Hydroxychloroquine sulfate, crystal form of enantiomer thereof and preparation method of crystal form

文档序号：1082803 发布日期：2020-10-20 浏览：32次中文

阅读说明：本技术 一种硫酸羟氯喹及其对映体的晶型和制备方法 (Hydroxychloroquine sulfate, crystal form of enantiomer thereof and preparation method of crystal form ) 是由李光辉覃志俊莫泽艺董雪林吴挺强胡双龙蔡强焦慎超于 2020-07-23 设计创作，主要内容包括：一种硫酸羟氯喹及其对映体的晶型和制备方法。本发明提供了一种A晶型硫酸羟氯喹,所述的A晶型硫酸羟氯喹的X-射线粉末衍射图谱在10.8o、13.0o、13.3o、16.9o、17.2o、17.5o、19.9o、21.3o、23.5o、24.0o和26.7o±0.2o具有特征峰,不含有羟氯喹氮氧化物；本发明提供了一种羟氯喹晶体,X-射线粉末衍射图谱在7.5o、14.9o、16.5o、19.2o、19.6o、22.8o、23.6o和26.7o±0.2o具有特征峰；本发明提供了一种S-羟氯喹硫酸盐一水合物,X-射线粉末衍射图谱在12.2o、13.0o、14.9o、17.8o、22.7o、23.3o、25.0o和26.2o±0.2o具有特征峰；本发明还提供了一种R-羟氯喹硫酸盐,X-射线粉末衍射图谱在12.2o、13.0o、14.9o、17.8o、22.7o、23.3o、25.0o和26.2o±0.2o具有特征峰。(A hydroxychloroquine sulfate and crystal forms of enantiomers thereof and a preparation method. The invention provides a crystal form A hydroxychloroquine sulfate, wherein the X-ray powder diffraction pattern of the crystal form A hydroxychloroquine sulfate is 10.8 o 、13.0 o 、13.3 o 、16.9 o 、17.2 o 、17.5 o 、19.9 o 、21.3 o 、23.5 o 、24.0 o And 26.7 o ±0.2 o Has a characteristic peak and does not contain hydroxychloroquine oxynitride; the invention provides a hydroxychloroquine crystal, wherein the X-ray powder diffraction pattern is 7.5 o 、14.9 o 、16.5 o 、19.2 o 、19.6 o 、22.8 o 、23.6 o And 26.7 o ±0.2 o Has a characteristic peak; the invention provides S-hydroxychloroquine sulfate monohydrate, and the X-ray powder diffraction pattern is 12.2 o 、13.0 o 、14.9 o 、17.8 o 、22.7 o 、23.3 o 、25.0 o And 26.2 o ±0.2 o Has a characteristic peak; the invention also provides an R-hydroxychloroquine sulfate with an X-ray powder diffraction pattern of 12.2 o 、13.0 o 、14.9 o 、17.8 o 、22.7 o 、23.3 o 、25.0 o And 26.2 o ±0.2 o Has characteristic peaks.)

1. The A crystal form hydroxychloroquine sulfate is characterized in that an X-ray powder diffraction pattern expressed by a 2 theta angle is 10.8^o、13.0^o、13.3^o、16.9^o、17.2^o、17.5^o、19.9^o、21.3^o、23.5^o、24.0^oAnd 26.7^o±0.2^oHas a characteristic peak;

the A crystal form hydroxychloroquine sulfate does not contain hydroxychloroquine oxynitride.

2. The hydroxychloroquine crystal is characterized in that an X-ray powder diffraction pattern expressed by a 2 theta angle is 7.5^o、14.9^o、16.5^o、19.2^o、19.6^o、22.8^o、23.6^oAnd 26.7^o±0.2^oHas characteristic peaks.

3. The S-hydroxychloroquine sulfate monohydrate is characterized in that an X-ray powder diffraction pattern expressed by a 2 theta angle is 12.2^o、13.0^o、14.9^o、17.8^o、22.7^o、23.3^o、25.0^oAnd 26.2^o±0.2^oHas characteristic peaks.

4. The R-hydroxychloroquine sulfate is characterized in that the X-ray powder diffraction pattern expressed by the 2 theta angle is 12.2^o、13.0^o、14.9^o、17.8^o、22.7^o、23.3^o、25.0^oAnd 26.2^o±0.2^oHas characteristic peaks.

5. A process for preparing hydroxychloroquine sulfate crystalline form a as claimed in claim 1, wherein, in the step of salification, the reaction temperature is not greater than 25 ℃.

6. The method of claim 5, wherein hydroxychloroquine is dissolved in an organic solvent, a sulfuric acid solution is slowly added at 15-25 ℃ to adjust the pH, the temperature is kept at 1 for stirring crystallization, the temperature is reduced to 10-15 ℃, the temperature is kept at 2 for stirring crystallization, and the hydroxychloroquine sulfate of the crystal form A is obtained through filtration and drying.

7. A process for preparing S-hydroxychloroquine sulfate monohydrate as claimed in claim 3, wherein, in the step of salification, the reaction temperature is not more than 30 ℃;

the S-hydroxychloroquine sulfate monohydrate does not contain hydroxychloroquine oxynitride.

8. A process for preparing the R-hydroxychloroquine sulfate of claim 4, wherein, in the salt formation step, the reaction temperature is not greater than 35 ℃;

the R-hydroxychloroquine sulfate does not contain hydroxychloroquine nitrogen oxides.

9. A method for preparing optical pure hydroxychloroquine side chain mandelate is characterized in that (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol is dissolved in an organic solvent, and L- (+) -mandelic acid is added for salification or D- (-) -mandelic acid is added for salification;

the molar ratio of the salified L- (+) -mandelic acid or salified D- (-) -mandelic acid to (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol is 1: 1.9-2.3;

the weight ratio of the (+/-) -2- [ (4-amino pentyl) ethylamino ] ethanol to the organic solvent is 1: 2.5-4.5, wherein the organic solvent is C1-C4 monohydric alcohol.

10. The method of claim 9, wherein the organic solvent is isopropanol.

Technical Field

The invention relates to a hydroxychloroquine sulfate crystal and a preparation method thereof, in particular to S-hydroxychloroquine sulfate, R-hydroxychloroquine sulfate and a hydroxychloroquine sulfate crystal.

Background

Hydroxychloroquine sulfate (Hydroxychloroquine sulfate), chemically named 2- [ [4- [ (7-chloro-4-quinolyl) amino group]Pentyl radical]Ethylamino group]-ethanol sulfate, chemical structure is shown as formula I, hydroxychloroquine is its free alkali,clinically, it is used for rheumatoid arthritis, juvenile chronic arthritis, discoid lupus erythematosus and systemic lupus erythematosus, and skin lesions caused or aggravated by sunlight.

S-hydroxychloroquine sulfate, chemically named (S) - (+) -2- [ [4- [ (7-chloro-4-quinolyl) amino group]Pentyl radical]Ethylamino group]-ethanol sulfate, chemical structure as shown in formula II, S-hydroxychloroquine as its free alkali,

r-hydroxychloroquine sulfate, chemically named (R) - (-) -2- [ [4- [ (7-chloro-4-quinolinyl) amino]Pentyl radical]Ethylamino group]-ethanol sulfate, chemical structure is shown as formula III, R-hydroxychloroquine is its free alkali,

in the case of hydroxychloroquine sulfate disclosed in patent CN102050781B, concentrated sulfuric acid is added under the condition of an organic solvent of esters and alcohols to obtain hydroxychloroquine sulfate.

Patent CN103724261B discloses adding concentrated sulfuric acid into an organic solvent, and then slowly dropping hydroxychloroquine organic solvent to prepare hydroxychloroquine sulfate.

Patents CN104230803A and CN109456266A both disclose that hydroxychloroquine sulfate is prepared by adding concentrated sulfuric acid into organic solvent containing water and alcohols.

Patent CN108727263A discloses a hydroxychloroquine sulfate of crystal form A, according to the disclosure, the disclosed hydroxychloroquine sulfate of crystal form A is more stable than hydroxychloroquine sulfate in the prior art, the key technical characteristics of the preparation method are that a sulfuric acid aqueous solution with a mass fraction of 40% -60% is adopted, and the preparation method is characterized by adopting means of XRPD, DSC and IR.

Although the stability of the hydroxychloroquine sulfate in the crystal form a prepared by the method disclosed in patent CN108727263A is good, the preparation method has certain defects, and in the preparation method, after the addition of the sulfuric acid solution is finished, the temperature needs to be raised for reaction, so that the risk of generating hydroxychloroquine oxynitride (CAS: 1449223-88-4) and etherification products exists, and further the hydroxychloroquine oxynitride and the etherification products remain in the product, and therefore, the method needs to be improved.

The patent CN105693606 discloses an asymmetric synthesis method of optically pure R/S-hydroxychloroquine, and because S-hydroxychloroquine and R-hydroxychloroquine have different biological properties, the deep research on the two isomers has important significance for the application of the medicine in new fields, and the acquisition of a stable crystal form is an important link of research and development.

S-hydroxychloroquine or R-hydroxychloroquine is generally prepared by condensation reaction of (S) -2- [ (4-aminopentyl) ethylamino ] ethanol or (R) -2- [ (4-aminopentyl) ethylamino ] ethanol and 4, 7-dichloroquinoline, and the prior art can adopt (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol and chiral resolution reagent L- (+) -mandelic acid (namely S- (+) -mandelic acid) or D- (-) -mandelic acid (namely R- (-) -mandelic acid) to be prepared by resolution, the resolution method disclosed needs repeated resolution and crystallization, and has the disadvantages of complex operation and low yield.

In view of the above problems, the inventors have conducted intensive research work to reduce the risk of production of hydroxychloroquine nitroxide (CAS: 1449223-88-4) and etherification products while maintaining the hydroxychloroquine sulfate crystal form a; on the other hand, the method is to study the resolution of the hydroxychloroquine side chain, simplify the operation and prepare the optically pure hydroxychloroquine sulfate crystal by adopting the optically pure hydroxychloroquine side chain obtained by the resolution.

Disclosure of Invention

The inventor carries out intensive research on the risks existing in the preparation of the hydroxychloroquine sulfate in the crystal form A by the existing method, and unexpectedly finds that the hydroxychloroquine sulfate in the crystal form A can be obtained when the reaction is carried out at low temperature, the production of hydroxychloroquine oxynitride can be avoided, the yield is over 80%, and the purity is more than 99.6%, preferably more than 99.8%, and more preferably more than 99.9%.

The invention provides a preparation method of A crystal form hydroxychloroquine sulfate, wherein the hydroxychloroquine sulfate does not contain hydroxychloroquine nitrogen oxide, and the preparation method is characterized in that in the step of salifying, the reaction temperature is not more than 25 ℃.

Preferably, the preparation method of the hydroxychloroquine sulfate crystal form A is characterized by dissolving hydroxychloroquine in an organic solvent, slowly adding a sulfuric acid solution at 15-25 ℃ to adjust the pH, keeping the temperature for 1, stirring and crystallizing, cooling to 10-15 ℃, keeping the temperature for 2, stirring and crystallizing, filtering and drying to obtain the hydroxychloroquine sulfate crystal form A;

wherein the organic solvent is an alcohol solvent, preferably monohydric alcohol of C1-C4;

wherein the weight ratio of the hydroxychloroquine to the organic solvent is 1: 3.5-4.5;

wherein the mass fraction concentration of the sulfuric acid solution is 40-60%, preferably 50-55%;

wherein the pH value is adjusted to 2-3;

wherein the temperature of the heat preservation 1 is 15-25 ℃;

wherein the stirring time of the heat preservation 1 is 3-5 h;

wherein the temperature of the heat preservation 2 is 10-15 ℃;

wherein the stirring time of the heat preservation 2 is 5-8 h;

wherein the drying temperature is 50-65 ℃, and preferably 60 ℃;

wherein the drying time is 6-10 h;

wherein the drying adopts a vacuum drying mode.

The hydroxychloroquine sulfate prepared by the method provided by the invention has the following X-ray diffraction pattern data:

the XPRD test conditions of the invention are as follows:

the instrument comprises the following steps: panalytical X' Pert3 powder X-ray diffractometer; target: cu, Ka; wavelength K alpha 1: 1.54060A, K alpha 2: 1.54443A; pipe pressure: 40 kV; pipe flow: 40 mA; step length [ 2 ]^o2θ]: 0.0260; time of scanning per step s]：37.9440。

Further, the invention provides a preparation method of the A crystal form hydroxychloroquine sulfate, which is characterized by comprising the following steps:

1) condensation reaction: reacting 4, 7-dichloroquinoline with a hydroxychloroquine side chain in the presence of an alcohol organic solvent, adjusting the pH value after the reaction is finished, extracting by adopting halogenated alkane, concentrating, and recrystallizing to obtain hydroxychloroquine;

2) salt forming reaction: dissolving the hydroxychloroquine obtained in the step 1) in an organic solvent, slowly adding a sulfuric acid solution at 15-25 ℃ to adjust the pH value, keeping the temperature for 1, stirring and crystallizing, cooling to 10-15 ℃, keeping the temperature for 2, stirring and crystallizing, filtering, and drying to obtain the hydroxychloroquine sulfate with the crystal form A.

The hydroxychloroquine crystal prepared by the method provided by the invention has the following X-ray diffraction pattern data:

the A crystal form hydroxychloroquine sulfate has an X-ray powder diffraction pattern expressed by a 2 theta angle of 10.8^o、13.0^o、13.3^o、16.9^o、17.2^o、17.5^o、19.9^o、21.3^o、23.5^o、24.0^oAnd 26.7^o±0.2^oHas a characteristic peak; the hydroxychloroquine crystal has an X-ray powder diffraction pattern expressed by a 2 theta angle of 7.5^o、14.9^o、16.5^o、19.2^o、19.6^o、22.8^o、23.6^oAnd 26.7^o±0.2^oHas characteristic peaks.

The preparation and the crystal form of the S-hydroxychloroquine sulfate monohydrate are researched, a splitting method is adopted, high-yield (S) -2- [ (4-amino pentyl) ethylamino ] ethanol is adopted, the (S) -2- [ (4-amino pentyl) ethylamino ] ethanol and 4, 7-dichloroquinoline are subjected to condensation reaction to prepare S-hydroxychloroquine, sulfate is formed at low temperature, and S-hydroxychloroquine sulfate monohydrate is obtained and does not contain S-hydroxychloroquine oxynitride impurities.

The invention provides a preparation method of S-hydroxychloroquine sulfate monohydrate, which is characterized in that in the salifying step, the reaction temperature is not more than 30 ℃.

Preferably, the preparation method of the S-hydroxychloroquine sulfate monohydrate is characterized by dissolving S-hydroxychloroquine in an organic solvent, slowly adding a sulfuric acid solution at 15-25 ℃ to adjust the pH, keeping the temperature for 1, stirring, crystallizing, cooling to 10-15 ℃, keeping the temperature for 2, stirring, crystallizing, filtering and drying to obtain the S-hydroxychloroquine sulfate monohydrate;

wherein the organic solvent is an alcohol solvent, preferably monohydric alcohol of C1-C4;

wherein the weight ratio of the hydroxychloroquine to the organic solvent is 1: 3.5-4.5;

wherein the mass fraction concentration of the sulfuric acid solution is 40-60%, preferably 50-55%;

wherein the pH value is adjusted to 2-3;

wherein the temperature of the heat preservation 1 is 15-25 ℃;

wherein the stirring time of the heat preservation 1 is 0.5-2 h;

wherein the temperature of the heat preservation 2 is 10-15 ℃;

wherein the stirring time of the heat preservation 2 is 5-8 h;

wherein the drying temperature is 50-65 ℃, and preferably 60 ℃;

wherein the drying time is 6-10 h;

wherein the drying adopts a vacuum drying mode.

The S-hydroxychloroquine sulfate monohydrate prepared by the method provided by the invention has the following X-ray diffraction pattern data:

further, the preparation method of the S-hydroxychloroquine sulfate monohydrate provided by the invention is characterized by comprising the following steps:

1) condensation reaction: reacting 4, 7-dichloroquinoline with an S-hydroxychloroquine side chain in the presence of an alcohol organic solvent, adjusting the pH value after the reaction is finished, extracting by adopting halogenated alkane, and concentrating to obtain hydroxychloroquine;

The invention also provides a preparation method of (S) -2- [ (4-amino pentyl) ethylamino ] ethanol S- (+) -mandelate, which is characterized in that (+/-) -2- [ (4-amino pentyl) ethylamino ] ethanol is dissolved in an organic solvent, and L- (+) -mandelic acid is added for salification;

wherein the molar ratio of the L- (+) -mandelic acid to the (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol is 1: 1.9-2.3, preferably 1: 2;

wherein the weight ratio of the (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol to the organic solvent is 1: 2.5-4.5, preferably 1: 3;

wherein the organic solvent is C1-C4 monohydric alcohol, preferably isopropanol;

preferably, the method further comprises filtering and drying.

The (S) -2- [ (4-amino pentyl) ethylamino ] ethanol S- (+) -mandelate prepared by the method provided by the invention is neutralized in alkaline aqueous solution, extracted by dichloromethane, dried and concentrated to obtain the (S) -2- [ (4-amino pentyl) ethylamino ] ethanol.

The S-hydroxychloroquine sulfate monohydrate provided by the invention has an X-ray powder diffraction pattern expressed by a 2 theta angle of 12.2^o、13.0^o、14.9^o、17.8^o、22.7^o、23.3^o、25.0^oAnd 26.2^o±0.2^oHas characteristic peaks.

The preparation and the crystal form of the R-hydroxychloroquine sulfate are researched, a resolution method is adopted, high-yield (R) -2- [ (4-amino pentyl) ethylamino ] ethanol is adopted, the (R) -2- [ (4-amino pentyl) ethylamino ] ethanol and 4, 7-dichloroquinoline are subjected to condensation reaction to prepare the R-hydroxychloroquine, the R-hydroxychloroquine sulfate is formed into sulfate under the low-temperature condition, and the R-hydroxychloroquine sulfate does not contain R-hydroxychloroquine oxynitride impurities.

The invention provides a preparation method of R-hydroxychloroquine sulfate, wherein the R-hydroxychloroquine sulfate does not contain hydroxychloroquine nitrogen oxide, and is characterized in that in the step of salifying, the reaction temperature is not more than 35 ℃.

Preferably, the preparation method of the R-hydroxychloroquine sulfate is characterized in that the R-hydroxychloroquine is dissolved in an organic solvent, a sulfuric acid solution is slowly added at the temperature of 15-25 ℃ to adjust the pH value, the temperature is kept 1, stirring and crystallization are carried out, the temperature is reduced to 10-15 ℃, the temperature is kept 2, stirring and crystallization are carried out, and the R-hydroxychloroquine sulfate is obtained after filtration and drying;

wherein the organic solvent is an alcohol solvent, preferably monohydric alcohol of C1-C4;

wherein the weight ratio of the hydroxychloroquine to the organic solvent is 1: 3.5-4.5;

wherein the mass fraction concentration of the sulfuric acid solution is 40-60%, preferably 50-55%;

wherein the pH value is adjusted to 2-3;

wherein the temperature of the heat preservation 1 is 15-25 ℃;

wherein the stirring time of the heat preservation 1 is 0.5-2 h;

wherein the temperature of the heat preservation 2 is 10-15 ℃;

wherein the stirring time of the heat preservation 2 is 5-8 h;

wherein the drying temperature is 50-65 ℃, and preferably 60 ℃;

wherein the drying time is 6-10 h;

wherein the drying adopts a vacuum drying mode.

The R-hydroxychloroquine sulfate prepared by the method provided by the invention has the following X-ray diffraction pattern data:

further, the preparation method of the R-hydroxychloroquine sulfate provided by the invention is characterized by comprising the following steps:

1) condensation reaction: reacting 4, 7-dichloroquinoline with an R-hydroxychloroquine side chain in the presence of an alcohol organic solvent, adjusting the pH value after the reaction is finished, extracting by adopting halogenated alkane, and concentrating to obtain hydroxychloroquine;

The invention also provides a preparation method of (R) -2- [ (4-aminopentyl) ethylamino ] ethanol R- (-) -mandelate, which is characterized in that (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol is dissolved in an organic solvent, and D- (-) -mandelic acid is added for salification;

wherein the molar ratio of the D- (-) -mandelic acid to the (+ -) -2- [ (4-aminopentyl) ethylamino ] ethanol is 1: 1.9-2.3, preferably 1: 2;

wherein the weight ratio of the (+/-) -2- [ (4-aminopentyl) ethylamino ] ethanol to the organic solvent is 1: 2.5-4.5, preferably 1: 3;

wherein the organic solvent is C1-C4 monohydric alcohol, preferably isopropanol;

preferably, the method further comprises filtering and drying.

The (R) -2- [ (4-amino pentyl) ethylamino ] ethanol R- (-) -mandelate prepared by the method provided by the invention is neutralized in alkaline aqueous solution, extracted by dichloromethane, dried and concentrated to obtain the (R) -2- [ (4-amino pentyl) ethylamino ] ethanol.

The R-hydroxychloroquine sulfate provided by the invention has an X-ray powder diffraction pattern expressed by a 2 theta angle of 12.2^o、13.0^o、14.9^o、17.8^o、22.7^o、23.3^o、25.0^oAnd 26.2^o±0.2^oHas characteristic peaks.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

In the invention: the term "XRPD" refers to powder X-ray diffraction;

the term "HPLC" refers to high performance liquid chromatography;

the hydroxychloroquine side chain is 5- (N-ethyl-N-2-hydroxyethyl amino) -2-pentylamine;

the S-hydroxychloroquine side chain is (S) -2- [ (4-amino pentyl) ethylamino ] ethanol;

the R-hydroxychloroquine side chain is (R) -2- [ (4-amino pentyl) ethylamino ] ethanol;

the optically pure hydroxychloroquine sulfate is S-hydroxychloroquine sulfate or R-hydroxychloroquine sulfate;

the optically pure hydroxychloroquine side chain is (S) -2- [ (4-aminopentyl) ethylamino ] ethanol (the structural formula is shown in a formula VI) or (R) -2- [ (4-aminopentyl) ethylamino ] ethanol (the structural formula is shown in a formula VII);

the optically pure hydroxychloroquine side chain mandelate is (R) -2- [ (4-aminopentyl) ethylamino ] ethanol R- (-) -mandelate (the structural formula is shown in the formula V) or (S) -2- [ (4-aminopentyl) ethylamino ] ethanol S- (+) -mandelate (the structural formula is shown in the formula IV);

the hydroxychloroquine sulfate and the hydroxychloroquine sulfate are different names of the same substance;

the invention has the beneficial effects that: (1) the hydroxychloroquine sulfate crystal form A with high chemical stability is prepared by using a simple and feasible preparation method, the method avoids high-temperature reaction, reduces the risk of production of hydroxychloroquine nitrogen oxides, is easy for industrial production, and has stable and reliable quality; (2) for the optically pure hydroxychloroquine sulfate, specific reaction conditions are adopted, and the optically pure hydroxychloroquine side chain mandelate is obtained by high-yield resolution; the preparation method is simple and feasible, the optically pure hydroxychloroquine sulfate is prepared, the method avoids high-temperature reaction, reduces the risk of generating corresponding hydroxychloroquine nitrogen oxides, is easy for industrial production, and has stable and reliable quality.

Drawings

FIG. 1 example 1 Hydroxychloroquine XRPD spectrum

FIG. 2 example 2 Hydroxychloroquine sulfate XRPD spectrum

FIG. 3 example 2 hydroxychloroquine sulfate HPLC chemical purity profile

FIG. 4 XRPD spectrum of example 9S-hydroxychloroquine sulfate monohydrate

FIG. 5 HPLC optical purity spectrum of example 9S-hydroxychloroquine sulfate monohydrate

FIG. 6 XRPD spectrum of example 15R-hydroxychloroquine sulfate

FIG. 7 HPLC optical purity spectrum of example 15R-hydroxychloroquine sulfate

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions.

The method for detecting the purity of the hydroxychloroquine and the salt thereof comprises the following steps:

the instrument comprises the following steps: preparing an ultraviolet detector and an electronic analytical balance by using a high performance liquid chromatograph;

a chromatographic column: octadecylsilane chemically bonded silica is used as a packed column;

flow rate: 1.0 ml/min; detection wavelength: 242 nm; sample introduction amount: 20 mu l of the mixture; column temperature: 35 ℃;

mobile phase A: acetonitrile: water: phosphoric acid (100: 900:2, V/V/V);

mobile phase B: acetonitrile: water: phosphoric acid (800: 200:1, V/V/V);

elution was performed with the following gradient:

the instrument related to the XPRD test of the invention is a PANALYTICAL X' Pert3 powder X-ray diffractometer, and the conditions are as follows: the instrument comprises the following steps: (ii) a Target: cu, Ka; wavelength K alpha 1: 1.54060A, K alpha 2: 1.54443A; pipe pressure: 40 kV; pipe flow: 40 mA; step size [ o2 θ ]: 0.0260; scanning time [ s ] per step: 37.9440.

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Hydroxychloroquine sulfate, crystal form of enantiomer thereof and preparation method of crystal form

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