CN116969886A - Hydroxychloroquine sulfate crystal form C and preparation method and application thereof - Google Patents
Hydroxychloroquine sulfate crystal form C and preparation method and application thereof Download PDFInfo
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- CN116969886A CN116969886A CN202310826591.7A CN202310826591A CN116969886A CN 116969886 A CN116969886 A CN 116969886A CN 202310826591 A CN202310826591 A CN 202310826591A CN 116969886 A CN116969886 A CN 116969886A
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- hydroxychloroquine
- 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 64
- 239000013078 crystal Substances 0.000 title claims abstract description 49
- 229960002927 hydroxychloroquine sulfate Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000003960 organic solvent Substances 0.000 claims abstract description 25
- 229960004171 hydroxychloroquine Drugs 0.000 claims abstract description 24
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000010521 absorption reaction Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 239000011259 mixed solution Substances 0.000 claims abstract description 5
- 238000004321 preservation Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 4
- 208000006926 Discoid Lupus Erythematosus Diseases 0.000 claims description 3
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 3
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- JCBIVZZPXRZKTI-UHFFFAOYSA-N 2-[4-[(7-chloroquinolin-4-yl)amino]pentyl-ethylamino]ethanol;sulfuric acid Chemical group OS(O)(=O)=O.ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 JCBIVZZPXRZKTI-UHFFFAOYSA-N 0.000 claims 2
- 230000003902 lesion Effects 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000009826 distribution Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 206010040882 skin lesion Diseases 0.000 description 2
- 231100000444 skin lesion Toxicity 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 102220042174 rs141655687 Human genes 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Toxicology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to hydroxychloroquine sulfate crystal form C, and a preparation method and application thereof. The granularity D90 of the hydroxychloroquine sulfate crystal form C is smaller than 10 microns; the reflection angles 2 theta of the X-ray powder diffraction pattern have characteristic absorption peaks at 9.7+/-0.1, 15.5+/-0.1, 18.5+/-0.1, 20.3+/-0.1, 24.6+/-0.1 and 26.9+/-0.1. The preparation method of the hydroxychloroquine sulfate crystal form C comprises the following steps: stirring hydroxychloroquine and an organic solvent at 20-30 ℃ until the hydroxychloroquine and the organic solvent are dissolved, adding a mixed solution of sulfuric acid, water and the organic solvent, and crystallizing by heat preservation, cooling and crystallizing; filtering and drying to obtain hydroxychloroquine sulfate crystal form C. The invention provides a novel hydroxychloroquine sulfate crystal form with smaller granularity, and the preparation method is simple and feasible, can prepare hydroxychloroquine sulfate crystal form C with granularity smaller than 10 microns without micronization, and is easy for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to hydroxychloroquine sulfate crystal form C, and a preparation method and application thereof.
Background
Hydroxychloroquine sulfate is mainly used for treating rheumatoid arthritis, juvenile chronic arthritis, discoid lupus erythematosus, systemic lupus erythematosus and skin lesions caused or aggravated by sunlight clinically. When related preparation of hydroxychloroquine sulfate is studied, larger differences exist among different polymorphs of the same medicine, such as solubility, dissolution speed, bioavailability, stability, fluidity and the like, and the differences of the properties directly influence the efficacy and application of the medicine.
In the prior art, the invention patent with publication number of CN108727263A discloses a hydroxychloroquine sulfate A crystal form, and the preparation method comprises the following steps: mixing hydroxychloroquine with an organic solvent, dropwise adding a sulfuric acid aqueous solution with the mass fraction of 40% -60% until turbidity, firstly preserving heat at 35-55 ℃, then cooling to below 15 ℃, preserving heat, and crystallizing to obtain hydroxychloroquine sulfate crystal form A. The hydroxychloroquine sulfate crystal form A has good thermal stability, but poor hygroscopicity, and low storage stability and solubility. The invention patent with publication number of CN112480000A discloses a hydroxychloroquine sulfate B crystal form, which is prepared by the following steps: stirring hydroxychloroquine and an organic solvent at 0-20 ℃ until the hydroxychloroquine and the organic solvent are dissolved, adding a sulfuric acid aqueous solution with the mass fraction of 50-80%, controlling the temperature to be not more than 10 ℃ in the dripping process, preserving heat for 6-24 hours at 5-15 ℃ after the dripping is finished, filtering, and drying to obtain hydroxychloroquine sulfate crystal form B. The hydroxychloroquine sulfate crystal form B has the advantages of small hygroscopicity, higher solubility and better storage stability. Therefore, the development of the novel hydroxychloroquine sulfate crystal form has important significance in the aspects of improving the product quality, optimizing the production process, changing the physical form, directionally delivering, improving the solubility and the like.
According to the invention, the product granularity is a key factor influencing the storage stability, solubility, processing, physicochemical properties and pharmaceutical properties of the preparation product, so that the development and preparation of hydroxychloroquine sulfate with better granularity and crystal form have important significance for further improving the bioavailability of related preparations.
Disclosure of Invention
The invention aims at providing hydroxychloroquine sulfate crystal form C.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the reflection angle 2 theta of the hydroxychloroquine sulfate crystal form C of the X-ray powder diffraction spectrum has characteristic absorption peaks at 9.7+/-0.1, 15.5+/-0.1, 18.5+/-0.1, 20.3+/-0.1, 24.6+/-0.1 and 26.9+/-0.1.
Further, the X-ray powder diffraction pattern of hydroxychloroquine sulfate form C is shown in FIG. 3.
Further, the hydroxychloroquine sulfate form C has a particle size D90 of less than 10 microns.
The second purpose of the invention is to provide a preparation method of hydroxychloroquine sulfate crystal form C.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the preparation method of hydroxychloroquine sulfate crystal form C comprises the following steps:
1) Mixing hydroxychloroquine with the organic solvent A and the organic solvent B, and stirring until the mixture is dissolved to obtain a reaction solution;
2) Adding a mixed solution of sulfuric acid, an organic solvent A and water into the reaction solution obtained in the step 1), preserving heat, crystallizing, cooling and growing crystals; filtering and drying to obtain hydroxychloroquine sulfate crystal form C.
The research of the invention finds that in the related technical field, the crystallization temperature and the type of the used organic solvent are key factors influencing the granularity of the product, so that the invention strictly controls the crystallization temperature and the type and the proportion of the crystallization solvent during the preparation. By controlling the conditions, the preparation method is further optimized, and the hydroxychloroquine acid crystal form C with the granularity below 10 microns is finally prepared.
In order to achieve a certain particle size of the product, micronization is often carried out in the art, however, micronization affects the productivity of the production. In view of the above, the preparation method of the hydroxychloroquine acid crystal form C is optimized and explored, and the product is controlled to reach a better granularity through crystallization without micronization. Compared with hydroxychloroquine sulfate in the prior art, the hydroxychloroquine acid crystal form C has higher bioavailability.
Further, the organic solvent A and the organic solution B are any two different combinations of methanol, isopropanol and acetonitrile.
Preferably, when the organic solvent a is methanol, the organic solution B is acetonitrile; or when the organic solvent A is isopropanol, the organic solution B is acetonitrile.
Further, the mass ratio of the total amount of the organic solvent A to the organic solution B in the step 1) and the step 2) is 1:3-1:5; more preferably 1:3.
Further, in the step 2), the mass ratio of the sulfuric acid to the organic solvent A to the water is 1:2:2-1:2:4; more preferably 1:2:3.
Further, in the step 1), the temperature at which hydroxychloroquine is mixed with the organic solvent is 20 ℃ to 30 ℃.
Further, in the step 2), when a mixed solution of sulfuric acid, an organic solvent A and water is added into the reaction solution, the temperature is controlled to be not more than 30 ℃; the temperature of the heat preservation crystallization is 25-35 ℃; the temperature of the cooling and crystal growing is 5-15 ℃ and the time is 2h.
Further, the drying is vacuum drying, and the temperature is 50 ℃.
As a preferred preparation method, the method comprises the following steps:
(1) Adding 100g of hydroxychloroquine, 50g of isopropanol and 400g of acetonitrile into a reaction bottle, and stirring at a temperature of 20-30 ℃ until the components are dissolved;
(2) 50g of isopropanol, 50g of water and 25g of sulfuric acid are added into a beaker to prepare a solution, and after hydroxychloroquine is dissolved and clarified, the prepared solution is added into a system to crystallize at a temperature below 30 ℃. After the dripping is finished, the mixture is stirred at 30-35 ℃ for crystallization, then cooled to 5-10 ℃ for crystal growth for 2 hours, filtered, and dried in vacuum at 50 ℃ to constant weight, thus obtaining hydroxychloroquine sulfate crystal form C.
As a preferred preparation method, the method comprises the following steps:
(1) Adding 100g of hydroxychloroquine, 50g of methanol and 300g of acetonitrile into a reaction bottle, and stirring at a temperature of 20-30 ℃ until the components are dissolved;
(2) Adding 50g of methanol, 75g of water and 25g of sulfuric acid into a beaker to prepare a liquid, dissolving and clarifying hydroxychloroquine, and adding the prepared liquid into a system to crystallize at the temperature of below 30 ℃. After the dripping is finished, the mixture is stirred at 25 to 30 ℃ for crystallization, then cooled to 10 to 15 ℃ for crystal growth for 2 hours, filtered, and dried to constant weight at 50 ℃ in vacuum, thus obtaining hydroxychloroquine sulfate crystal form C.
The invention further aims to provide an application of the hydroxychloroquine sulfate crystal form C in preparing a medicament for treating rheumatoid arthritis, juvenile chronic arthritis, discoid lupus erythematosus, systemic lupus erythematosus and/or skin lesions caused or aggravated by sunlight.
The invention has the beneficial effects that:
(1) The invention provides a novel crystal form of hydroxychloroquine sulfate, wherein the granularity D90 of the crystal form C of hydroxychloroquine sulfate is smaller than 10 microns, and the crystal form C of hydroxychloroquine sulfate has higher bioavailability, better storage stability, solubility, physical and chemical properties, pharmaceutical properties and the like compared with the conventional hydroxychloroquine sulfate. The hydroxychloroquine sulfate crystal form C with smaller granularity has important significance for further improving the bioavailability of related preparations, and provides a new choice for developing hydroxychloroquine sulfate preparation products.
(2) The preparation method provided by the invention is simple and feasible, micronization is not needed, and the hydroxychloroquine sulfate crystal form C with the granularity D90 smaller than 10 microns can be prepared only by optimizing the reaction conditions such as crystallization temperature, crystallization solvent types, proportion and the like, and compared with hydroxychloroquine sulfate in the prior art, the hydroxychloroquine sulfate has higher bioavailability. The preparation method provided by the invention has the characteristics of easiness in industrial production and stable and reliable quality.
Drawings
FIG. 1 is a graph showing the particle size distribution of hydroxychloroquine sulfate form C prepared in example 1;
FIG. 2 is an HPLC chart of hydroxychloroquine sulfate form C prepared in example 1;
FIG. 3 is an X-ray powder diffraction pattern of hydroxychloroquine sulfate form C prepared in example 1;
FIG. 4 is a graph showing the particle size distribution of hydroxychloroquine sulfate form C prepared in example 2;
FIG. 5 is a graph showing the particle size distribution of hydroxychloroquine sulfate form A prepared in comparative example 1;
FIG. 6 is an X-ray powder diffraction spectrum of hydroxychloroquine sulfate form A prepared in comparative example 1.
Detailed Description
The technical scheme of the present invention will be further clearly and completely described in connection with specific embodiments. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. Therefore, all other embodiments obtained by those skilled in the art without undue burden are within the scope of the invention based on the embodiments of the present invention.
EXAMPLE 1.10 preparation of less than micrometer hydroxychloroquine sulfate form C
100g hydroxychloroquine, 50g isopropanol and 400g acetonitrile are added into a reaction bottle, and the temperature is controlled to be 20-30 ℃ and stirred until the hydroxychloroquine, the isopropanol and the 400g acetonitrile are dissolved. Adding 50g of isopropanol, 50g of water and 25g of sulfuric acid into a beaker to prepare a liquid, dissolving and clarifying hydroxychloroquine, and adding the prepared liquid into a system to crystallize at the temperature of below 30 ℃. After the dripping is finished, the mixture is stirred at 30-35 ℃ for crystallization, then cooled to 5-10 ℃ for crystal growth for 2 hours, filtered, and dried in vacuum at 50 ℃ to constant weight, 104.8g of hydroxychloroquine sulfate of crystal form C is obtained, and the molar yield is 81.11%.
The particle size distribution of hydroxychloroquine sulfate crystal form C prepared by the method is shown in fig. 1 and table 1, d90=4.39 μm, the HPLC chart is shown in fig. 2, the integral result is shown in table 2, and the purity is 99.43%. Hydroxychloroquine sulfate of form C has an X-ray powder diffraction spectrum as shown in fig. 3, with characteristic absorption peaks at 2θ=9.7±0.1, 15.5±0.1, 18.5±0.1, 20.3±0.1, 24.6±0.1, 26.9±0.1. The X-ray powder diffraction results are shown in tables 3 and 4.
TABLE 1 particle size distribution detection results of hydroxychloroquine sulfate form C prepared in EXAMPLE 1
TABLE 2 integral results Table of FIG. 1
TABLE 3.X ray powder diffraction test results Table 1
TABLE 4X-ray powder diffraction test result 2
EXAMPLE 2.10 preparation of less than micrometer hydroxychloroquine sulfate form C
100g hydroxychloroquine, 50g methanol and 300g acetonitrile are added into a reaction bottle, and the temperature is controlled between 20 ℃ and 30 ℃ and stirred until the mixture is dissolved. Adding 50g of methanol, 75g of water and 25g of sulfuric acid into a beaker to prepare a liquid, dissolving and clarifying hydroxychloroquine, and adding the prepared liquid into a system to crystallize at the temperature of below 30 ℃. After the dripping is finished, the mixture is stirred at 25-30 ℃ for crystallization, then cooled to 10-15 ℃ for crystal growth for 2 hours, filtered, and dried to constant weight at 50 ℃ in vacuum, thus obtaining hydroxychloroquine sulfate of crystal form C with granularity below 10 microns, the granularity distribution of which is shown in fig. 4 and table 5, D90=6.24 μm.
TABLE 5 particle size distribution detection results of hydroxychloroquine sulfate form C
Comparative example 1 preparation of hydroxychloroquine sulfate form A with reference to patent CN108727263A
100g hydroxychloroquine, 100g methanol and 400g acetonitrile are added into a reaction bottle, and the temperature is controlled to be 20-35 ℃ and stirred until the hydroxychloroquine, the methanol and the 400g acetonitrile are dissolved. Preparing 40% sulfuric acid solution, dissolving and clarifying hydroxychloroquine, and then adding the prepared solution into a system for crystallization at a temperature of between 20 and 35 ℃. After the dripping is finished, preserving heat and stirring for 5 hours at 35-55 ℃ for crystallization, cooling to below 15 ℃ for crystal growth for 2 hours, filtering, and vacuum drying to constant weight at 50 ℃ to obtain hydroxychloroquine sulfate crystal form A. The particle size was 100 μm or more, and the particle size distribution was d90= 148.94 μm as shown in fig. 5 and table 6. Hydroxychloroquine sulfate of form a has an X-ray powder diffraction spectrum as shown in fig. 6, and the comparative patent CN108727263a likewise has characteristic absorption peaks at 2θ=16.9 °, 17.1 °, 17.5 °, 19.9 °, 21.3 °, 23.5 °, 23.9 ° and 26.7 °.
TABLE 6 particle size distribution detection results of hydroxychloroquine sulfate form A
Claims (10)
1. The hydroxychloroquine sulfate crystal form C is characterized in that the reflection angle 2 theta of an X-ray powder diffraction pattern of the hydroxychloroquine sulfate crystal form C has characteristic absorption peaks at 9.7+/-0.1, 15.5+/-0.1, 18.5+/-0.1, 20.3+/-0.1, 24.6+/-0.1 and 26.9+/-0.1.
2. The hydroxychloroquine sulfate form C of claim 1, wherein the X-ray powder diffraction pattern of hydroxychloroquine sulfate form C is shown in figure 3.
3. The hydroxychloroquine sulfate form C of claim 1, wherein the hydroxychloroquine sulfate form C has a particle size D90 of less than 10 microns.
4. A process for the preparation of hydroxychloroquine sulphate form C according to any one of claims 1 to 3, comprising the steps of:
1) Mixing hydroxychloroquine with the organic solvent A and the organic solvent B, and stirring until the mixture is dissolved to obtain a reaction solution;
2) Adding a mixed solution of sulfuric acid, an organic solvent A and water into the reaction solution obtained in the step 1), preserving heat, crystallizing, cooling and growing crystals; filtering and drying to obtain hydroxychloroquine sulfate crystal form C.
5. The method according to claim 4, wherein the organic solvent A and the organic solution B are any two different combinations of methanol, isopropanol and acetonitrile.
6. The method according to claim 5, wherein the mass ratio of the total amount of the organic solvent A to the organic solution B in the step 1) and the step 2) is 1:3 to 1:5.
7. The method according to claim 4, wherein the mass ratio of the sulfuric acid, the organic solvent and the water is 1:2:2 to 1:2:4.
8. The process according to claim 4, wherein in step 1), the temperature at which hydroxychloroquine is mixed with the organic solvent is 20℃to 30 ℃.
9. The method according to claim 4, wherein in step 2), when a mixed solution of sulfuric acid, an organic solvent A and water is added to the reaction solution, the temperature is controlled to not more than 30 ℃; the temperature of the heat preservation crystallization is 25-35 ℃; the temperature of the cooling and crystal growing is 5-15 ℃ and the time is 2h.
10. Use of hydroxychloroquine sulphate form C according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of rheumatoid arthritis, juvenile chronic arthritis, discoid lupus erythematosus, systemic lupus erythematosus and/or cutaneous lesions induced or exacerbated by sunlight.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310826591.7A CN116969886A (en) | 2023-07-06 | 2023-07-06 | Hydroxychloroquine sulfate crystal form C and preparation method and application thereof |
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