CN111548284A - Method for refining doxycycline hydrochloride - Google Patents
Method for refining doxycycline hydrochloride Download PDFInfo
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- CN111548284A CN111548284A CN202010302070.8A CN202010302070A CN111548284A CN 111548284 A CN111548284 A CN 111548284A CN 202010302070 A CN202010302070 A CN 202010302070A CN 111548284 A CN111548284 A CN 111548284A
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- acetone
- doxycycline hydrochloride
- doxycycline
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- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960004082 doxycycline hydrochloride Drugs 0.000 title claims abstract description 76
- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000007670 refining Methods 0.000 title claims abstract description 26
- 239000012046 mixed solvent Substances 0.000 claims abstract description 60
- 239000007787 solid Substances 0.000 claims abstract description 60
- 239000000706 filtrate Substances 0.000 claims abstract description 37
- 238000001035 drying Methods 0.000 claims abstract description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960003722 doxycycline Drugs 0.000 claims abstract description 25
- 238000001914 filtration Methods 0.000 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 238000005406 washing Methods 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 18
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 15
- 239000012467 final product Substances 0.000 claims abstract description 8
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 238000004806 packaging method and process Methods 0.000 claims abstract description 7
- 239000000725 suspension Substances 0.000 claims abstract description 7
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 claims abstract 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 156
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 238000001291 vacuum drying Methods 0.000 claims description 30
- 239000013078 crystal Substances 0.000 claims description 26
- 238000002425 crystallisation Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 18
- 238000004321 preservation Methods 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000047 product Substances 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 27
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 19
- 239000012535 impurity Substances 0.000 description 18
- 238000001514 detection method Methods 0.000 description 5
- 239000012085 test solution Substances 0.000 description 4
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
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- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
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- RTGDFNSFWBGLEC-TVPGTPATSA-N 2-morpholin-4-ylethyl (z)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1h-2-benzofuran-5-yl)-4-methylhex-4-enoate Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(\C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-TVPGTPATSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 241000589902 Leptospira Species 0.000 description 1
- 208000001572 Mycoplasma Pneumonia Diseases 0.000 description 1
- 201000008235 Mycoplasma pneumoniae pneumonia Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940126525 broad-spectrum semisynthetic tetracycline antibiotic Drugs 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 208000028104 epidemic louse-borne typhus Diseases 0.000 description 1
- GTCCMGFBIWUBLQ-UHFFFAOYSA-N formamide;hydrochloride Chemical compound Cl.NC=O GTCCMGFBIWUBLQ-UHFFFAOYSA-N 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 201000003265 lymphadenitis Diseases 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 208000006379 syphilis Diseases 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 206010061393 typhus Diseases 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
- C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
- C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
- C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for refining doxycycline hydrochloride, which belongs to the technical field of chemical substance purification and comprises the following steps: s1, adding the raw materials into the mixed solvent until the raw materials are clear, and filtering; s2, adding concentrated ammonia water into the filtrate, stirring, cooling, keeping the temperature, crystallizing, centrifuging, filtering and drying to obtain doxycycline solid; s3, adding doxycycline solid into the mixed solvent to prepare a suspension, stirring, controlling the temperature, and dropwise adding concentrated hydrochloric acid solution; s4, controlling the temperature, stirring, maintaining the temperature, crystallizing, filtering, washing and drying to obtain refined doxycycline hydrochloride solid; and S5, crushing the refined doxycycline hydrochloride solid, and packaging to obtain the final product doxycycline hydrochloride. The refining method can obtain high-purity doxycycline hydrochloride, has simple refining steps and high product yield, is suitable for industrial mass production, and is favorable for improving the quality of preparation products and reducing toxic and side effects when the refined doxycycline hydrochloride is used for preparing subsequent products.
Description
Technical Field
The invention relates to doxycycline hydrochloride, in particular to a method for refining doxycycline hydrochloride, belonging to the technical field of chemical substance purification.
Background
Doxycycline hydrochloride (Doxycycline hydrochloride) with chemical name of 6-methyl-4- (dimethylamino) -3, 5, 10, 12, 12 a-pentahydroxy-1, 11-dioxo-1, 4, 4a, 5, 5a, 6, 11, 12 a-octahydro-2-tetracene formamide hydrochloride hemihydrate hemiethanolate with molecular formula C22H24N2O8·HCl·1/2H2O·1/2C2H5OH; molecular weight: 512.94, structural formula:
doxycycline hydrochloride is a broad-spectrum semisynthetic tetracycline antibiotic, is effective on gram-positive bacteria, gram-negative bacteria and chlamydia, and is clinically used for treating respiratory tract infection, biliary tract infection, tonsillitis, lymphadenitis, cellulitis, senile chronic bronchitis, mycoplasma pneumonia, syphilis, gonorrhea, typhus, cholera, regression fever, and preventing malignant malaria and leptospira.
The impurities of more than 0.1 percent (area normalized purity of high performance liquid chromatography) in the commercial doxycycline hydrochloride bulk drug comprise beta-doxycycline (impurity A in European pharmacopoeia, the content of the impurities is not more than 2.0 percent specified by the pharmacopoeia) and 2-acetyl-2-decarburized amide doxycycline (impurity F in European pharmacopoeia, the content of the impurities is not more than 2.0 percent specified by the pharmacopoeia), and the total impurity content of the preparation is overhigh due to overhigh content of the impurities, the quality of the doxycycline hydrochloride preparation can be seriously influenced, and the side effect is improved; but the physicochemical properties of the impurity A and the impurity F are very close to those of doxycycline and are difficult to remove.
As for the refined crystal of doxycycline hydrochloride, anhydrous ethanol is always adopted to suspend free alkali and hydrochloric acid is added to refine the crystal, but the purity of doxycycline hydrochloride prepared by the method is not high; or the content of one of the impurity A or the impurity F is obviously reduced after refining, but the contents of the two impurities can not be simultaneously reduced to a lower level.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for refining doxycycline hydrochloride to obtain high-purity doxycycline hydrochloride.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for refining doxycycline hydrochloride comprises the following steps:
step S1, adding doxycycline hydrochloride serving as a raw material into a mixed solvent of water and acetone until the doxycycline hydrochloride is dissolved clearly, filtering to obtain a first filtrate and a first filter residue, washing the first filter residue with the mixed solvent of water and acetone, filtering to obtain a second filtrate, and mixing the second filtrate with the first filtrate to obtain a filtrate;
step S2, controlling the temperature, adding concentrated ammonia water into the filtrate obtained in the step S1 to adjust the pH value to 5.5-6.5, stirring, cooling, preserving heat, crystallizing, centrifuging and filtering to obtain a first solid crystal, washing the first solid crystal by a mixed solvent of water and acetone, and drying to obtain a doxycycline solid;
step S3, adding the doxycycline solid in the step S2 into a mixed solvent of absolute ethyl alcohol and acetone to prepare a suspension, stirring, controlling the temperature, and dropwise adding a concentrated hydrochloric acid solution;
step S4, controlling the temperature of the solution obtained in the step S3, stirring, maintaining the temperature, crystallizing, filtering to obtain a second solid crystal, washing the second solid crystal with absolute ethyl alcohol, and drying to obtain refined doxycycline hydrochloride solid;
and S5, crushing the refined doxycycline hydrochloride solid obtained in the step S4, and packaging to obtain the final product doxycycline hydrochloride.
The technical scheme of the invention is further improved as follows: and the volume ratio of water to acetone in the mixed solvent of water and acetone in the step S1 and the step S2 is 2: 1-1: 2.
The technical scheme of the invention is further improved as follows: the volume ratio of water to acetone in the mixed solvent of water and acetone in the step S1 and the step S2 is 1: 1.
The technical scheme of the invention is further improved as follows: the volume-mass ratio of the mixed solvent of water and acetone to the raw material doxycycline hydrochloride in the step S1 is 5-10: 1.
The technical scheme of the invention is further improved as follows: the volume-mass ratio of the mixed solvent of water and acetone to the raw material doxycycline hydrochloride in the step S1 is 7-9: 1.
The technical scheme of the invention is further improved as follows: the concentration of the concentrated ammonia water in the step S2 is 25-28%, and the concentration of the concentrated hydrochloric acid solution in the step S3 is 35-37%; the temperature is controlled to be 25 +/-5 ℃ in the step S2, and the temperature for thermal crystallization is controlled to be 15 +/-5 ℃ in the step S2.
The technical scheme of the invention is further improved as follows: the volume ratio of the absolute ethyl alcohol to the acetone in the mixed solvent of the absolute ethyl alcohol and the acetone in the step S3 is 2: 1-1: 2.
The technical scheme of the invention is further improved as follows: the volume ratio of the absolute ethyl alcohol to the acetone in the mixed solvent of the absolute ethyl alcohol and the acetone in the step S3 is 1: 1.
The technical scheme of the invention is further improved as follows: the volume-mass ratio of the mixed solvent of the absolute ethyl alcohol and the acetone to the doxycycline solid in the step S3 is 5-15: 1, and the temperature for heat preservation and crystallization in the step S4 is 15 +/-5 ℃.
The technical scheme of the invention is further improved as follows: the drying in the step S2 and the step S4 is vacuum drying, the conditions during the vacuum drying are that the drying temperature is 35 +/-5 ℃, the vacuum degree is-0.08 +/-0.01 MPa, and the vacuum drying time is 10 +/-2 h.
Due to the adoption of the technical scheme, the invention has the technical progress that:
the refining method can obtain high-purity doxycycline hydrochloride, has simple refining steps and high product yield, is suitable for industrial mass production, and is favorable for improving the quality of preparation products and reducing toxic and side effects when the refined doxycycline hydrochloride is used for preparing subsequent products.
Drawings
Figure 1 is a process flow diagram of a doxycycline hydrochloride refining process of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following examples:
as shown in fig. 1, a method for refining doxycycline hydrochloride comprises the following steps:
step S1, adding doxycycline hydrochloride serving as a raw material into a mixed solvent of water and acetone until the doxycycline hydrochloride is dissolved clearly, filtering to obtain a first filtrate and a first filter residue, washing the first filter residue with the mixed solvent of water and acetone, filtering to obtain a second filtrate, and mixing the second filtrate with the first filtrate to obtain a filtrate; wherein the volume ratio of water to acetone in the mixed solvent of water and acetone is 2: 1-1: 2, preferably 1: 1; wherein the volume-to-mass ratio of the mixed solvent of water and acetone to the raw material doxycycline hydrochloride is 5-10: 1 (unit is ml/g), preferably 7-9: 1;
step S2, controlling the temperature to be 25 +/-5 ℃, adding concentrated ammonia water into the filtrate obtained in the step S1 to adjust the pH value to 5.5-6.5, stirring and cooling to 15 +/-5 ℃, preserving heat and crystallizing, then carrying out centrifugal filtration to obtain a first solid crystal, washing the first solid crystal by a mixed solvent of water and acetone, and drying to obtain a doxycycline solid; the volume ratio of water to acetone in the mixed solvent of water and acetone is 2: 1-1: 2, preferably 1: 1; wherein the concentration of the concentrated ammonia water is 25-28%, and the temperature of heat preservation and crystallization is 15 +/-5 ℃; wherein the drying is vacuum drying, the conditions of the vacuum drying are that the drying temperature is 35 +/-5 ℃, the vacuum degree is-0.08 +/-0.01 MPa, and the vacuum drying time is 10 +/-2 h;
step S3, adding the doxycycline solid in the step S2 into a mixed solvent of absolute ethyl alcohol and acetone to prepare a suspension, stirring, controlling the temperature, and dropwise adding a concentrated hydrochloric acid solution; wherein the concentration of the concentrated hydrochloric acid solution is 35-37%; wherein the volume ratio of the anhydrous ethanol to the acetone in the mixed solvent of the anhydrous ethanol and the acetone is 2: 1-1: 2, preferably 1: 1; the volume-to-mass ratio of the mixed solvent of the absolute ethyl alcohol and the acetone to the doxycycline solid is 5-15: 1 (unit is ml/g).
Step S4, controlling the temperature of the solution obtained in the step S3 to be 15 +/-5 ℃, stirring, carrying out heat preservation and crystallization, filtering to obtain a second solid crystal, washing the second solid crystal with absolute ethyl alcohol, and drying to obtain refined doxycycline hydrochloride solid; wherein the temperature for heat preservation and crystallization is 15 +/-5 ℃; wherein the drying is vacuum drying, the conditions of the vacuum drying are that the drying temperature is 35 +/-5 ℃, the vacuum degree is-0.08 +/-0.01 MPa, and the vacuum drying time is 10 +/-2 h;
and S5, crushing the refined doxycycline hydrochloride solid obtained in the step S4, and packaging to obtain the final product doxycycline hydrochloride.
Example 1
A method for refining doxycycline hydrochloride comprises the following steps:
step S1, adding 400g of raw material doxycycline hydrochloride into a mixed solvent of water and acetone until the mixture is clear, then carrying out reduced pressure filtration to obtain a first filtrate and a first filter residue, washing the first filter residue with the mixed solvent of water and acetone, then carrying out filtration to obtain a second filtrate, and combining the second filtrate and the first filtrate to obtain a filtrate; wherein the volume ratio of water to acetone in the mixed solvent of water and acetone is 1:1, and the volume mass ratio of the mixed solvent of water and acetone to the raw material doxycycline hydrochloride is 8: 1;
step S2, controlling the temperature to be 25 ℃, adding concentrated ammonia water into the filtrate obtained in the step S1 to adjust the pH value to 6.0, stirring, cooling to 15 ℃, preserving heat, crystallizing, performing centrifugal filtration to obtain a first solid crystal, washing the first solid crystal by a mixed solvent of water and acetone, and drying to obtain 322g of doxycycline solid; the volume ratio of water to acetone in the mixed solvent of water and acetone is 1: 1; wherein the concentration of the concentrated ammonia water is 26 percent, the temperature for heat preservation and crystallization is 15 ℃, and the time is 4.5 hours; wherein the drying is vacuum drying, and the conditions during the vacuum drying are that the drying temperature is 35 ℃, the vacuum degree is-0.08 MPa, and the vacuum drying time is 10 hours;
step S3, adding the doxycycline solid in the step S2 into a mixed solvent of absolute ethyl alcohol and acetone to prepare a suspension, stirring, controlling the temperature, and dropwise adding a concentrated hydrochloric acid solution; wherein the concentration of the concentrated hydrochloric acid solution is 36 percent; wherein the volume ratio of the anhydrous ethanol to the acetone in the mixed solvent of the anhydrous ethanol and the acetone is 1: 1; the volume-mass ratio of the mixed solvent of the absolute ethyl alcohol and the acetone to the doxycycline solid is 10: 1.
Step S4, controlling the temperature of the solution obtained in the step S3 to be 15 ℃, stirring, carrying out heat preservation and crystallization, filtering to obtain a second solid crystal, washing the second solid crystal with absolute ethyl alcohol, and drying to obtain 331g of refined doxycycline hydrochloride solid; wherein the temperature for heat preservation and crystallization is 15 ℃, and the time is 4.5 h; wherein the drying is vacuum drying, and the conditions during the vacuum drying are that the drying temperature is 35 ℃, the vacuum degree is-0.08 MPa, and the vacuum drying time is 10 hours;
and S5, crushing the refined doxycycline hydrochloride solid obtained in the step S4, and packaging to obtain the final product doxycycline hydrochloride.
Example 2
A method for refining doxycycline hydrochloride comprises the following steps:
step S1, adding 400g of raw material doxycycline hydrochloride into a mixed solvent of water and acetone until the mixture is clear, then carrying out reduced pressure filtration to obtain a first filtrate and a first filter residue, washing the first filter residue with the mixed solvent of water and acetone, then carrying out filtration to obtain a second filtrate, and combining the second filtrate and the first filtrate to obtain a filtrate; wherein the volume ratio of water to acetone in the mixed solvent of water and acetone is 2:1, and the volume mass ratio of the mixed solvent of water and acetone to the raw material doxycycline hydrochloride is 7: 1;
step S2, controlling the temperature to be 28 ℃, adding concentrated ammonia water into the filtrate obtained in the step S1 to adjust the pH value to 6.5, stirring and cooling to 18 ℃, preserving heat for crystallization, then carrying out centrifugal filtration to obtain a first solid crystal, washing the first solid crystal by a mixed solvent of water and acetone, and drying to obtain 316g of doxycycline solid; the volume ratio of water to acetone in the mixed solvent of water and acetone is 2: 1; wherein the concentration of the concentrated ammonia water is 27 percent, the temperature for heat preservation and crystallization is 18 ℃, and the time is 5 hours; wherein the drying is vacuum drying, the conditions of the vacuum drying are that the drying temperature is 38 ℃, the vacuum degree is-0.07 MPa, and the vacuum drying time is 12 hours;
step S3, adding the doxycycline solid in the step S2 into a mixed solvent of absolute ethyl alcohol and acetone to prepare a suspension, stirring, controlling the temperature, and dropwise adding a concentrated hydrochloric acid solution; wherein the concentration of the concentrated hydrochloric acid solution is 36.5 percent; wherein the volume ratio of the absolute ethyl alcohol to the acetone in the mixed solvent of the absolute ethyl alcohol and the acetone is 2: 1; the volume-to-mass ratio of the mixed solvent of the absolute ethyl alcohol and the acetone to the doxycycline solid is 8: 1.
Step S4, controlling the temperature of the solution obtained in the step S3 to be 18 ℃, stirring, carrying out heat preservation and crystallization, filtering to obtain a second solid crystal, washing the second solid crystal with absolute ethyl alcohol, and drying to obtain 310g of refined doxycycline hydrochloride solid; wherein the temperature for heat preservation and crystallization is 18 ℃ and the time is 5 h; wherein the drying is vacuum drying, the conditions of the vacuum drying are that the drying temperature is 38 ℃, the vacuum degree is-0.07 MPa, and the vacuum drying time is 12 hours;
and S5, crushing the refined doxycycline hydrochloride solid obtained in the step S4, and packaging to obtain the final product doxycycline hydrochloride.
Example 3
A method for refining doxycycline hydrochloride comprises the following steps:
step S1, adding 400g of raw material doxycycline hydrochloride into a mixed solvent of water and acetone until the mixture is clear, then carrying out reduced pressure filtration to obtain a first filtrate and a first filter residue, washing the first filter residue with the mixed solvent of water and acetone, then carrying out filtration to obtain a second filtrate, and combining the second filtrate and the first filtrate to obtain a filtrate; wherein the volume ratio of water to acetone in the mixed solvent of water and acetone is 1:2, and the volume mass ratio of the mixed solvent of water and acetone to the raw material doxycycline hydrochloride is 9: 1;
step S2, controlling the temperature to be 23 ℃, adding concentrated ammonia water into the filtrate obtained in the step S1 to adjust the pH value to 5.5, stirring and cooling to 13 ℃, preserving heat for crystallization, then carrying out centrifugal filtration to obtain a first solid crystal, washing the first solid crystal by a mixed solvent of water and acetone, and drying to obtain 328g of doxycycline solid; the volume ratio of water to acetone in the mixed solvent of water and acetone is 1: 2; wherein the concentration of the concentrated ammonia water is 25%, the temperature for heat preservation and crystallization is 13 ℃, and the time is 4 h; wherein the drying is vacuum drying, the conditions of the vacuum drying are that the drying temperature is 33 ℃, the vacuum degree is-0.09 MPa, and the vacuum drying time is 11 h;
step S3, adding the doxycycline solid in the step S2 into a mixed solvent of absolute ethyl alcohol and acetone to prepare a suspension, stirring, controlling the temperature, and dropwise adding a concentrated hydrochloric acid solution; wherein the concentration of the concentrated hydrochloric acid solution is 35.5 percent; wherein the volume ratio of the anhydrous ethanol to the acetone in the mixed solvent of the anhydrous ethanol and the acetone is 1: 2; the volume-to-mass ratio of the mixed solvent of the absolute ethyl alcohol and the acetone to the doxycycline solid is 13: 1.
Step S4, controlling the temperature of the solution obtained in the step S3 to be 13 ℃, stirring, carrying out heat preservation and crystallization, filtering to obtain a second solid crystal, washing the second solid crystal with absolute ethyl alcohol, and drying to obtain 296g of refined doxycycline hydrochloride solid; wherein the temperature for heat preservation and crystallization is 13 ℃, and the time is 4 hours; wherein the drying is vacuum drying, the conditions of the vacuum drying are that the drying temperature is 33 ℃, the vacuum degree is-0.09 MPa, and the vacuum drying time is 11 h;
and S5, crushing the refined doxycycline hydrochloride solid obtained in the step S4, and packaging to obtain the final product doxycycline hydrochloride.
In order to fully illustrate the advantages of the present invention, the doxycycline hydrochloride and the raw material drug obtained by refining in examples 1 to 3 are subjected to quality detection, it is known that the doxycycline hydrochloride used as the raw material drug in examples 1 to 3 is taken from the same batch, the specific detection object is the content of the related substance of doxycycline hydrochloride before and after refining, and the detection method and the detection result are as follows:
detection method-related substances:
octadecylsilane bonded silica gel as a packing material (Agilent Eclipse Plus C184.6X 250mm5 μm or equivalent performance column); using (acetonitrile-water- (67.9g/L tetrabutylammonium hydrogen sulfate, using concentrated ammonia water to adjust the pH value to 7.0) -solution A (111.6 g disodium ethylene diamine tetraacetate is weighed to 900ml water, using concentrated ammonia water to adjust the pH value to 7.0, adding water to dilute to 1000ml) as a mobile phase (13:17:35: 35); the column temperature was 35 ℃; the detection wavelength is 280 nm; the flow rate was 1ml per minute; the sample introduction temperature was 5 ℃. Weighing 5mg of an EP system suitability reference substance (doxycline for system reliability CRS), adding 1g/LHCl solution to dissolve and dilute to 10ml, injecting 20 mu l into a liquid chromatograph, and recording a chromatogram, wherein the separation degree between an EP impurity A peak and an EP impurity B peak is not less than 2.0, and the separation degree between the EP impurity B peak and a doxycycline peak is not less than 2.0.
Taking about 20.0mg of the product, precisely weighing, placing in a 25ml measuring flask, adding 1g/L hydrochloric acid solution for dissolving, diluting to scale, and shaking uniformly to obtain a test solution; 1ml was measured precisely and diluted to 100ml with 1g/L hydrochloric acid solution as a control solution. Precisely measuring 20 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 2 times. If an impurity peak exists in a chromatogram of a test solution, the peak area of an EP impurity A is not more than 2 times (2.0%) of the main peak area of a control solution, the peak area of an EP impurity B is not more than 0.5 times (0.5%) of the main peak area of the control solution, the peak area of an EP impurity C is not more than 0.2 times (0.2%) of the main peak area of the control solution, the peak area of an EP impurity F is not more than 1.0% of the main peak area of the control solution, other single impurity peaks are not more than 0.1 times (0.1%) of the main peak area of the control solution, and the sum of the peak areas of all impurities is not more than 3 times (3.0%). Chromatographic peaks in the chromatogram of the test solution, which are 0.05 times (0.05%) smaller than the area of the main peak of the control solution, are ignored.
The results are shown in the following table: wherein "intermediate solid" in table 1 refers to doxycycline solid obtained in step S3 in the corresponding examples, "final product" refers to doxycycline hydrochloride in step S4 or S5 in the corresponding examples, and "content (%)" refers to mass content percentage.
TABLE 1
Claims (10)
1. A method for refining doxycycline hydrochloride is characterized in that: the method comprises the following steps:
step S1, adding doxycycline hydrochloride serving as a raw material into a mixed solvent of water and acetone until the doxycycline hydrochloride is dissolved clearly, filtering to obtain a first filtrate and a first filter residue, washing the first filter residue with the mixed solvent of water and acetone, filtering to obtain a second filtrate, and mixing the second filtrate with the first filtrate to obtain a filtrate;
step S2, controlling the temperature, adding concentrated ammonia water into the filtrate obtained in the step S1 to adjust the pH value to 5.5-6.5, stirring, cooling, preserving heat, crystallizing, centrifuging and filtering to obtain a first solid crystal, washing the first solid crystal by a mixed solvent of water and acetone, and drying to obtain a doxycycline solid;
step S3, adding the doxycycline solid in the step S2 into a mixed solvent of absolute ethyl alcohol and acetone to prepare a suspension, stirring, controlling the temperature, and dropwise adding a concentrated hydrochloric acid solution;
step S4, controlling the temperature of the solution obtained in the step S3, stirring, maintaining the temperature, crystallizing, filtering to obtain a second solid crystal, washing the second solid crystal with absolute ethyl alcohol, and drying to obtain refined doxycycline hydrochloride solid;
and S5, crushing the refined doxycycline hydrochloride solid obtained in the step S4, and packaging to obtain the final product doxycycline hydrochloride.
2. The method for refining doxycycline hydrochloride according to claim 1, wherein the method comprises the following steps: and the volume ratio of water to acetone in the mixed solvent of water and acetone in the step S1 and the step S2 is 2: 1-1: 2.
3. The method for refining doxycycline hydrochloride according to claim 2, wherein the method comprises the following steps: the volume ratio of water to acetone in the mixed solvent of water and acetone in the step S1 and the step S2 is 1: 1.
4. The method for refining doxycycline hydrochloride according to claim 1, wherein the method comprises the following steps: the volume-mass ratio of the mixed solvent of water and acetone to the raw material doxycycline hydrochloride in the step S1 is 5-10: 1.
5. The method of claim 4, wherein the doxycycline hydrochloride is prepared by the following steps: the volume-mass ratio of the mixed solvent of water and acetone to the raw material doxycycline hydrochloride in the step S1 is 7-9: 1.
6. The method for refining doxycycline hydrochloride according to claim 1, wherein the method comprises the following steps: the concentration of the concentrated ammonia water in the step S2 is 25-28%, and the concentration of the concentrated hydrochloric acid solution in the step S3 is 35-37%; the temperature is controlled to be 25 +/-5 ℃ in the step S2, and the temperature for thermal crystallization is controlled to be 15 +/-5 ℃ in the step S2.
7. The method for refining doxycycline hydrochloride according to claim 1, wherein the method comprises the following steps: the volume ratio of the absolute ethyl alcohol to the acetone in the mixed solvent of the absolute ethyl alcohol and the acetone in the step S3 is 2: 1-1: 2.
8. The method of claim 7, wherein the doxycycline hydrochloride is prepared by the following steps: the volume ratio of the absolute ethyl alcohol to the acetone in the mixed solvent of the absolute ethyl alcohol and the acetone in the step S3 is 1: 1.
9. The method for refining doxycycline hydrochloride according to claim 1, wherein the method comprises the following steps: the volume-mass ratio of the mixed solvent of the absolute ethyl alcohol and the acetone to the doxycycline solid in the step S3 is 5-15: 1, and the temperature for heat preservation and crystallization in the step S4 is 15 +/-5 ℃.
10. The method for refining doxycycline hydrochloride according to claim 1, wherein the method comprises the following steps: the drying in the step S2 and the step S4 is vacuum drying, the conditions during the vacuum drying are that the drying temperature is 35 +/-5 ℃, the vacuum degree is-0.08 +/-0.01 MPa, and the vacuum drying time is 10 +/-2 h.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106543025A (en) * | 2015-09-21 | 2017-03-29 | 瑞普（天津）生物药业有限公司 | A kind of preparation method of high-purity hydrochloric acid doxycycline |
| CN107162925A (en) * | 2017-05-16 | 2017-09-15 | 扬州联博药业有限公司 | A kind of method for preparing Doxycycline Hyclate working reference substance |
| CN107417563A (en) * | 2017-04-12 | 2017-12-01 | 扬州联博药业有限公司 | A kind of method that Doxycycline Hyclate is reclaimed in the refinement mother liquor from Doxycycline Hyclate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106543025A (en) * | 2015-09-21 | 2017-03-29 | 瑞普（天津）生物药业有限公司 | A kind of preparation method of high-purity hydrochloric acid doxycycline |
| CN107417563A (en) * | 2017-04-12 | 2017-12-01 | 扬州联博药业有限公司 | A kind of method that Doxycycline Hyclate is reclaimed in the refinement mother liquor from Doxycycline Hyclate |
| CN107162925A (en) * | 2017-05-16 | 2017-09-15 | 扬州联博药业有限公司 | A kind of method for preparing Doxycycline Hyclate working reference substance |
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