin standard with a potency of 80 EU / vial, dissolve it in water for bacterial endotoxin testing, vortex mix for 15 min, and dilute to six concentrations: 1.000, 0.500, 0.250, 0.125, 0.062, and 0.031 EU / mL. Take three vials of Limulus Amebocyte Lysate (LAL) reagent and add them to water for bacterial endotoxin testing respectively. Let them stand until fully dissolved, then mix and set aside. Take 16 vials of endotoxin analyzer, number them, and add 0.1 mL of LAL reagent to each. Take two parallel tubes for each point. Tubes 1-2 contain water for endotoxin testing as a negative control, tubes 3-4 contain the endotoxin standard as a positive control, and tubes 5-16 contain the endotoxin standard diluted to six concentrations: 1.000, 0.500, 0.250, 0.125, 0.062, and 0.031 EU / mL.

[0032] The detection of bacterial endotoxins in samples involves diluting the sample to a certain concentration and then placing it in a reactor for testing. If the detected value is within the range of the standard curve, the bacterial endotoxin content in the sample is calculated according to the dilution factor; if the detected value is not within the range of the curve, the sample is re-diluted and tested again.

[0033] The oxytetracycline used in the following examples and comparative examples all came from the same batch, and the bacterial endotoxin content in the oxytetracycline was 62 EU / mg.

[0034] The pretreatment method of activated carbon in the following examples is as follows: Weigh 100g of activated carbon, add 350mL of 2mol / L sodium hydroxide solution, soak for 2h, filter, wash three times with 100mL of purified water, and then place the wet activated carbon product at 300℃ for 1h and cool to room temperature for use.

[0035] Both the United States Pharmacopeia and the European Pharmacopoeia require that the bacterial endotoxin content of oxytetracycline hydrochloride not exceed 0.4 EU / mg.

[0036] Example 1

[0037] Preparation of injectable grade oxytetracycline hydrochloride

[0038] At room temperature, 22.2 g of calcium chloride was weighed and dissolved in 400 mL of isopropanol (Ca... 2+Add 40g of oxytetracycline (0.5mol / L), stir to dissolve, heat to 53℃, then add 1g of pretreated activated carbon, continue stirring and maintaining the temperature for 30min, filter while hot, collect the filtrate, cool the filtrate to 0℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then vacuum dry the wet product at 60℃ for 2h to obtain 37.8g of oxytetracycline hydrochloride, yield 94.5%, according to the European Pharmacopoeia standard, calculated on anhydrous basis, containing oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 97.5%, the bacterial endotoxin content was 0.381 EU / mg, and all quality indicators met the requirements of the United States Pharmacopeia and the European Pharmacopeia.

[0039] Example 2

[0040] Preparation of injectable grade oxytetracycline hydrochloride

[0041] At room temperature, 26.6 g of calcium chloride was weighed and dissolved in 400 mL of isopropanol (Ca... 2+ Add 40g of oxytetracycline (0.6mol / L), stir to dissolve, heat to 52℃, then add 1g of pretreated activated carbon, continue stirring and heating for 30min, filter while hot, collect the filtrate, cool the filtrate to -5℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then vacuum dry the wet product at 60℃ for 2h to obtain 38.1g of oxytetracycline hydrochloride, yield 95.3%. According to the European Pharmacopoeia standard, calculated on anhydrous basis, it contains oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 97.75%, the bacterial endotoxin content was 0.212 EU / mg, and all quality indicators met the requirements of the United States Pharmacopeia and the European Pharmacopeia.

[0042] Example 3

[0043] Preparation of injectable grade oxytetracycline hydrochloride

[0044] At room temperature, 35.5 g of calcium chloride was weighed and dissolved in 400 mL of isopropanol (Ca... 2+Add 40g of oxytetracycline (0.8mol / L), stir to dissolve, heat to 53℃, then add 1.2g of pretreated activated carbon, continue stirring and maintaining the temperature for 30min, filter while hot, collect the filtrate, cool the filtrate to -3℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then vacuum dry the wet product at 60℃ for 2h to obtain 37.9g ​​of oxytetracycline hydrochloride, yield 94.8%, according to the European Pharmacopoeia standard, calculated on anhydrous basis, containing oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 97.42%, the bacterial endotoxin content was 0.050 EU / mg, and all quality indicators met the requirements of the United States Pharmacopeia and the European Pharmacopeia.

[0045] Example 4

[0046] Preparation of injectable grade oxytetracycline hydrochloride

[0047] At room temperature, 35.5 g of calcium chloride was weighed and dissolved in 400 mL of isopropanol (Ca... 2+ Add 40g of oxytetracycline (0.8mol / L), stir to dissolve, heat to 53℃, then add 0.8g of pretreated activated carbon, continue stirring and maintaining the temperature for 30min, filter while hot, collect the filtrate, cool the filtrate to -3℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then vacuum dry the wet product at 60℃ for 2h to obtain 38.1g of oxytetracycline hydrochloride, yield 95.3%, according to the European Pharmacopoeia standard, calculated on anhydrous basis, containing oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 97.39%, the bacterial endotoxin content was 0.126 EU / mg, and all quality indicators met the requirements of the United States Pharmacopeia and the European Pharmacopeia.

[0048] Example 5

[0049] Preparation of oxytetracycline hydrochloride

[0050] At room temperature, weigh out 4.5g of calcium chloride and dissolve it in 400mL of isopropanol (low concentration of Ca). 2+Add 40g of oxytetracycline (0.1mol / L), stir to dissolve, heat to 52℃, then add 1g of pretreated activated carbon, continue stirring and heating for 30min, filter while hot, collect the filtrate, cool the filtrate to -5℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then dry the wet product under vacuum at 60℃ for 2h to obtain 38.3g of oxytetracycline hydrochloride, yield 95.8%. According to the European Pharmacopoeia standard, calculated on anhydrous basis, it contains oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 97.81%, and the bacterial endotoxin content was 0.832 EU / mg, which did not meet the pharmacopoeia requirements.

[0051] Example 6

[0052] Preparation of oxytetracycline hydrochloride

[0053] At room temperature, 13.3 g of calcium chloride was weighed and dissolved in 400 mL of isopropanol (low concentration of Ca). 2+ Add 40g of oxytetracycline (0.3mol / L), stir to dissolve, heat to 52℃, then add 1g of pretreated activated carbon, continue stirring and heating for 30min, filter while hot, collect the filtrate, cool the filtrate to -5℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then vacuum dry the wet product at 60℃ for 2h to obtain 38.2g of oxytetracycline hydrochloride, yield 95.5%. According to the European Pharmacopoeia standard, calculated on anhydrous basis, it contains oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 97.79%, and the bacterial endotoxin content was 0.496 EU / mg, which did not meet the pharmacopoeia requirements.

[0054] Example 7

[0055] Preparation of oxytetracycline hydrochloride

[0056] At room temperature, 35.5 g of calcium chloride was weighed and dissolved in 400 mL of isopropanol (Ca... 2+Add 40g of oxytetracycline (0.8mol / L), stir to dissolve, heat to 53℃, then add 0.1g of pretreated activated carbon (reduce the amount of activated carbon), continue to heat and stir for 30min, filter while hot, collect the filtrate, cool the filtrate to -3℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then vacuum dry the wet product at 60℃ for 2h to obtain 38.3g of oxytetracycline hydrochloride, yield 95.8%, according to the European Pharmacopoeia standard, calculated on anhydrous basis, containing oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 97.23%, and the bacterial endotoxin content was 0.873 EU / mg, which did not meet the pharmacopoeia requirements.

[0057] Example 8

[0058] Preparation of oxytetracycline hydrochloride

[0059] At room temperature, 35.5 g of calcium chloride was weighed and dissolved in 400 mL of isopropanol (Ca... 2+ Add 40g of oxytetracycline (0.8mol / L), stir to dissolve, heat to 53℃, then add 0.4g of pretreated activated carbon (reduce the amount of activated carbon), continue to heat and stir for 30min, filter while hot, collect the filtrate, cool the filtrate to -3℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then vacuum dry the wet product at 60℃ for 2h to obtain 38.2g of oxytetracycline hydrochloride, yield 95.5%, according to the European Pharmacopoeia standard, calculated on anhydrous basis, containing oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 97.03%, and the bacterial endotoxin content was 0.515 EU / mg, which did not meet the pharmacopoeia requirements.

[0060] Example 9

[0061] Preparation of oxytetracycline hydrochloride

[0062] At room temperature, 26.6 g of calcium chloride was weighed and dissolved in 400 mL of methanol (Ca... 2+Add 40g of oxytetracycline (0.6mol / L), stir to dissolve, heat to 52℃, then add 1g of pretreated activated carbon, continue stirring and heating for 30min, filter while hot, collect the filtrate, cool the filtrate to -5℃, add 17.2g of 22% hydrogen chloride-methanol solution dropwise, crystallization occurs, after the addition is complete, keep warm at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then dry the wet product under vacuum at 60℃ for 2h to obtain 37.2g of oxytetracycline hydrochloride, yield 93.0%. According to the European Pharmacopoeia standard, calculated on anhydrous basis, it contains oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 97.11%, and the bacterial endotoxin content was 1.187 EU / mg, which did not meet the pharmacopoeia requirements.

[0063] Example 10

[0064] Preparation of oxytetracycline hydrochloride

[0065] At room temperature, 26.6 g of calcium chloride was weighed and dissolved in 400 mL of isopropanol (Ca... 2+ Add 40g of oxytetracycline (0.6mol / L), stir to dissolve, heat to 52℃, then add 1g of pretreated activated carbon, continue stirring and maintaining the temperature for 30min, filter while hot, collect the filtrate, cool the filtrate to 20℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then dry the wet product under vacuum at 60℃ for 2h to obtain 36.3g of oxytetracycline hydrochloride, yield 90.8%. According to the European Pharmacopoeia standard, calculated on anhydrous basis, it contains oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 95.21%, and the bacterial endotoxin content was 0.233 EU / mg. The bacterial endotoxin content met the pharmacopoeia requirements, but the yield and content were reduced.

[0066] Example 11

[0067] Preparation of injectable grade oxytetracycline hydrochloride

[0068] At room temperature, 26.6 g of calcium chloride was weighed and dissolved in 400 mL of isopropanol (Ca... 2+Add 40g of oxytetracycline (0.6mol / L), stir to dissolve, heat to 52℃, then add 1g of pretreated activated carbon, continue stirring and heating for 30min, filter while hot, collect the filtrate, cool the filtrate to 10℃, add 17.2g of 22% hydrogen chloride-isopropanol solution dropwise, crystallization occurs, after the addition is complete, keep at 0℃ for 2h, filter, wash 3 times with frozen isopropanol (20mL×3), then dry the wet product under vacuum at 60℃ for 2h to obtain 36.8g of oxytetracycline hydrochloride, yield 92.0%. According to the European Pharmacopoeia standard, calculated on anhydrous basis, it contains oxytetracycline hydrochloride (C 22 H 24 N2O 9. The HCl content was 96.12%, and the bacterial endotoxin content was 0.194 EU / mg. The bacterial endotoxin content met the pharmacopoeia requirements, but the yield and content were reduced.

[0069] Figure 1 This is a high-performance liquid chromatogram of the injectable grade oxytetracycline hydrochloride prepared in Example 2 of the present invention. Figure 2 This is the high-performance liquid chromatogram of oxytetracycline hydrochloride prepared in Example 10 of the present invention. Figure 3 This is a high-performance liquid chromatogram of injectable grade oxytetracycline hydrochloride prepared in Example 11 of the present invention; (The chromatogram is provided in the original text.) Figure 1 , Figure 2 and Figure 3 It can be seen that the purity of oxytetracycline hydrochloride decreases with increasing salt formation temperature, indicating that low-temperature salt formation can reduce the generation of degradation impurities. In Examples 5 and 6, as Ca... 2+ Decreasing the concentration leads to an increase in bacterial endotoxin content. In Examples 7 and 8, reducing the amount of activated carbon also resulted in an increase in bacterial endotoxin content. In Example 9, compared to Example 2, isopropanol was replaced with methanol while other conditions remained unchanged; the endotoxin content in the product failed to meet pharmacopoeia requirements.

[0070] The following comparative examples all used oxytetracycline hydrochloride prepared using existing technical methods. After testing, the bacterial endotoxin content of all samples did not meet the requirements of the United States Pharmacopoeia and the European Pharmacopoeia.

[0071] Comparative Example 1

[0072] In a reactor, 300 g of oxytetracycline, 1350 mL of methanol, and 30 mL of methanol hydrochloride were added sequentially. After stirring for 30 mL, the mixture was heated to 50°C until all the oxytetracycline was dissolved. 4 g of activated carbon was added, and the temperature was further increased to 57°C. After stirring for 15 min, the mixture was filtered. The filtrate was cooled to 26°C, and then 39 g of dry hydrogen chloride gas was introduced while stirring. The temperature was gradually lowered to 2°C, and the mixture was stirred for 4 h. After filtration, the filter cake was washed with 100 mL of cold methanol and dried to obtain 280.5 g of oxytetracycline hydrochloride, with a yield of 93.5%. According to the European Pharmacopoeia standard, calculated on anhydrous basis, the oxytetracycline hydrochloride content is [missing value]. 22 H24 The content of N2O9.HCl was 97.32%, and the bacterial endotoxin content was 2.550 EU / mg, which did not meet the pharmacopoeia requirements.

[0073] Comparative Example 2

[0074] (1) Dissolution: Add 50g of oxytetracycline base to 350mL of ethanol, then add 3.85mL of hydrochloric acid-ethanol mixed solution, stir, and heat to 41℃ until completely dissolved to obtain a mixed solution;

[0075] (2) Activated carbon decolorization treatment: Add 0.1g of activated carbon to the mixed solution obtained in step (1), filter, and obtain oxytetracycline ethanol solution;

[0076] (3) Cooling and crystallization: Add 5 mL of concentrated hydrochloric acid to the oxytetracycline ethanol solution obtained in step (2), stir, cool to 6°C to crystallize, filter after 1.5 h, wash the filter cake with 6°C ethanol to obtain wet oxytetracycline hydrochloride.

[0077] (4) Drying: The wet product of oxytetracycline hydrochloride obtained in step (3) was dried to obtain 46.1g of oxytetracycline hydrochloride product, with a yield of 92.2%. According to the European Pharmacopoeia standard, calculated on an anhydrous basis, it contains oxytetracycline hydrochloride (C 22 H 24 The content of N2O9.HCl was 97.12%, and the bacterial endotoxin content was 8.343 EU / mg, which did not meet the pharmacopoeia requirements.

[0078] Comparative Example 3

[0079] Take 210 mL of methanol, 50 g of oxytetracycline base, and 5 g of calcium chloride (Ca 2+ (0.21 mol / L) Oxytetracycline base and calcium chloride were added to methanol, and the temperature was adjusted to 30℃. After stirring evenly, the mixture was filtered to obtain the filtrate. The temperature of the filtrate was controlled within the range of 21-23℃, and a methanol solution containing the equivalent of 2.6 g of hydrogen chloride was added to the filtrate to obtain a mixed solution. The mixed solution was intermittently stirred for 4 hours to precipitate oxytetracycline hydrochloride. After stirring, the mixture was filtered, washed with cold methanol, and dried to obtain 47.1 g of oxytetracycline hydrochloride, with a yield of 94.2%. According to the European Pharmacopoeia standard, calculated on an anhydrous basis, it contains oxytetracycline hydrochloride (C 22 H 24 The content of N2O9.HCl was 96.86%, and the bacterial endotoxin content was 5.349 EU / mg, which did not meet the pharmacopoeia requirements.

Claims

1. A method for preparing injectable grade oxytetracycline hydrochloride, characterized in that, Oxytetracycline, containing Ca 2+ Isopropanol and pretreated activated carbon were mixed, stirred and filtered. After the filtrate was cooled, a 22% hydrogen chloride-isopropanol solution was added dropwise. The mixture was stirred to crystallize, filtered, washed, and dried to obtain injectable grade oxytetracycline hydrochloride. The Ca 2+ The concentration is 0.5~0.8 mol / L; the amount of activated carbon used is 2~3% of oxytetracycline.

2. The method for preparing injectable grade oxytetracycline hydrochloride according to claim 1, characterized in that, The mass-to-volume ratio of oxytetracycline and isopropanol is 1:

10.

3. The method for preparing injectable grade oxytetracycline hydrochloride according to claim 1, characterized in that, The mass ratio of oxytetracycline to hydrogen chloride-isopropanol solution is 1:0.4~0.

5.

4. The method for preparing injectable grade oxytetracycline hydrochloride according to claim 1, characterized in that, The specific steps are as follows: 1) Soak activated carbon in a 2 mol / L sodium hydroxide solution for 2 hours, then wash with purified water, and bake the wet activated carbon at 300℃ for 1 hour to obtain pretreated activated carbon. 2) Dissolve oxytetracycline in a solution containing Ca 2+ In isopropanol, the temperature is raised to 50-53°C, the pretreated activated carbon obtained in step 1) is added, and the mixture is stirred for 30 minutes. The mixture is then filtered, and the filtrate is collected. The filtrate contains Ca... 2+ The concentration is 0.5~0.8 mol / L; the mass-to-volume ratio of oxytetracycline and isopropanol is 1:10; the amount of activated carbon used is 2~3% of the amount of oxytetracycline. 3) Cool the filtrate collected in step 2) to -5℃~0℃, add dropwise a 22% hydrogen chloride-isopropanol solution, stir and crystallize at 0℃, keep warm for 2h, filter, wash with frozen isopropanol, and vacuum dry to obtain injectable grade oxytetracycline hydrochloride. The mass ratio of oxytetracycline to hydrogen chloride-isopropanol solution is 1:0.4~0.

5.

5. The method for preparing injectable grade oxytetracycline hydrochloride according to claim 4, characterized in that, In step 1), the mass-to-volume ratio of activated carbon to sodium hydroxide solution is 1:3~4.

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