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New maropitant crystal form and preparation method thereof

A maropy, amorphous technology, applied in organic chemical methods, separation/purification of carboxylic acid compounds, digestive system, etc. Problems such as poor water solubility and physicochemical stability, poor solubility of the free base crystal form of maropitant, etc., to achieve the effects of stable properties, good water solubility, and improved effectiveness

Pending Publication Date: 2021-06-18
凯默斯医药科技上海有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the crystal form has poor water solubility and physical and chemical stability
Patent CN106977512A discloses a preparation method of maropitan free base, but the solubility of the maropitan free base crystal form is not good
In addition, there are very few reports on other crystal forms of maropitan in the prior art
[0005] As we all know, for drugs, different salt forms or different crystal forms may have different colors, melting points, stability, apparent solubility, dissolution rate, etc. These properties will directly affect the stability, solubility, and Hygroscopicity, bioavailability, etc., and thus lead to differences in drug quality and clinical efficacy

Method used

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  • New maropitant crystal form and preparation method thereof
  • New maropitant crystal form and preparation method thereof
  • New maropitant crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The preparation of embodiment 1 amorphous maropitan citric acid

[0030] Dissolve 500.0 g of Maropitan free base (HPLC content 98.0%) and 224.0 g of citric acid monohydrate in 3.5 L of acetone, heat up to reflux to dissolve, heat filter, and add 3.5 L of methyl tert-butyl ether dropwise to the filtrate , stood at room temperature for crystallization overnight, filtered, and the filter cake was washed with methyl tert-butyl ether to obtain 688.0 g of crude product of maropitan citric acid monohydrate, with a yield of 95.0%.

[0031] Add 688.0g of crude Maropitan citric acid monohydrate to 2.8L of acetone and heat up to 50°C to dissolve, filter, and concentrate the filtrate to dryness at 40°C under reduced pressure, and dry the obtained sample under reduced pressure at 70°C for 72 hours to obtain 685.7g of white powder Amorphous maropitan citric acid, yield 100%, HPLC content 100.10%, HPLC purity 99.91%.

[0032] Karl Fischer moisture detection method:

[0033] Accurate...

Embodiment 2

[0037] The preparation of embodiment 2 amorphous maropitan citric acid

[0038] Dissolve 500.0 g of Maropitan free base (HPLC content 98.0%) and 250.0 g of citric acid monohydrate in 2.5 L of acetone, heat up to reflux for 1 hour, heat filter, and add methyl tert-butyl ether dropwise to the filtrate 5.0 L, stand at room temperature for crystallization overnight, filter, and wash the filter cake with methyl tert-butyl ether to obtain 673.5 g of crude product of maropitan citric acid monohydrate, with a yield of 93.0%.

[0039] Add 673.5g of crude Maropitan citric acid monohydrate to 4.0L of acetone and heat up to 40°C to dissolve, filter, and concentrate the filtrate to dryness at 50°C under reduced pressure, and dry the obtained sample under reduced pressure at 75°C for 65 hours to obtain 671.2g of white powder Amorphous Maropitan citric acid, yield 100%, HPLC content 99.95%, HPLC purity 99.92%.

[0040] Karl Fischer moisture detection method:

[0041] Accurately weigh 0.2g ...

Embodiment 3

[0045] The preparation of embodiment 3 amorphous maropitan citric acid

[0046] Dissolve 500.0 g of Maropitan free base (HPLC content 98.0%) and 225.0 g of citric acid monohydrate in 5 L of acetone, heat up to reflux for 1 hour, heat filter, and add 5 L of methyl tert-butyl ether dropwise to the filtrate , stood at room temperature for crystallization overnight, filtered, and the filter cake was washed with methyl tert-butyl ether to obtain 681.0 g of crude product of maropitan citric acid monohydrate, with a yield of 94.0%.

[0047] Add 681.0 g of crude Maropitan citric acid monohydrate to 8.3 L of acetone and raise the temperature to 25°C to dissolve, filter, and concentrate the filtrate to dryness at 35°C under reduced pressure, and dry the obtained sample under reduced pressure at 60°C for 80 hours to obtain 678.7 g of white powder Amorphous Maropitan citric acid, yield 100%, HPLC content 99.92%, HPLC purity 99.85%.

[0048] Karl Fischer moisture detection method:

[004...

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Abstract

The invention relates to a novel maropitant crystal form and a preparation method thereof. The invention provides an amorphous maropitant citric acid compound, and a preparation method, a pharmaceutical composition and application thereof. The amorphous maropitant citric acid compound provided by the invention is stable in property, good in water solubility and high in bioavailability, and an effective solution is provided for improving the safety and effectiveness of medicines. Meanwhile, the preparation method of the amorphous maropitant citric acid compound disclosed by the invention is simple in process, high in yield, high in purity and suitable for industrial mass production.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method and application of a new crystal form of maropitan. Background technique [0002] The chemical name of maropitan is (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl alcohol)quinuclidin-3-amine, which belongs to the alternative quinine One of the drugs is a receptor antagonist of type 1 neurokinin (NK1), which can act on the central nervous system by inhibiting substance P (the key neurotransmitter that causes vomiting), so maropitan can inhibit peripheral Sexual and central vomiting. Maropitan has also been developed as citrate monohydrate, the trade name is Cerenia (antiemetic), originally developed by Pfizer, the drug was approved by the FDA in 2007 for the prevention and treatment of acute vomiting in dogs, and was subsequently approved Prescription medication for cats. The chemical structural formula of maropitan citrate monohydrate al...

Claims

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Application Information

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IPC IPC(8): C07D453/02C07C59/265C07C51/43A61P1/08A61K31/49
CPCA61P1/08C07B2200/07C07B2200/13C07C59/265C07D453/02
Inventor 宿磊李峰陈真贵傅霖陈刚
Owner 凯默斯医药科技上海有限公司
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