Crystals of hydroxychloroquine sulfate

A technology of hydroxychloroquine sulfate and crystals, which is applied in the field of crystals of hydroxychloroquine sulfate, and can solve problems such as visual impairment and retinal damage in patients

Pending Publication Date: 2021-10-22
GENELABS TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Long-term administration of high doses may damage the retina and result in impaired vision in some patients due to drug accumulation in ocular tissues

Method used

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  • Crystals of hydroxychloroquine sulfate
  • Crystals of hydroxychloroquine sulfate
  • Crystals of hydroxychloroquine sulfate

Examples

Experimental program
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Effect test

example 1

[0041] Example 1: Preparation and Characterization of Type A Crystals of (S)-(+)-Hydroxychloroquine Sulfate

[0042] Form A crystals of (S)-(+)-hydroxychloroquine sulfate were prepared according to the method described below.

[0043] Preparation of (+)-hydroxychloroquine solution in salt-free form

[0044]Dissolve 5 g of (±)-hydroxychloroquine sulfate in 11 mL of water at room temperature. Then, 25 mL of ethyl acetate and 14 mL of aqueous sodium hydroxide solution (2M) were added to the resulting solution, and the reaction solution was stirred at room temperature for 1 hr. The organic phase was separated from the aqueous phase, dried over sodium sulfate and concentrated to an oil. This oil was dissolved in 5 mL of acetonitrile. 45 mL of water was added dropwise to the solution at room temperature. The resulting solution was stirred overnight at room temperature and a white precipitate formed. The precipitate was isolated by centrifugation and dried under vacuum at room t...

example 2

[0087] Example 2: Preparation and Characterization of Type B Crystals of (S)-(+)-Hydroxychloroquine Sulfate

[0088] To prepare type B crystals of (S)-(+)-hydroxychloroquine sulfate, type A crystals (1.5 g) of (S)-(+)-hydroxychloroquine sulfate were dissolved in ethanol (5 mL), and then dissolved at 50 Stirred at °C for 4 hours to precipitate and obtain (S)-(+)-hydroxychloroquine sulfate type B crystals (1.5 g), ee 99%.

[0089] Form B crystals were analyzed by PXRD. Such as image 3 As shown, it is 8.1±0.1°, 8.8±0.1°, 12.8±0.1°, 14.5±0.1°, 16.7±0.1°, 17.6±0.1°, 19.0±0.1°, 20.2±0.1°, The diffraction peaks at 21.4±0.1°, 21.7±0.1°, 22.3±0.1°, 23.8±0.1°, 25.7±0.1°, 26.0±0.1°, 26.7±0.1°, 28.2±0.1° and 29.3±0.1° are feature.

[0090]Crystals were also analyzed by DSC. Such as Figure 4 As shown, it has an endothermic peak at 245.2±0.1°C in the differential scanning calorimetry curve.

example 3

[0091] Example 3: Hygroscopicity of (S)-(+)-type A crystal, B-type crystal and amorphous form of hydroxychloroquine sulfate

[0092] Use the VTI-SA vapor adsorption analyzer of TAInstruments (New Castle, DE, USA) to carry out dynamic vapor adsorption analysis on (S)-(+)-hydroxychloroquine sulfate A-type crystal, B-type crystal and amorphous form, to compare its hygroscopicity. Each was exposed to a series of steps in relative humidity (RH) change at 25°C, i.e., each step increased 5% RH from 0 to 95% RH, and each subsequent step decreased 5% RH from 95% to 5% RH. Then record the moisture content of the humidity increase step and the humidity decrease step, respectively generate as Figure 7 , Figure 8 and Figure 9 The adsorption and desorption curves are shown.

[0093] Referring to the adsorption curves in the figure, (i) Type A crystals do not adsorb water at RHs up to 85%, and Type B crystals only adsorb water at RHs higher than 60%, compared to amorphous forms at RH...

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Abstract

Two crystals of (S)-(+)-hydroxychloroquine sulfate. One crystal features diffraction peaks at 12.3 + / - 0.1 degrees, 13.1 + / - 0.1 degrees, 17.9 + / - 0.1 degrees, 22.8 + 0.1 degrees, 23.4 + 0.1 degrees, 25.1 + / - 0.1 degrees, and 26.3 + / - 0.1 degrees as 2theta angles in a powder X-ray diffraction pattern. The other crystal features diffraction peaks at 12.8 + / - 0.1 degrees, 14.5 + / - 0.1 degrees, 16.7 + 0.1 degrees, 17.6 + 0.1 degrees, 20.2 + / - 0.1 degrees, 21.4 + / - 0.1 degrees, 23.8 + / - 0.1 degrees, 25.7 + / - 0.1 degrees, and 26.0 + / - 0.1 degrees as 2theta angles in a powder X-ray diffraction pattern. Also disclosed are methods of preparing crystals of (S)-(+)-hydroxychloroquine sulfate.

Description

technical field [0001] The present invention relates to crystals of hydroxychloroquine sulfate. Background technique [0002] (±)-Hydroxychloroquine sulfate is one of the essential drugs in the World Health Organization's standard list, used for the treatment of discoid lupus erythematosus and systemic lupus erythematosus, chronic polymorphic light eruption, chronic rheumatoid arthritis and malaria caused by falciparum Malaria caused by Plasmodium falciparum and Plasmodium vivax. [0003] The drug has two optical isomers, namely (R)-(-)-isomer and (S)-(+)-isomer. It is administered to patients as a racemic (50:50) mixture of these two isomers. Long-term administration of high doses may damage the retina and result in impaired vision in some patients due to accumulation of the drug in ocular tissues. [0004] An animal study using a rat pleuritic macrophage model showed that the (S)-(+)-isomer was not only 70% more potent than the (R)-(-)-isomer, but also had The accumula...

Claims

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Application Information

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IPC IPC(8): C07D215/46
CPCC07D215/46C07B2200/13Y02A50/30C07D215/42A61K31/4706
Inventor 陈正姚迺东
Owner GENELABS TECH INC
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