CN111377861A - Method for purifying hydroxychloroquine sulfate - Google Patents
Method for purifying hydroxychloroquine sulfate Download PDFInfo
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- CN111377861A CN111377861A CN201811625880.6A CN201811625880A CN111377861A CN 111377861 A CN111377861 A CN 111377861A CN 201811625880 A CN201811625880 A CN 201811625880A CN 111377861 A CN111377861 A CN 111377861A
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- hydroxychloroquine sulfate
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- ZAVJTSLIGAGALR-UHFFFAOYSA-N 2-(2,2,2-trifluoroacetyl)cyclooctan-1-one Chemical compound FC(F)(F)C(=O)C1CCCCCCC1=O ZAVJTSLIGAGALR-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 229960002927 hydroxychloroquine sulfate Drugs 0.000 title claims abstract description 67
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000002425 crystallisation Methods 0.000 claims abstract description 32
- 230000008025 crystallization Effects 0.000 claims abstract description 31
- 238000010992 reflux Methods 0.000 claims abstract description 30
- 239000002245 particle Substances 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 239000012043 crude product Substances 0.000 claims abstract description 17
- 238000001816 cooling Methods 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 13
- 239000011259 mixed solution Substances 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 7
- 239000012046 mixed solvent Substances 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 86
- 239000012535 impurity Substances 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 14
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 26
- 238000003756 stirring Methods 0.000 description 19
- 239000000203 mixture Substances 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002386 leaching Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- HXEWMTXDBOQQKO-UHFFFAOYSA-N 4,7-dichloroquinoline Chemical compound ClC1=CC=NC2=CC(Cl)=CC=C21 HXEWMTXDBOQQKO-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 229960004171 hydroxychloroquine Drugs 0.000 description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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 1
- XUVXSSOPXQRCGL-UHFFFAOYSA-N 2-[4-aminopentyl(ethyl)amino]ethanol Chemical compound OCCN(CC)CCCC(C)N XUVXSSOPXQRCGL-UHFFFAOYSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
Landscapes
- 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 purifying hydroxychloroquine sulfate, which comprises the following steps: (1) dissolving the hydroxychloroquine sulfate crude product in water or a mixed solvent of water and a first solvent to obtain a mixed solution I; (2) adding a second solvent into the mixed solution I, and performing reflux crystallization; (3) cooling, filtering and drying to obtain the refined hydroxychloroquine sulfate. The method has excellent purification effect, can obtain hydroxychloroquine sulfate with the purity of over 99.5 percent and the particle size Dx (90) of more than or equal to 200 mu m, has simple and convenient operation, low cost, safety and environmental protection, and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for purifying hydroxychloroquine sulfate.
Background
Hydroxychloroquine sulfate has the following structural formula, and the chemical name is (+/-) -2[ [4- [ (7-chloro-4-quinolyl) amino]Pentyl radical]-ethylamino group]Ethanol sulfate with CAS number 747-36-4 and molecular formula C18H26ClN3O·H2SO4. Hydroxychloroquine sulfate was synthesized by Surrey and Hammer in 1946 and first marketed in the united states in 1956 as an antimalarial. 29/5/1998, hydroxychloroquine sulfate tablets are approved by the FDA in the united states for the treatment of lupus erythematosus and rheumatoid arthritis. Due to the unique action mechanism and better safety, hydroxychloroquine sulfate is widely applied to the clinical application of the rheumatism field, and after 90 years in the 20 th century, hydroxychloroquine sulfate is selected for clinical treatment of more than 90% of rheumatism, and has the following structure:
at present, the common method for controlling the quality of hydroxychloroquine sulfate is to improve the purity of hydroxychloroquine through recrystallization, salify the high-purity hydroxychloroquine and sulfuric acid, and filter to obtain the hydroxychloroquine sulfate. The quality control is only controlled from the source, no proper method is available for product control, the preparation process hardly meets the GMP requirement, and the hydroxychloroquine sulfate medicine is easy to have abnormal conditions such as unqualified related substances, clarity, acidity and crystal form, and related solutions for the abnormal conditions are not reported in literature data at present.
Therefore, a purification method of the finished hydroxychloroquine sulfate is needed to provide hydroxychloroquine sulfate with high purity.
Disclosure of Invention
The invention aims to provide a method for purifying hydroxychloroquine sulfate, wherein the purity of the product is more than 99.5 percent, the maximum known single impurity is less than or equal to 0.1 percent, the maximum unknown single impurity is less than or equal to 0.05 percent, the total impurity is less than or equal to 0.50 percent, and the particle size Dx (90) is more than or equal to 200 mu m.
In a first aspect of the present invention, there is provided a method for purifying hydroxychloroquine sulfate, said method comprising the steps of:
(1) dissolving the hydroxychloroquine sulfate crude product in water or a mixed solvent of water and a first solvent to obtain a mixed solution I;
(2) adding a second solvent into the mixed solution I, and performing reflux crystallization;
(3) cooling, filtering and drying to obtain the refined hydroxychloroquine sulfate.
In another preferred embodiment, the first solvent is selected from the group consisting of: methanol, ethanol, dimethyl sulfoxide, or a combination thereof.
In another preferred embodiment, the first solvent is selected from methanol or ethanol, preferably ethanol.
In another preferred embodiment, the second solvent is selected from the group consisting of: methanol, ethanol, isopropanol, acetone, or combinations thereof.
In another preferred embodiment, the volume ratio of water to the first solvent in the mixed solvent is 1:0-10, preferably 1:1-5, more preferably 1:2-4, and most preferably 1: 3-4.
In another preferred embodiment, the weight ratio of the hydroxychloroquine sulfate crude product to the water is 1:0.5-5, preferably 1:1-3, more preferably 1: 1-2.
In another preferred embodiment, the dissolution temperature is 0-100 ℃, preferably 30-90 ℃, more preferably 50-80 ℃, most preferably 60-80 ℃.
In another preferred embodiment, the dissolution is carried out under stirring.
In another preferred embodiment, the X-ray powder diffraction pattern of the obtained refined hydroxychloroquine sulfate product contains the following characteristic peaks measured by the 2 theta reflection angle: 12.9 +/-0.2 degrees, 16.9 +/-0.2 degrees, 17.1 +/-0.2 degrees, 17.5 +/-0.2 degrees, 19.9 +/-0.2 degrees, 21.3 +/-0.2 degrees, 23.5 +/-0.2 degrees, 23.9 +/-0.2 degrees and 26.7 +/-0.2 degrees.
In another preferred embodiment, the weight-to-volume (g/mL) ratio of the crude hydroxychloroquine sulfate to the second solvent is 1:5-15, preferably 1:6-12, and more preferably 1: 8-10.
In another preferred example, in the step (2), after the reflux crystallization, the method further comprises the steps of:
(2-1) cooling and continuing to crystallize.
In another preferred example, in the step (2-1), the crystallization has one or more of the following characteristics:
1) the crystallization temperature is 10-50 ℃, preferably 20-40 ℃, and more preferably 30-40 ℃;
2) the crystallization time is 1-24h, preferably 3-22h, more preferably 3-15 h.
In another preferred embodiment, the reflow crystallization has one or more of the following characteristics:
1) the temperature of the reflux crystallization is 60-90 ℃, preferably 60-80 ℃, and more preferably 75-80 ℃;
2) the reflux crystallization time is 0.5-5h, preferably 0.5-3h, more preferably 0.5-2 h.
In another preferred example, the reflux crystallization is stirring reflux crystallization or standing reflux crystallization;
in another preferred embodiment, the refined hydroxychloroquine sulfate has one or more of the following characteristics:
1) the purity of the refined hydroxychloroquine sulfate product is more than or equal to 99.5 percent;
2) the maximum known single impurity content of the refined hydroxychloroquine sulfate is less than or equal to 0.1 percent;
3) the maximum unknown single impurity content of the refined hydroxychloroquine sulfate is less than or equal to 0.05 percent;
4) the total impurity content of the refined hydroxychloroquine sulfate is less than or equal to 0.50 percent;
5) the particle size Dx (90) of the refined hydroxychloroquine sulfate is 200-;
the percentage is calculated by the total mass of the hydroxychloroquine sulfate refined product.
In another preferred embodiment, the known single impurity is selected from: impurity A, impurity B, impurity C, impurity D, impurity E, impurity F or impurity G specified by hydroxychloroquine sulfate quality standard in European pharmacopoeia.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor develops a hydroxychloroquine sulfate purification method which is dissolved and crystallized at a reflux temperature to obtain a product, and surprisingly, the hydroxychloroquine sulfate product prepared by the purification method has the purity of more than or equal to 99.5 percent, the maximum known single impurity content of less than or equal to 0.1 percent, the maximum unknown single impurity content of less than or equal to 0.05 percent, the total impurity content of less than or equal to 0.50 percent, the particle size Dx (90) of more than or equal to 200 mu m, the crystallization yield of more than 84 percent, the purity is high, the yield is high, the crystal particle size is large, and the dissolution rate of the medicine can be effectively controlled due to the large particle size. The present invention has been completed based on this finding.
Purification method
The invention provides a method for purifying hydroxychloroquine sulfate, which comprises the following steps:
(1) dissolving the hydroxychloroquine sulfate crude product in water or a mixed solvent of water and a first solvent to obtain a mixed solution I;
(2) adding a second solvent into the mixed solution I, and performing reflux crystallization;
(3) cooling, filtering and drying to obtain the refined hydroxychloroquine sulfate.
In another preferred embodiment, the first solvent is selected from the group consisting of: methanol, ethanol, dimethyl sulfoxide, or a combination thereof.
In another preferred embodiment, the volume ratio of water to the first solvent in the mixed solvent is 1:0-10, preferably 1:1-5, more preferably 1:2-4, and most preferably 1: 3-4.
In another preferred embodiment, the weight ratio of the hydroxychloroquine sulfate crude product to the water is 1:0.5-5, preferably 1:1-3, more preferably 1: 1-2.
In another preferred embodiment, the dissolution temperature is 0-100 ℃, preferably 30-90 ℃, more preferably 50-80 ℃, most preferably 60-80 ℃.
In another preferred embodiment, the weight-to-volume (g/mL) ratio of the crude hydroxychloroquine sulfate to the second solvent is 1:5-15, preferably 1:6-12, and more preferably 1: 8-10.
In another preferred example, in the step (2), after the reflux crystallization, the method further comprises the steps of:
(2-1) cooling and continuing to crystallize.
In another preferred example, in the step (2-1), the crystallization has one or more of the following characteristics:
1) the crystallization temperature is 10-50 ℃, preferably 20-40 ℃, and more preferably 30-40 ℃;
2) the crystallization time is 1-24h, preferably 3-22h, more preferably 3-15 h.
In another preferred embodiment, the reflow crystallization has one or more of the following characteristics:
1) the temperature of the reflux crystallization is 60-90 ℃, preferably 60-80 ℃, and more preferably 75-80 ℃;
2) the reflux crystallization time is 0.5-5h, preferably 0.5-3h, more preferably 0.5-2 h.
The invention has the advantages that:
1. the method has excellent purification effect, the purity of the hydroxychloroquine sulfate product is more than or equal to 99.5 percent, the maximum known single impurity content is less than or equal to 0.1 percent, the maximum unknown single impurity content is less than or equal to 0.05 percent, the total impurity content is less than or equal to 0.50 percent, and the particle size Dx (90) is more than or equal to 200 mu m.
2. The solvent used in the method is cheap, easy to obtain and recycle, the operation is simple and safe, and the common reaction vessel can meet the requirements, so that the method is suitable for large-scale production.
3. The method has high purification yield, and the crystallization yield is over 84 percent.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
The test materials and reagents used in the following examples are commercially available without specific reference.
Instrument and detection method
High performance liquid chromatography with an apparatus of Agilent 1260, a chromatographic column of YMC Triart C8, 4.6mm × 250mm, 5 μm, a mobile phase A of 4.17g potassium dihydrogen phosphate and 0.435g dipotassium hydrogen phosphate, water to dissolve into 1L buffer solution, 3ml triethylamine to adjust the pH value to 7.4 (+ -0.05) with triethylamine, a mobile phase B of methanol-acetonitrile (30:70), a flow rate of 1.0ml/min, a detection wavelength of 254nm, a column temperature of 33 ℃ (-1.0 ℃), an elution gradient:
x-ray powder diffraction related conditions: the instrument model is as follows: bruker D8ADVANCE, target: cu target, detector: LynxEye, a divergence slit of 1.0mm, a cable-stayed slit of 0.4 degrees, continuous scanning with a step length of 0.02 degrees, a speed of 8 degrees/min, and a scanning range of 3-45 degrees.
And (3) particle size detection: laser particle sizer, model: mastersizer 3000, dispersant name Dry dispersion, blue light source: 470nm, measurement range: 0.01-3500 mu m, and dry measurement.
Example 1
Preparing a hydroxychloroquine sulfate crude product:
0.91Kg of 4, 7-dichloroquinoline, 0.9Kg of phenol and 10g of potassium iodide are put into a 20L reaction kettle, stirred and heated to 120 ℃, 1.32Kg of 5- (N-ethyl-N-2-hydroxyethylamino) -2-pentylamine is slowly added dropwise, and after the dropwise addition is finished, the stirring is continued for 18 hours at the temperature of 125 ℃ and 130 ℃. Cooling to room temperature, adding 20% sodium hydroxide alkali solution to adjust pH to 12 under stirring, extracting with toluene for three times, concentrating under reduced pressure to remove toluene, dissolving residue in 1.5L anhydrous alcohol, cooling to room temperature, slowly adding concentrated sulfuric acid, adjusting pH to 6-7.5, stirring, and slowly crystallizing. Standing at 5 deg.C for more than 6 hr. Filtering to obtain a wet product of the hydroxychloroquine sulfate crude product. Vacuum drying at 80 deg.C for 4 hr. 0.89kg of hydroxychloroquine sulfate crude product is obtained, the purity is 95 percent, the mp is 235-240 ℃, and the yield is 45.76 percent.
Example 2
600g of the crude hydroxychloroquine sulfate, 600ml of water and 1200ml of ethanol are respectively added into a 10L round-bottom three-neck flask, then the mixture is stirred and heated to 70 ℃, the mixture is kept warm and stirred until the mixture is completely dissolved, 6L of ethanol is slowly added, then the mixture is heated to reflux (78-80 ℃), the reflux crystallization is carried out for 1h, then the mixture is stirred and cooled to 30-40 ℃, the mixture is continuously stirred for 1h, the filtration is carried out, a small amount of ethanol is leached, and a filter cake is dried to obtain 578.5g of white solid with the yield of 96.41%. The purity of the high performance liquid chromatography is 99.85 percent,maximum single impurity of 0.05%, particle diameter Dx(90) 339 μm. Main characteristic peaks measured by 2 theta reflection angle in X-ray powder diffraction spectrum: 12.95 degrees, 17.10 degrees, 17.21 degrees, 17.47 degrees, 19.90 degrees, 21.15 degrees, 23.5 degrees, plus or minus 0.2 degrees, 23.9 degrees, plus or minus 0.2 degrees and 26.7 degrees, plus or minus 0.2 degrees.
Example 3
80g of the hydroxychloroquine sulfate crude product, 40ml of water and 120ml of ethanol are respectively added into a 1L round-bottom three-neck flask, then the mixture is stirred and heated to reflux, the reflux is continued for 0.5h, 640ml of ethanol is slowly added, the reflux and the stirring are performed for crystallization for 0.5, then the mixture is stirred and cooled to 40 ℃, the stirring is continued for 3h, the filtration is performed, a small amount of ethanol is used for leaching, and the filter cake is dried to obtain 70.1g of white solid with the yield of 87.67%. High performance liquid chromatography purity 99.58%, maximum single impurity 0.09%, particle diameter Dx (90) 259 μm. Main characteristic peaks measured by 2 theta reflection angle in X-ray powder diffraction spectrum: 12.87 °, 16.85 °, 17.11 °, 17.45 °, 19.84 °, 21.25 °, 23.52 °, 23.90 °, 26.64 °.
Example 4
80.1g of the hydroxychloroquine sulfate crude product, 40ml of water and 120ml of ethanol are respectively added into a 1L round-bottom three-neck flask, then the mixture is stirred and heated to reflux, the reflux is continued for 1h, 680ml of ethanol is slowly added, the reflux and the stirring are carried out for crystallization for 2h, then the temperature is reduced to 30 ℃, the stirring is continued for 3h, the filtration is carried out, a small amount of ethanol is used for leaching, and the filter cake is dried to obtain 71.45g of white solid with the yield of 89.23%. The purity of the high performance liquid chromatography is 99.61 percent, the maximum single impurity content is 0.08 percent, and the particle size Dx (90) is 418 mu m. Main characteristic peaks measured by 2 theta reflection angle in X-ray powder diffraction spectrum: 12.90 °, 16.89 °, 17.15 °, 17.47 °, 19.87 °, 21.27 °, 23.54 °, 23.94 °, 26.66 °.
Example 5
Respectively adding 128.7g of hydroxychloroquine sulfate crude product, 64.35g of water and 193.05g of ethanol into a 2L round-bottom three-neck flask, stirring and heating to reflux, carrying out hot filtration, transferring the filtrate into the 2L round-bottom three-neck flask, adding 1158.3g of ethanol, continuing to reflux and stir for 0.5h, cooling to 30-40 ℃, stirring for 15h, filtering, leaching with a small amount of ethanol, and drying the filter cake to obtain 109.0g of white solid, wherein the yield is 84.69%, the purity of the high performance liquid chromatography is 99.97%, the maximum single impurity content is 0.03%, and the particle size Dx (90) is 273 mu m. . Main characteristic peaks measured by 2 theta reflection angle in X-ray powder diffraction spectrum: 12.85 °, 16.85 °, 17.10 °, 17.43 °, 19.83 °, 21.22 °, 23.52 °, 23.88 °, 26.66 °.
Example 6
97g of hydroxychloroquine sulfate crude product, 48.5ml of water and 145.5ml of absolute ethyl alcohol are respectively added into a 1L round-bottom three-neck flask, then stirring and heating are carried out until reflux is achieved, 776ml of absolute ethyl alcohol is slowly added, then stirring and cooling are carried out until the temperature is 35 ℃, stirring is continuously carried out for 3 hours, filtering is carried out, a small amount of ethyl alcohol is used for leaching, a filter cake is dried to obtain 89.06g of white solid, the yield is 91.8%, the purity of a high performance liquid chromatography is 99.98%, the maximum single impurity content is 0.03%, and the particle size Dx (90) is 339 microns. Main characteristic peaks measured by 2 theta reflection angle in X-ray powder diffraction spectrum: 12.91 °, 16.91 °, 17.15 °, 17.48 °, 19.88 °, 21.28 °, 23.55 °, 23.95 °, 26.68 °.
Example 7
101.5g of hydroxychloroquine sulfate crude product, 50.5ml of water and 152ml of ethanol are respectively added into a 2L round-bottom three-neck flask, then the mixture is stirred and heated to 60-70 ℃, the mixture is kept warm and stirred until the mixture is completely dissolved, 812ml of ethanol is slowly added, the mixture is refluxed, stirred and crystallized for 2 hours, then the mixture is cooled to 35 ℃, the mixture is continuously stirred for 22 hours, filtered, a small amount of ethanol is leached, a filter cake is dried to obtain 93.3g of white solid, the yield is 91.92%, the purity is 99.84% according to high performance liquid chromatography detection, the maximum single impurity content is 0.03%, and the particle size Dx (90) is 379. Main characteristic peaks measured by 2 theta reflection angle in X-ray powder diffraction spectrum: 12.91 °, 16.93 °, 17.17 °, 17.52 °, 19.91 °, 21.33 °, 23.58 °, 23.96 °, 26.72 °.
Comparative example 1
Adding 80g of the hydroxychloroquine sulfate crude product and 800g of methanol into a 2L round-bottom three-neck flask respectively, stirring and heating to reflux, refluxing for 1 hour, stirring and cooling to 0-10 ℃, continuing stirring for 9 hours, filtering, leaching with a small amount of ethanol, and drying a filter cake to obtain 20.0g of white solid, wherein the yield is 25.0%, and the particle size Dx (90) is 128 mu m. .
Comparative example 2
Heating, refluxing and dissolving 2.38kg of hydroxychloroquine sulfate crude product, 1.19kg of water and 2.38 liters of ethanol, cooling to 20 ℃, adding 20.23 liters of ethanol, stirring for 1 hour, filtering, leaching with a small amount of ethanol, and drying a filter cake to obtain 2.33kg of white solid with the yield of 97.7 percent, the purity of 99.64 percent by high performance liquid chromatography, the maximum single impurity content of 0.09 percent and the particle size Dx (90) of 124 mu m. . Characteristic peaks measured by 2 theta reflection angle in X-ray powder diffraction spectrum: 9.71 °, 12.89 °, 15.87 °, 18.39 °, 19.44 °, 25.28 °.
Hydroxychloroquine sulfate is a water-soluble medicine, the particle size is too small, the medicine can be dissolved out quickly, the proper particle size needs to be controlled, and the general crystallization process comprises heating for dissolution and then cooling for crystallization, as in comparative example 2. Surprisingly, the purity of the hydroxychloroquine sulfate product obtained by the purification method is more than 99.5%, the maximum known single impurity is less than or equal to 0.1%, the maximum unknown single impurity is less than or equal to 0.05%, the total impurity is less than or equal to 0.50%, the yield is more than 84%, the particle size Dx (90) is more than or equal to 200 mu m, the yield of the comparative example 1 is obviously lower than that of the comparative example 1 and the comparative example 2, the product obtained by the comparative example 2 using the cooling crystallization method is not an original crystal form, and the particle size is obviously smaller than that of the product of the invention, so that the purification method of hydroxychloroquine sulfate has better effect.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A method for purifying hydroxychloroquine sulfate, said method comprising the steps of:
(1) dissolving the hydroxychloroquine sulfate crude product in water or a mixed solvent of water and a first solvent to obtain a mixed solution I;
(2) adding a second solvent into the mixed solution I, and performing reflux crystallization;
(3) cooling, filtering and drying to obtain the refined hydroxychloroquine sulfate.
2. The method of claim 1, wherein the first solvent is selected from the group consisting of: methanol, ethanol, dimethyl sulfoxide, or a combination thereof.
3. The method of claim 1, wherein the second solvent is selected from the group consisting of: methanol, ethanol, isopropanol, acetone, or combinations thereof.
4. The method according to claim 1, wherein the volume ratio of water to the first solvent in the mixed solvent is 1:0-10, preferably 1:1-5, more preferably 1:2-4, and most preferably 1: 3-4.
5. The method according to claim 1, wherein the weight ratio of the hydroxychloroquine sulfate crude product to the water is 1:0.5-5, preferably 1:1-3, more preferably 1: 1-2.
6. The method according to claim 1, wherein the temperature of dissolution is 0-100 ℃, preferably 30-90 ℃, more preferably 50-80 ℃, most preferably 60-80 ℃.
7. The method as claimed in claim 1, wherein the X-ray powder diffraction pattern of the obtained refined hydroxychloroquine sulfate contains the following characteristic peaks measured at 2 θ reflection angles: 12.9 +/-0.2 degrees, 16.9 +/-0.2 degrees, 17.1 +/-0.2 degrees, 17.5 +/-0.2 degrees, 19.9 +/-0.2 degrees, 21.3 +/-0.2 degrees, 23.5 +/-0.2 degrees, 23.9 +/-0.2 degrees and 26.7 +/-0.2 degrees.
8. The method according to claim 1, wherein the weight to volume (g/mL) ratio of the crude hydroxychloroquine sulfate to the second solvent is 1:5-15, preferably 1:6-12, more preferably 1: 8-10.
9. The method of claim 1, wherein the reflow crystallization has one or more of the following characteristics:
1) the temperature of the reflux crystallization is 60-90 ℃, preferably 60-80 ℃, and more preferably 75-80 ℃;
2) the reflux crystallization time is 0.5-5h, preferably 0.5-3h, more preferably 0.5-2 h.
10. The method of claim 1, wherein the refined hydroxychloroquine sulfate has one or more of the following characteristics:
1) the purity of the refined hydroxychloroquine sulfate product is more than or equal to 99.5 percent;
2) the maximum known single impurity content of the refined hydroxychloroquine sulfate is less than or equal to 0.1 percent;
3) the maximum unknown single impurity content of the refined hydroxychloroquine sulfate is less than or equal to 0.05 percent;
4) the total impurity content of the refined hydroxychloroquine sulfate is less than or equal to 0.50 percent;
5) the particle size Dx (90) of the refined hydroxychloroquine sulfate is 200-;
the percentage is calculated by the total mass of the hydroxychloroquine sulfate refined product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113603642A (en) * | 2020-11-16 | 2021-11-05 | 上海中西三维药业有限公司 | Hydroxychloroquine sulfate hydrate, crystal form thereof, preparation method and application thereof |
| CN114720574A (en) * | 2020-12-22 | 2022-07-08 | 远大医药（中国）有限公司 | Method for detecting content of hydroxychloroquine sulfate in hydroxychloroquine sulfate tablet |
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| CN104230803A (en) * | 2014-08-28 | 2014-12-24 | 重庆康乐制药有限公司 | Preparation method of hydroxychloroquine sulfate |
| CN108689929A (en) * | 2018-07-05 | 2018-10-23 | 上海中西三维药业有限公司 | A kind of preparation method of hydroxychloroquine and its sulfate |
| CN108727263A (en) * | 2018-07-05 | 2018-11-02 | 上海中西三维药业有限公司 | Hydroxychloroquine sulfate crystal form A and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104230803A (en) * | 2014-08-28 | 2014-12-24 | 重庆康乐制药有限公司 | Preparation method of hydroxychloroquine sulfate |
| CN108689929A (en) * | 2018-07-05 | 2018-10-23 | 上海中西三维药业有限公司 | A kind of preparation method of hydroxychloroquine and its sulfate |
| CN108727263A (en) * | 2018-07-05 | 2018-11-02 | 上海中西三维药业有限公司 | Hydroxychloroquine sulfate crystal form A and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113603642A (en) * | 2020-11-16 | 2021-11-05 | 上海中西三维药业有限公司 | Hydroxychloroquine sulfate hydrate, crystal form thereof, preparation method and application thereof |
| CN114720574A (en) * | 2020-12-22 | 2022-07-08 | 远大医药（中国）有限公司 | Method for detecting content of hydroxychloroquine sulfate in hydroxychloroquine sulfate tablet |
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