CN112480000A - Hydroxychloroquine sulfate crystal form B and preparation method thereof - Google Patents
Hydroxychloroquine sulfate crystal form B and preparation method thereof Download PDFInfo
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- CN112480000A CN112480000A CN202011286119.1A CN202011286119A CN112480000A CN 112480000 A CN112480000 A CN 112480000A CN 202011286119 A CN202011286119 A CN 202011286119A CN 112480000 A CN112480000 A CN 112480000A
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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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- 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
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a hydroxychloroquine sulfate crystal form B and a preparation method thereof, which are characterized by XRD and DSC. The hydroxychloroquine sulfate crystal form B provided by the invention is simple in preparation method, small in hygroscopicity, good in stability, capable of forming a regular crystal form and higher in solubility, so that the process treatment, the improvement of physicochemical properties and the improvement of the performance of the finished medicine of the medicine are facilitated.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a hydroxychloroquine sulfate crystal form B and a preparation method thereof.
Background
Hydroxychloroquine Sulfate (HCQ), chemical name: 2- [ [4- [ (7-chloro-4-quinolinyl) amino ] pentyl ] ethylamino ] -ethanol sulfate. The drug is successfully developed by Winthrop company, is firstly marketed in the United states in 1956, and is approved by FDA at 29.5.1998 for treating lupus erythematosus and rheumatoid arthritis, and the chemical structure of the drug is as follows:
discoid Lupus Erythematosus (DLE) is a relatively common skin mucosal connective tissue disease, and 25% -35% of the Discoid Lupus Erythematosus (DLE) has oral lesions, can be singly applied to the oral cavity without combining skin lesions, and has no obvious systemic symptoms. The etiology and pathogenesis of the cancer are unknown at present, and the cancer is difficult to treat and easy to relapse and cancerate. Traditional applications of chloroquine phosphate (CQ) for the treatment of DLE are effective, but have significant side effects. HCQ has anti-inflammatory, anti-histamine and immunosuppressive effects, reduces lymphocyte transformation rate, inhibits vascular permeability, and stabilizes lysosome membrane, so that the treatment of DLE with HCQ is targeted. To date, HCQ is considered safer than CQ. A number of clinical and literature reports have demonstrated satisfactory results for treatment of DLE with HCQ.
Systemic Lupus Erythematosus (SLE) is a disease rich in multiple antibodies in multiple system affected bodies, the etiology is unclear, and the treatment is troublesome. While anti-malarial drugs were used to treat SLE since 1950, Dobois found that 75-80% of SLE patients treated with anti-malarial drugs had improved rash, fever, and joint symptoms, especially skin lesions. Later studies found that antimalarial drugs can reduce or stop the use of corticosteroids in SLE patients and have antiallergic effects. Double-blind control studies of the hydroxychloroquine sulfate canada panel show that HCQ stabilizes the condition of SLE patients and significantly reduces relapse. Wallace et al found that HCQ treatment reduced the blood lipid levels in corticoid dependent patients and significantly reduced the occurrence of thrombosis. In view of the beneficial effects of HCQ in SLE, most scholars advocate HCQ for patients with mild to moderate SLE in combination with hormones, immunosuppressants for the adjuvant treatment of severe SLE.
When the antimalarial drug is applied to treating SLE, 90% of the international population selects hydroxychloroquine sulfate, while the domestic population may be influenced by factors such as cognition, drug sources and the like, and most of the international population selects chloroquine. In fact, from the safety perspective, hydroxychloroquine sulfate should be selected as much as possible when the patient's condition permits, and does not need to rely solely on antimalarial drugs to exert their therapeutic effects in a short time.
As scientists further research finds that hydroxychloroquine sulfate can play multiple immune regulation roles in rheumatic diseases, and it is the first choice that hydroxychloroquine sulfate has a remarkable anti-inflammatory effect, can stabilize lysosomes, inhibit the activity of enzymes, further inhibit the activation of inflammatory mediators, simultaneously inhibit the chemotaxis and infiltration of inflammatory cells such as neutrophils, and remarkably reduce the production of proinflammatory cytokines such as TNF alpha, IL-l and IL-6; secondly, hydroxychloroquine sulfate can inhibit the growth of fiber cells and the deposition of connective tissues so as to inhibit the proliferation of synovial membranes of arthritis patients; the hydroxychloroquine sulfate can inhibit the interaction of antigen and antibody and the synthesis of immune complex, and promote the reduction of the titer of rheumatoid factors, and the hydroxychloroquine sulfate can also influence the absorption of ultraviolet rays and prevent the damage of the ultraviolet rays to the skin. The above all provide a great deal of basis for the hydroxychloroquine sulfate in the clinical treatment of rheumatic diseases. In addition, many central large-scale clinical studies have also demonstrated that hydroxychloroquine sulfate exerts a significant therapeutic effect in the treatment of rheumatism.
At present, Chinese patent: CN108727263A discloses and reports a hydroxychloroquine sulfate crystal form A, wherein hydroxychloroquine is mixed with an organic solvent, a sulfuric acid aqueous solution with the mass fraction of 40-60% is dripped until the mixture is turbid, the temperature is kept at 35-55 ℃, then the temperature is reduced to below 15 ℃, and the temperature is kept and crystallization is carried out, so that the hydroxychloroquine sulfate crystal form A is obtained. The hydroxychloroquine sulfate crystal form A obtained by the patent has good thermal stability, but poor hygroscopicity, and low storage stability and solubility.
Therefore, the development of the novel hydroxychloroquine sulfate crystal form has important significance for the development of related preparations and the improvement of the bioavailability of hydroxychloroquine sulfate.
Disclosure of Invention
The invention aims to provide a hydroxychloroquine sulfate crystal form B on the basis of the prior art.
The invention also aims to provide a preparation method of the hydroxychloroquine sulfate crystal form B.
The third purpose of the invention is to provide a pharmaceutical composition or a preparation containing the crystal form B.
The technical scheme of the invention is as follows:
the hydroxychloroquine sulfate crystal form B has characteristic absorption peaks at reflection angles 2 theta of 8.8 +/-0.1, 9.8 +/-0.1, 13.0 +/-0.1, 8.8 +/-0.1, 15.9 +/-0.1, 18.5 +/-0.1, 19.6 +/-0.1 and 22.7 +/-0.1 in an X-ray powder diffraction pattern.
In a preferred embodiment, the hydroxychloroquine sulfate form B has an X-ray powder diffraction pattern as shown in figure 1. For example, the reflection angle 2 theta of the X-ray powder diffraction pattern has characteristic absorption peaks at 8.8, 9.8, 13.0, 8.8, 15.9, 18.5, 19.6 and 22.7.
The hydroxychloroquine sulfate crystal form B provided by the invention has an endothermic peak at 193-197 ℃.
In a preferred scheme, the DSC pattern of the hydroxychloroquine sulfate crystal form B provided by the invention is shown in figure 2, and an endothermic peak is formed at 195.5 ℃.
The invention provides a preparation method of hydroxychloroquine sulfate crystal form B, which comprises 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 dropwise adding process, preserving the temperature for 6-24 hours at 5-15 ℃ after the dropwise adding is finished, filtering, and drying to obtain the hydroxychloroquine sulfate crystal form B.
In a preferable scheme, the temperature is controlled not to exceed 10 ℃, for example, 5-10 ℃ in the process of dropwise adding 50-80% of sulfuric acid aqueous solution. Wherein the molar ratio of the hydroxychloroquine to the sulfuric acid is 1: 0.5-1.1, preferably 1: 0.8-0.9; more preferably 1: 0.72.
It is well known to those skilled in the art that, in the preparation of the crystal form, the kind of the crystallization solvent or the crystallization temperature has a considerable influence on the crystal form of the target substance to be prepared, and a new crystal form can be easily prepared by adjusting the kind and temperature of the solvent. When the hydroxychloroquine sulfate crystal form B is prepared, the dissolving, mixing and crystallizing temperatures of raw materials are strictly controlled, hydroxychloroquine is dissolved in an organic solvent at a lower temperature, the temperature in the process of dropwise adding a sulfuric acid aqueous solution is strictly controlled not to exceed 10 ℃, and then the heat preservation and crystallization are carried out at 5-15 ℃ to obtain a new hydroxychloroquine sulfate crystal form B.
Further, the mass fraction of sulfuric acid in the sulfuric acid aqueous solution is 65-75%, preferably 70%.
In the preparation process of the hydroxychloroquine sulfate crystal form B, hydroxychloroquine and an organic solvent are stirred to be dissolved at the temperature of 0-20 ℃, wherein the organic solvent is one or more of methanol, ethanol, n-butanol, ethyl acetate, tetrahydrofuran or acetone. For example, methanol or ethanol.
In a preferred embodiment, the volume-to-mass ratio of the above-mentioned organic solvent to hydroxychloroquine is from 4ml/g to 20ml/g, preferably from 8ml/g to 10 ml/g.
The invention provides a pharmaceutical composition, which comprises hydroxychloroquine sulfate crystal form B as an active ingredient or a main active ingredient, and pharmaceutically acceptable auxiliary materials.
The invention also relates to a preparation which is characterized by comprising an effective dose of hydroxychloroquine sulfate crystal form B.
By adopting the technical scheme of the invention, the advantages are as follows:
the hydroxychloroquine sulfate crystal form B provided by the invention is simple in preparation method, small in hygroscopicity, good in stability, capable of forming a regular crystal form and higher in solubility, so that the process treatment, the improvement of physicochemical properties and the improvement of the performance of the finished medicine of the medicine are facilitated.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of hydroxychloroquine sulfate form B obtained in example 1 of the present application;
FIG. 2 is a differential scanning calorimetry graph of hydroxychloroquine sulfate form B obtained in example 1 of the present application;
FIG. 3 is an HPLC chromatogram of hydroxychloroquine sulfate form B obtained in example 1 of the present application;
FIG. 4 is an X-ray powder diffraction pattern of hydroxychloroquine sulfate crystal form A obtained in comparative example 1 of the present application;
FIG. 5 is a differential scanning calorimetry graph of the hydroxychloroquine sulfate crystal form A obtained in comparative example 1 of the present application;
FIG. 6 is an HPLC chromatogram of hydroxychloroquine sulfate crystal form A obtained in comparative example 1 of the present application.
Detailed Description
The invention will be described in more detail hereinafter by means of examples, which are given for the purpose of further illustration and which are included for a better understanding of the invention, but are not to be construed as limiting the invention.
EXAMPLE 1 preparation of Hydroxychloroquine sulfate form B
Adding 1100g of hydroxychloroquine and 8800ml of ethanol into a reaction bottle, stirring until the mixture is dissolved, and controlling the temperature to be 5-10 ℃. 330g of sulfuric acid aqueous solution with the mass fraction of 70 percent is dripped, and the temperature is controlled not to exceed 10 ℃. After the dropwise addition, stirring for 12h at the temperature of 5-10 ℃, filtering, and drying in vacuum at 50 ℃ to constant weight to obtain 1401.2g of hydroxychloroquine sulfate in the B crystal form, wherein the yield is 98.6%, and the HPLC purity is 99.93% (shown in a DSC (DSC) graph 1, an XRD (XRD) graph 2 and an HPLC (HPLC) graph 3).
Comparative example 1 preparation of hydroxychloroquine sulfate crystal form a
Adding 1100g of hydroxychloroquine and 880ml of ethanol into a reaction bottle, stirring until the mixture is dissolved, and controlling the temperature to be 35-40 ℃. And (3) dropwise adding 330g of 70% sulfuric acid aqueous solution, and controlling the temperature to be 35-40 ℃. After the dropwise addition, stirring for 12h at the temperature of 35-40 ℃, cooling to 15-25 ℃, filtering, and drying in vacuum at the temperature of 50 ℃ to constant weight to obtain 1259.2g of hydroxychloroquine sulfate in the crystal form A, wherein the yield is 88.6%, and the HPLC purity is 99.94% (shown in a DSC (DSC) diagram, an XRD (XRD) diagram is shown in figure 4, and an HPLC (HPLC) diagram is shown in figure 6).
Comparative example 2 referring to example 2 in Chinese patent CN108727263A
Dissolving hydroxychloroquine (1mol) obtained in example 1 in absolute ethyl alcohol, wherein the weight of the absolute ethyl alcohol is 5 times of that of hydroxychloroquine, dropwise adding a 40% sulfuric acid aqueous solution (0.96mol) into the absolute ethyl alcohol until the absolute ethyl alcohol is turbid when the temperature is controlled to be 25 ℃, heating to 50 ℃ after dropwise adding, carrying out heat preservation and crystallization for 5 hours, then cooling to below 15 ℃ and carrying out heat preservation for 1 hour, filtering, and drying at 50 ℃ to obtain the hydroxychloroquine sulfate crystal form A, wherein the yield is 90.5%, and the purity is 99.8%.
Example 2 evaluation test for stability of Hydroxychloroquine sulfate Crystal form
1. Experiment of influence factor
The product and the influence factor test on the crystal forms in comparative example 1 and comparative example 2 were performed according to the relevant regulations (appendix XIX C of the second part of chinese pharmacopoeia 2015 year edition).
(1) High-temperature test: taking a proper amount of the test sample, opening the sample into a temperature and humidity regulating box, placing the sample for 60 days at the temperature of 60 ℃, sampling the sample respectively on the 5 th day, the 10 th day, the 30 th day and the 60 th day, and detecting according to the requirements of the stability focus investigation project.
TABLE 1 high temperature test results
(2) High humidity test: taking a proper amount of the test sample, opening the test sample into a temperature and humidity regulating box, respectively placing the test sample for 5 days, 10 days, 30 days and 60 days under the condition that the relative humidity is 90 +/-5 percent at 25 ℃, sampling, detecting according to the requirements of important stability investigation projects, and simultaneously accurately weighing the weight of the test sample before and after the test to investigate the moisture absorption and deliquescence performance of the test sample.
TABLE 2 high humidity test results
(3) Strong light irradiation test: placing the sample in an illumination box with an appropriate opening, sampling for 5 days, 10 days, 30 days and 60 days under the condition of the illumination of 4500lx +/-500 lx, and detecting according to the stability focus examination item.
TABLE 3 test results of intense light irradiation
Influence factor test results show that: the product is placed under the conditions of high temperature (60 ℃), relative humidity (90 +/-5%) and illumination (4500lx +/-500 lx) for 60 days, all indexes are in accordance with the regulations, no obvious change is caused compared with 0 day, impurities are basically in the same level, the content of the impurities is low, the stability is good, and the hygroscopicity is low. In contrast, the hydroxychloroquine sulfate crystal form a in comparative examples 1 and 2 is left under the same conditions for 60 days, and related substances have increasing trends in different degrees.
2. And (3) accelerated test:
accelerated testing of the product was carried out according to the relevant regulations (appendix XIX C of the second part of the pharmacopoeia 2015 year).
Taking a proper amount of three batches of pilot samples, simulating a commercially available package, standing for 6 months under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-5%, and sampling once at the end of 1 month, 2 months, 3 months and 6 months respectively, and detecting according to a stability key investigation project.
And taking a proper amount of hydroxychloroquine sulfate crystal form A in the comparative examples 1 and 2, and detecting according to a stability focus investigation project under the same condition.
TABLE 4 accelerated test results
The results of accelerated tests show that: under the condition of simulating the packaging condition on the market, three batches of the product to be tested are placed for 6 months under the conditions of the temperature of 40 ℃ plus or minus 2 ℃ and the relative humidity of 75 percent plus or minus 5 percent, all detection indexes have no significant change, the impurities are basically at the same level, the impurity content is low, the stability is good, and the hygroscopicity is low. And the hydroxychloroquine sulfate crystal form A in the comparative examples 1 and 2 is placed under the same conditions for 6 months, and related substances have increasing trends in different degrees.
3. And (3) long-term test:
the long-term test of the product is carried out according to the relevant regulations (appendix XIX C of the second part of the pharmacopoeia 2015 year edition).
Taking a proper amount of three batches of pilot samples, simulating a commercial package, standing for 12 months under the conditions of the temperature of 25 +/-2 ℃ and the relative humidity of 60 +/-10%, sampling at the end of 3 months, 6 months, 9 months and 12 months respectively, detecting according to a stability key examination item, and comparing the result with the data of 0 month.
And taking a proper amount of hydroxychloroquine sulfate crystal form A in the comparative examples 1 and 2, and detecting according to a stability focus investigation project under the same condition.
TABLE 5 Long-term test results
The long-term test results show that: the samples of the product are placed in an environment with the temperature of 25 ℃ plus or minus 2 ℃ and the relative humidity of 60 percent plus or minus 10 percent for 12 months under the simulated commercial packaging condition, and the detection data of 3 rd, 6 th, 9 th and 12 th months are compared with the data of 0 month, and all detection indexes have no significant change. The test result shows that: the product is stable under long-term test conditions. And the hydroxychloroquine sulfate crystal form A in the comparative examples 1 and 2 is placed under the same conditions for 12 months, and related substances have increasing trends in different degrees.
Claims (10)
1. The hydroxychloroquine sulfate crystal form B is characterized in that characteristic absorption peaks exist at positions of 8.8 +/-0.1, 9.8 +/-0.1, 13.0 +/-0.1, 8.8 +/-0.1, 15.9 +/-0.1, 18.5 +/-0.1, 19.6 +/-0.1 and 22.7 +/-0.1 of reflection angle 2 theta of an X-ray powder diffraction pattern of the hydroxychloroquine sulfate crystal form B.
2. The hydroxychloroquine sulfate crystalline form B of claim 2, wherein said hydroxychloroquine sulfate crystalline form B has an X-ray powder diffraction pattern as shown in figure 1.
3. The hydroxychloroquine sulfate crystalline form B as claimed in claim 1 or 2, wherein said hydroxychloroquine sulfate crystalline form B has an endothermic peak at 193-.
4. The hydroxychloroquine sulfate crystalline form B of claim 3, wherein said hydroxychloroquine sulfate crystalline form B has a DSC profile as shown in figure 2, and an endothermic peak at 195.5 ℃.
5. A process for the preparation of hydroxychloroquine sulfate form B according to claim 1, wherein said hydroxychloroquine sulfate form B is prepared according to the following process: 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 dropwise adding process, preserving the temperature for 6-24 hours at 5-15 ℃ after the dropwise adding is finished, filtering, and drying to obtain the hydroxychloroquine sulfate crystal form B.
6. The method for preparing hydroxychloroquine sulfate crystal form B according to claim 5, wherein the molar ratio of hydroxychloroquine to sulfuric acid is 1: 0.5-1.1, preferably 1: 0.8-0.9; more preferably 1: 0.72; the mass fraction of the sulfuric acid in the sulfuric acid aqueous solution is 65-75%, and preferably 70%.
7. The preparation method of hydroxychloroquine sulfate crystal form B as claimed in claim 5, wherein said organic solvent is one or more of methanol, ethanol, n-butanol, ethyl acetate, tetrahydrofuran or acetone; preferably methanol or ethanol; the volume mass ratio of the organic solvent to the hydroxychloroquine is 4 ml/g-20 ml/g, preferably 8 ml/g-10 ml/g.
8. The preparation method of hydroxychloroquine sulfate crystal form B according to claim 5, wherein the temperature during heat preservation is 5-10 ℃; the heat preservation time is 10-16 hours, preferably 12 hours; the drying is vacuum drying, the drying temperature is 40-60 ℃, and preferably, the drying temperature is 50 ℃.
9. A pharmaceutical composition is characterized in that the composition comprises hydroxychloroquine sulfate crystal form B as an active ingredient or a main active ingredient, and pharmaceutically acceptable auxiliary materials.
10. A formulation characterized in that it comprises an effective dose of hydroxychloroquine sulfate form B.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114213324A (en) * | 2021-11-10 | 2022-03-22 | 华南理工大学 | Hydroxychloroquine eutectic crystal, preparation method, content determination method and application thereof |
| CN114315716A (en) * | 2021-11-10 | 2022-04-12 | 华南理工大学 | Hydroxychloroquine novel eutectic crystal, preparation method, content determination method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108658858A (en) * | 2017-06-27 | 2018-10-16 | 上海中西三维药业有限公司 | A kind of preparation method of the preparation and process for purification and its sulfate of hydroxychloroquine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108658858A (en) * | 2017-06-27 | 2018-10-16 | 上海中西三维药业有限公司 | A kind of preparation method of the preparation and process for purification and its sulfate of hydroxychloroquine |
Non-Patent Citations (1)
| Title |
|---|
| 裘雯梅 等: "硫酸羟氯喹的工艺优化", 《中国医药工业杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114213324A (en) * | 2021-11-10 | 2022-03-22 | 华南理工大学 | Hydroxychloroquine eutectic crystal, preparation method, content determination method and application thereof |
| CN114315716A (en) * | 2021-11-10 | 2022-04-12 | 华南理工大学 | Hydroxychloroquine novel eutectic crystal, preparation method, content determination method and application thereof |
| CN114315716B (en) * | 2021-11-10 | 2024-02-23 | 华南理工大学 | Hydroxychloroquine eutectic, preparation method thereof, content determination method and application |
| CN114213324B (en) * | 2021-11-10 | 2024-02-23 | 华南理工大学 | Hydroxychloroquine eutectic, preparation method thereof, content determination method and application |
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