CN108727263A - Hydroxychloroquine sulfate crystal form A and preparation method thereof - Google Patents
Hydroxychloroquine sulfate crystal form A and preparation method thereof Download PDFInfo
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- CN108727263A CN108727263A CN201810731676.6A CN201810731676A CN108727263A CN 108727263 A CN108727263 A CN 108727263A CN 201810731676 A CN201810731676 A CN 201810731676A CN 108727263 A CN108727263 A CN 108727263A
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- crystal form
- hydroxychloroquine
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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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- 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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Abstract
The invention discloses a kind of hydroxychloroquine sulfate crystal form A and preparation method thereof, and are characterized using the means of XRPD, DSC and IR.The hydroxychloroquine sulfate crystal form A of the present invention improves the chemical stability of hydroxychloroquine sulfate, and preparation method is simple, is easy to industrialized production, while can also provide Research foundation for more hydroxychloroquine sulfate formulation developments.The aqueous sulfuric acid that use quality score is 40~60% in the preparation method of the present invention, safety and operability increase, and significantly reduce because using risk of exotherm caused by the concentrated sulfuric acid.
Description
Technical field
The present invention relates to hydroxychloroquine sulfate crystal form A and preparation method thereof.
Background technology
Hydroxychloroquine sulfate (Hydroxychloroquine Sulfate), entitled 2- [[4- [(the chloro- 4- quinoline of 7- of chemistry
Base) amino] amyl] ethylamino]-alcohol sulfate salt, No. CAS is 747-36-40.Hydroxychloroquine sulfate is developed by Winthrop companies
Success is listed in multiple countries and regions such as France, Denmark, Japan, Germany, Finland in 1956 in U.S.'s Initial Public Offering.
U.S. FDA is used to treat lupus erythematosus, rheumatoid arthritis in approval on May 29th, 1998 hydroxychloroquine sulfate piece.Sulfuric acid hydroxyl
Chloroquine is because its clinical application of unique mechanism of action and preferable safety in rheumatism field is more and more extensive, 90 years 20th century
After generation, the clinical treatment of 90% or more rheumatism selects hydroxychloroquine sulfate, structure as follows：
Hydroxychloroquine sulfate is that one kind has a high potential, and be beneficial to man disease control and the drug for the treatment of, and at present also
There is no the report of hydroxychloroquine sulfate crystal form.
Invention content
Problem to be solved by this invention is provided for the problem of the stability difference of hydroxychloroquine sulfate in the prior art
A kind of hydroxychloroquine sulfate crystal form A and preparation method thereof.Present invention firstly discloses a kind of hydroxychloroquine sulfate crystal form A and its preparation sides
Method, and characterized using the means of XRPD, DSC and IR.The hydroxychloroquine sulfate crystal form A of the present invention improves hydroxychloroquine sulfate
Chemical stability, preparation method is simple, is easy to industrialized production, while can also be that more hydroxychloroquine sulfate formulation developments carry
For Research foundation.The aqueous sulfuric acid that use quality score is 40~60% in the preparation method of the present invention, safety and can grasp
The property made increase is significantly reduced because using risk of exotherm caused by the concentrated sulfuric acid.
The present invention provides a kind of hydroxychloroquine sulfate crystal form A, the X-ray powder diffraction collection that is indicated with 2 θ angles with
Lower position has characteristic peak：16.9 °, 17.1 °, 17.5 °, 19.9 °, 21.3 °, 23.5 °, 23.9 ° and 26.7 °.
Preferably, the XRPD collection of illustrative plates of the hydroxychloroquine sulfate crystal form A is as shown in Figure 1.
In addition, hydroxychloroquine sulfate crystal form A of the present invention, can be characterized with the infrared absorption pattern that KBr tablettings measure,
With infrared absorption pattern as shown in Figure 2, there is characteristic peak at following position：3424,3214,2972,1613,1553,
1458,1366,1342,1215,1111,824,620 and 605cm-1。
The differential scanning thermal map spectrum (DSC) of hydroxychloroquine sulfate crystal form A of the present invention is as shown in Fig. 2, it is deposited at 246 DEG C
In endothermic peak.
The present invention also provides a kind of preparation methods of the hydroxychloroquine sulfate crystal form A comprising following steps：By hydroxyl
The aqueous sulfuric acid that chloroquine, organic solvent and mass fraction are 40~60% mixes, and crystallization obtains hydroxychloroquine sulfate crystal form A i.e.
It can.
Preferably, the preparation method of the hydroxychloroquine sulfate crystal form A includes the following steps：By hydroxychloroquine with it is organic molten
Agent mixes, and the aqueous sulfuric acid that mass fraction is 40~60% is added dropwise to muddiness, crystallization obtains hydroxychloroquine sulfate crystal form A.
More preferably, the preparation method of the hydroxychloroquine sulfate crystal form A includes the following steps：By hydroxychloroquine and organic solvent
Mixing, the aqueous sulfuric acid that dropwise addition mass fraction is 40~60% to muddiness, first keeps the temperature at 35 DEG C~55 DEG C, then be cooled to 15 DEG C
Hereinafter, heat preservation, crystallization obtain hydroxychloroquine sulfate crystal form A.
The temperature of the mixing of hydroxychloroquine and the organic solvent can be the ordinary temperature that this field carries out this generic operation, only
Otherwise it is rotten to influence hydroxychloroquine, preferably 0 DEG C~35 DEG C.
The dropping temperature for the aqueous sulfuric acid that the mass fraction is 40~60% can be that this field carries out this generic operation
Ordinary temperature, preferably 10-35 DEG C.
Described 35 DEG C~55 DEG C of preferred 5h-36h of soaking time, for example, 5h.
15 DEG C of preferred 0.5h-2h of soaking time below, for example, 1h.
The organic solvent is preferably ethyl acetate and/or absolute ethyl alcohol.When the organic solvent is ethyl acetate
When with the mixed solvent of absolute ethyl alcohol, the mass ratio of the absolute ethyl alcohol and ethyl acetate is preferably 4:1~5:1.
The dosage of the organic solvent can generally make hydroxychloroquine be completely dissolved to form uniform solution.Preferably, described
Hydroxychloroquine and the weight ratio of organic solvent are 1:3~1:8.
The dosage for the aqueous sulfuric acid that the mass fraction is 40~60% can be selected according to actual demand, usual energy
Enough it is enough to keep hydroxychloroquine solution muddy, the sulfuric acid mole in the aqueous sulfuric acid that preferably hydroxychloroquine is 40~60% with mass fraction
Than being 1:0.85~1:1.1.
The preparation method can also further comprise post-processing, after the post-processing can be for the routine of this field
Reason, is preferably filtered, dry.
The drying can be the conventional drying of this field, preferably be dried in vacuo.The vacuum drying temperature is excellent
It is selected as 50-80 DEG C.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined arbitrarily each preferably to get the present invention
Example.
The reagents and materials used in the present invention are commercially available.
In the present invention：Term " XRPD " refers to powder x-ray diffraction；
Term " IR " refers to infra-red sepectrometry；
Term " DSC " refers to differential scanning calorimetry；
Term " HPLC " refers to high performance liquid chromatography；
In the present invention, operation temperature is not such as limited, is carried out at room temperature.The room temperature be 0 DEG C~35 DEG C, preferably 20
DEG C~30 DEG C.
The positive effect of the present invention is that：Using the preparation method of simple possible, chemical stability has been prepared
Higher hydroxychloroquine sulfate crystal form A, the stability of crystal form is good, is easy to industrialized production, and stable quality is reliable.
Description of the drawings
Fig. 1 is the X-ray powder diffraction collection of hydroxychloroquine sulfate crystal form A made from the embodiment of the present invention 2.
Fig. 2 is the DSC collection of illustrative plates of hydroxychloroquine sulfate crystal form A made from the embodiment of the present invention 2.
Specific implementation mode
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
Product specification selects.
In following embodiment, such as without especially indicating, the purity is HPLC purity.
Powder X-ray diffraction test equipment model Bruker D8ADVANCE according to the present invention；Test condition：
Voltage, Current 40Kv, 40mA, Stand-End Position are 0-40 ° of 2 θ, and Increment is 0.02 ° of 2 θ,
Time per step are 0.5s, detect environment：26 DEG C, humidity 44%RH.
Differential scanning calorimeter model TADSC Q2000 according to the present invention；Test method：Equlibrate at
20 DEG C, 250.0 DEG C of 10.0 DEG C/min of Ramp to, N2Stream is 40mL/min, aluminium dish, capping.Detect environment：It is 25 DEG C, wet
Spend 55%RH.
The method for detecting purity of the present invention：HPLC chromatogram column DB-624,30m × 0.53mm × 3.0 μm；Detector FID；It carries
Gas N2；Column flow rate 2.0mL/min；Hydrogen 30mL/min；Air 300mL/min；200 DEG C of injector temperature；Detector temperature 250
℃；Split ratio 5:1；Sample size 1mL；GC circulation time 42min；35 DEG C of holding 15min of column temperature, 60 DEG C of guarantors are risen to 5 DEG C/min
5min is held, then 220 DEG C of holding 5min are risen to 30 DEG C/min.
Mobile phase A water-acetonitrile-orthophosphoric acid (90:10:0.2), Mobile phase B water-acetonitrile-orthophosphoric acid (20:80:0.1)).
The synthesis of 1 hydroxychloroquine of embodiment
By 100g 4, reactor is added in 7- dichloroquinolines and 130g 5- (N- ethyl-N-2- ethylol amines) -2- amylamines
In, it is passed through argon gas protection, 70 DEG C of heating makes 4,7- dichloroquinoline dissolved clarifications, heats up 115 DEG C and reacts 10 minutes, and heat up 137 DEG C of reactions
10 hours, cool down (80 DEG C or less) after completion of the reaction, pH is adjusted with sodium hydroxide solution (mass concentration 6%)>12, dichloromethane
Extraction, is washed to neutrality, removes dichloromethane under reduced pressure and obtain hydroxychloroquine crude product 157g, yield 92.5%.It is thick to full dose hydroxychloroquine
200g acetone and 250g methyl acetates are added in product and heats 65 DEG C of dissolved clarifications, after 4h slow coolings to 10 DEG C, filtering, filter cake is with third
Ketone and the washing of methyl acetate mixed solution mixed solvent, obtain hydroxychloroquine wet product, 60 DEG C of dry 4h obtain hydroxychloroquine dry product, yield
89.1%.
The preparation of embodiment 2-19 hydroxychloroquine sulfate crystal forms A
The hydroxychloroquine that embodiment 1 obtains is dissolved in organic solvent, it is water-soluble that the sulfuric acid that mass fraction is 40~60% is added dropwise
Liquid is to muddiness, after being added dropwise, is warming up to 35 DEG C~55 DEG C, keeps the temperature crystallization, and rear 15 DEG C of cooling or less heat preservation 1h is filtered, 50 DEG C
It is dry, obtain hydroxychloroquine sulfate crystal form A.
Wherein, the hydroxychloroquine sulfate crystal form A that prepared by embodiment 2 has X-ray powder diffraction spectrum as shown in Figure 1, tool
Have in 2 θ=16.9 °, 17.1 °, 17.5 °, 19.9 °, 21.3 °, 23.5 °, the characteristic peaks of 23.9 ° and 26.7 °；Its DSC collection of illustrative plates is such as
Shown in Fig. 2, at 246 DEG C, there are endothermic peaks.
The actual conditions of 1 embodiment 2-19 of table
In above table, the heat preservation in holding temperature and soaking time refers to the heat preservation at 35 DEG C~55 DEG C；It is anhydrous
The ratio of ethyl alcohol and ethyl acetate is mass ratio.
Comparative example 1
The hydroxychloroquine 50g that embodiment 1 obtains is added in 400g absolute ethyl alcohols and 35g purified waters, at 25 DEG C, is added dropwise dense
Sulfuric acid is to muddiness, after being added dropwise, heats up 55 DEG C, keeps the temperature 5 hours, rear 15 DEG C of cooling or less heat preservation 1h, filtering, 50 DEG C of dryings,
Obtain hydroxychloroquine sulfate.
The actual conditions of 2 comparative example 1 of table
Product derived above is studied its chemical stability, in order to study its stability using area normalization
Change method is determined total impurity content, and specific data are as shown in Table 3 and Table 4：
The total miscellaneous changes of contents under illumination condition of table 3
Total miscellaneous changes of contents at a temperature of 60 DEG C of table 4
From table 3 and table 4 as can be seen that the hydroxychloroquine sulfate crystal form A stability being prepared is preferable, in illumination and 60 DEG C of items
It is always miscellaneous to be substantially at same level (in allowable range of error), the hydroxychloroquine sulfate that comparative example obtains, total miscellaneous summary under part
There is rising.
Claims (10)
1. a kind of hydroxychloroquine sulfate crystal form A, which is characterized in that the X-ray powder diffraction collection indicated with 2 θ angles is with bottom
It sets with characteristic peak：16.9 °, 17.1 °, 17.5 °, 19.9 °, 21.3 °, 23.5 °, 23.9 ° and 26.7 °.
2. hydroxychloroquine sulfate crystal form A as described in claim 1, which is characterized in that the XRPD of the hydroxychloroquine sulfate crystal form A
Collection of illustrative plates is as shown in Figure 1.
3. hydroxychloroquine sulfate crystal form A as claimed in claim 2, which is characterized in that the infrared absorption pattern measured with KBr tablettings
Characterization, has characteristic peak at following position：3424,3214,2972,1613,1553,1458,1366,1342,1215,
1111,824,620 and 605cm-1。
4. hydroxychloroquine sulfate crystal form A as claimed in claim 3, which is characterized in that the differential of the hydroxychloroquine sulfate crystal form A
There are endothermic peaks as shown in Fig. 2, it is at 246 DEG C for scanning calorimeter collection of illustrative plates.
5. a kind of preparation method of hydroxychloroquine sulfate crystal form A according to any one of claims 1-4, which is characterized in that it is wrapped
Include following steps：The aqueous sulfuric acid that hydroxychloroquine, organic solvent and mass fraction are 40~60% is mixed, crystallization obtains sulphur
Sour hydroxychloroquine crystal form A.
6. the preparation method of hydroxychloroquine sulfate crystal form A as claimed in claim 5, which is characterized in that it includes the following steps：It will
Hydroxychloroquine is mixed with organic solvent, the aqueous sulfuric acid that mass fraction is 40~60% is added dropwise to muddiness, crystallization obtains sulfuric acid hydroxyl
Chloroquine crystal form A.
7. the preparation method of hydroxychloroquine sulfate crystal form A as claimed in claim 6, which is characterized in that it includes the following steps：It will
Hydroxychloroquine is mixed with organic solvent, the aqueous sulfuric acid that dropwise addition mass fraction is 40~60% to muddiness, first at 35 DEG C~55 DEG C
Heat preservation, then 15 DEG C are cooled to hereinafter, heat preservation, crystallization obtain hydroxychloroquine sulfate crystal form A.
8. the preparation method of hydroxychloroquine sulfate crystal form A as claimed in claim 7, which is characterized in that the hydroxychloroquine with have
The temperature of the mixing of solvent is 0 DEG C~35 DEG C；
And/or the temperature of dropwise addition of aqueous sulfuric acid that the mass fraction is 40~60% is 10~35 DEG C；
And/or described 35 DEG C~55 DEG C of soaking times are 5h-36h；
And/or 15 DEG C of soaking times below are 0.5h-2h；
And/or the organic solvent is ethyl acetate and/or absolute ethyl alcohol；
And/or the weight ratio of the hydroxychloroquine and organic solvent is 1:3~1:8；
And/or the hydroxychloroquine and mass fraction be 40~60% aqueous sulfuric acid in the molar ratio of sulfuric acid be 1:
0.85~1:1.1.
9. the preparation method of hydroxychloroquine sulfate crystal form A as claimed in claim 8, which is characterized in that the preparation method is also
Further comprise post-processing, the post-processing is filtering, dry.
10. the preparation method of hydroxychloroquine sulfate crystal form A as claimed in claim 9, which is characterized in that the drying is vacuum
It is dry；The vacuum drying temperature is 50-80 DEG C.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN111377861A (en) * | 2018-12-28 | 2020-07-07 | 欣凯医药化工中间体（上海）有限公司 | Method for purifying hydroxychloroquine sulfate |
| CN111474269A (en) * | 2020-05-29 | 2020-07-31 | 长沙市如虹医药科技股份有限公司 | Method for determining organic impurities in hydroxychloroquine sulfate |
| CN111662229A (en) * | 2020-07-08 | 2020-09-15 | 精华制药集团南通有限公司 | Preparation process of chloroquine phosphate |
| CN111793026A (en) * | 2020-07-23 | 2020-10-20 | 珠海润都制药股份有限公司 | Hydroxychloroquine sulfate, crystal form of enantiomer thereof and preparation method of crystal form |
| CN113185459A (en) * | 2021-04-23 | 2021-07-30 | 江西国药有限责任公司 | Hydroxychloroquine sulfate and preparation method thereof |
| CN113527202A (en) * | 2020-04-21 | 2021-10-22 | 健亚生物科技股份有限公司 | Hydroxychloroquine sulfate crystal |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113527202A (en) * | 2020-04-21 | 2021-10-22 | 健亚生物科技股份有限公司 | Hydroxychloroquine sulfate crystal |
| CN111474269A (en) * | 2020-05-29 | 2020-07-31 | 长沙市如虹医药科技股份有限公司 | Method for determining organic impurities in hydroxychloroquine sulfate |
| CN111662229A (en) * | 2020-07-08 | 2020-09-15 | 精华制药集团南通有限公司 | Preparation process of chloroquine phosphate |
| CN111793026A (en) * | 2020-07-23 | 2020-10-20 | 珠海润都制药股份有限公司 | Hydroxychloroquine sulfate, crystal form of enantiomer thereof and preparation method of crystal form |
| CN113185459A (en) * | 2021-04-23 | 2021-07-30 | 江西国药有限责任公司 | Hydroxychloroquine sulfate and preparation method thereof |
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Application publication date: 20181102 |