Novel hydroxychloroquine eutectic crystal, and preparation method, content determination method and application thereof

Abstract

The invention provides a novel hydroxychloroquine eutectic as well as a preparation method, a content determination method and application thereof. The novel hydroxychloroquine eutectic comprises a eutectic formed by hydroxychloroquine and 4-dimethylaminopyridine in a molar ratio of 2: 1. Compared with hydroxychloroquine, the novel hydroxychloroquine eutectic has higher dissolution rate and lower hygroscopicity compared with forms such as sulfate, phosphate and the like of hydroxychloroquine, the novel hydroxychloroquine eutectic can be prepared by various simple methods, and the novel hydroxychloroquine eutectic pharmaceutical composition has better dissolution rate, lower hygroscopicity and tabletting property, and can be used for preparing the pharmaceutical composition for preparing the hydroxychloroquine eutectic. And a novel hydroxychloroquine eutectic improved preparation with better curative effect and smaller side effect can be developed. The content determination method disclosed by the invention can be used for simultaneously and quantitatively determining the hydroxychloroquine and the 4-dimethylaminopyridine, and has the advantages of simplicity, rapidness, accuracy, reliability and good linear relationship in a high-concentration range.

Description

technical field

[0001] The invention belongs to the technical field of drug co-crystals, and in particular relates to a new co-crystal of hydroxychloroquine, a preparation method, a content determination method and an application thereof. Background technique

[0002] Hydroxychloroquine (Hydroxychloroquine) (HCQ) chemical name 2-[[4-[(7-chloro-4-quinolyl)-amino]pentyl]ethylamino]-ethanol has a chiral carbon center with ( -)-(R)-Hydroxychloroquine and (+)-(S)-Hydroxychloroquine are two optical isomers, which belong to 4-aminoquinoline drugs. The isomers are mixed in equal proportions, that is, racemic compound administration, the structural formula of (+)-(S)-hydroxychloroquine is shown in formula I, and the structural formula of (-)-(R)-hydroxychloroquine is shown in formula II :

[0003]

[0004] Hydroxychloroquine was first used in the treatment of malaria parasites, and the phosphate and sulfate salts of hydroxychloroquine are now widely used in the clinical treatmen...

Examples

Embodiment 1

[0097] This embodiment has prepared a kind of new eutectic of hydroxychloroquine, and specific process is:

[0098]Dissolve 134.1mg of hydroxychloroquine (HCQ) and 220.8mg of 4-dimethylaminopyridine (DIM) in 2.0mL of acetonitrile at 25.1°C±0.1°C, stir to form a suspension, beat for 24h, let stand for 12h, and filter The solid was vacuum dried overnight at room temperature to obtain the new co-crystal of hydroxychloroquine. The X-ray powder diffraction pattern of the product shows that there are characteristic peaks at 6.80°, 11.45°, and 16.88° at the diffraction angle 2θ, and it does not have the characteristic peak of 8.12° hydroxychloroquine, nor does it have the characteristic of 4-dimethylaminopyridine at 12.09° peak, with attached figure 1 Consistent, confirm that the obtained product is a new co-crystal of hydroxychloroquine.

Embodiment 2

[0100] This embodiment has prepared a kind of new eutectic of hydroxychloroquine, and specific process is:

[0101] Dissolve 149.8mg of hydroxychloroquine and 267.8mg of 4-dimethylaminopyridine in 2.0mL of acetonitrile at 25.1°C±0.1°C, stir and form a suspension, beating for 24h, then standing for 12h, filtering, and vacuum-drying the solid at room temperature overnight to obtain The new co-crystal of hydroxychloroquine. The X-ray powder diffraction pattern of the product shows that there are characteristic peaks at 6.96°, 11.53°, and 17.07° at the diffraction angle 2θ, and it does not have the characteristic peak of 8.12° hydroxychloroquine, nor does it have the characteristic of 4-dimethylaminopyridine at 12.09° peak, with attached figure 1 Similarly, it was confirmed that the obtained product was a new cocrystal of hydroxychloroquine.

Embodiment 3

[0103] This embodiment has prepared a kind of new eutectic of hydroxychloroquine, and specific process is:

[0104] Dissolve 180.6 mg of hydroxychloroquine and 172.5 mg of 4-dimethylaminopyridine in 1.2 mL of acetonitrile at 34.2 °C ± 0.1 °C, stir to form a suspension, beat for 24 hours, and then let stand for 12 hours. After filtration, the solid is vacuum-dried at room temperature overnight to obtain The new co-crystal of hydroxychloroquine. The X-ray powder diffraction pattern of product shows that there are characteristic peaks at 6.80 °, 11.44 °, 17.02 ° ° with diffraction angle 2θ, and attached figure 1 Similarly, neither the characteristic peak of 8.12° hydroxychloroquine nor the characteristic peak of 4-dimethylaminopyridine 12.09° confirms that the resulting product is a new cocrystal of hydroxychloroquine.

technical field

[0001] The invention belongs to the technical field of drug co-crystals, and in particular relates to a new co-crystal of hydroxychloroquine, a preparation method, a content determination method and an application thereof. Background technique

[0002] Hydroxychloroquine (Hydroxychloroquine) (HCQ) chemical name 2-[[4-[(7-chloro-4-quinolyl)-amino]pentyl]ethylamino]-ethanol has a chiral carbon center with ( -)-(R)-Hydroxychloroquine and (+)-(S)-Hydroxychloroquine are two optical isomers, which belong to 4-aminoquinoline drugs. The isomers are mixed in equal proportions, that is, racemic compound administration, the structural formula of (+)-(S)-hydroxychloroquine is shown in formula I, and the structural formula of (-)-(R)-hydroxychloroquine is shown in formula II :

[0003]

[0004] Hydroxychloroquine was first used in the treatment of malaria parasites, and the phosphate and sulfate salts of hydroxychloroquine are now widely used in the clinical treatmen...

Examples

Embodiment 1

[0097] This embodiment has prepared a kind of new eutectic of hydroxychloroquine, and specific process is:

[0098]Dissolve 134.1mg of hydroxychloroquine (HCQ) and 220.8mg of 4-dimethylaminopyridine (DIM) in 2.0mL of acetonitrile at 25.1°C±0.1°C, stir to form a suspension, beat for 24h, let stand for 12h, and filter The solid was vacuum dried overnight at room temperature to obtain the new co-crystal of hydroxychloroquine. The X-ray powder diffraction pattern of the product shows that there are characteristic peaks at 6.80°, 11.45°, and 16.88° at the diffraction angle 2θ, and it does not have the characteristic peak of 8.12° hydroxychloroquine, nor does it have the characteristic of 4-dimethylaminopyridine at 12.09° peak, with attached figure 1 Consistent, confirm that the obtained product is a new co-crystal of hydroxychloroquine.

Embodiment 2

[0100] This embodiment has prepared a kind of new eutectic of hydroxychloroquine, and specific process is:

[0101] Dissolve 149.8mg of hydroxychloroquine and 267.8mg of 4-dimethylaminopyridine in 2.0mL of acetonitrile at 25.1°C±0.1°C, stir and form a suspension, beating for 24h, then standing for 12h, filtering, and vacuum-drying the solid at room temperature overnight to obtain The new co-crystal of hydroxychloroquine. The X-ray powder diffraction pattern of the product shows that there are characteristic peaks at 6.96°, 11.53°, and 17.07° at the diffraction angle 2θ, and it does not have the characteristic peak of 8.12° hydroxychloroquine, nor does it have the characteristic of 4-dimethylaminopyridine at 12.09° peak, with attached figure 1 Similarly, it was confirmed that the obtained product was a new cocrystal of hydroxychloroquine.

Embodiment 3

[0103] This embodiment has prepared a kind of new eutectic of hydroxychloroquine, and specific process is:

[0104] Dissolve 180.6 mg of hydroxychloroquine and 172.5 mg of 4-dimethylaminopyridine in 1.2 mL of acetonitrile at 34.2 °C ± 0.1 °C, stir to form a suspension, beat for 24 hours, and then let stand for 12 hours. After filtration, the solid is vacuum-dried at room temperature overnight to obtain The new co-crystal of hydroxychloroquine. The X-ray powder diffraction pattern of product shows that there are characteristic peaks at 6.80 °, 11.44 °, 17.02 ° ° with diffraction angle 2θ, and attached figure 1 Similarly, neither the characteristic peak of 8.12° hydroxychloroquine nor the characteristic peak of 4-dimethylaminopyridine 12.09° confirms that the resulting product is a new cocrystal of hydroxychloroquine.

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