Vonorazan new crystal salt and preparation method thereof

A crystal form and crystal technology, applied in the field of Vonorazan L-malate crystal form and its preparation, to achieve good stability, meet the needs of clinical medication, and good solubility

Active Publication Date: 2019-12-20
HANGZHOU ZHONGMEI HUADONG PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In summary, there is a lack of a crystal form of Vonorazan salt that can satisfy both good solubility and good stability in the prior art.

Method used

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  • Vonorazan new crystal salt and preparation method thereof
  • Vonorazan new crystal salt and preparation method thereof
  • Vonorazan new crystal salt and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Salt Type Screening

[0042] Feed in different molar ratios of free state and counter ions. With reference to the pKa value of the compound, a total of 11 counterions were selected for salt screening experiments. The results are shown in Table 1.

[0043] Table 1 Salt sieve test results

[0044]

[0045]

Embodiment 2

[0046] Example 2 Preparation of Vonorazan L-malate crystal form

[0047]Dissolve 96.88mg of Vonorazan free base (due to the 1.9% weight gain of the sample, the actual weight is 95.04mg, the feeding amount and yield are calculated according to the actual weight, the same below) was dissolved in 0.8mL of 1,4-dioxane at room temperature , 38.03mg L-malic acid was dissolved in 0.6mL 1,4-dioxane, and the 1,4-dioxane solution of L-malic acid was added dropwise to the free base 1,4-dioxane under stirring condition In the ring solution, a white solid was precipitated. After stirring overnight, the solid was centrifuged and dried under vacuum at 50° C. to obtain 104.77 mg of white Vonorazan L-malate crystals, with a yield of 79%.

Embodiment 3

[0048] Embodiment 3 Preparation of Vonorazan succinate crystal form

[0049] Dissolve 78mg of Vonorazan free base in 0.6mL of isopropanol at room temperature, dissolve 27.06mg of succinic acid in 0.6mL of isopropanol, add the solution of succinic acid in isopropanol dropwise to the free base in isopropanol under stirring In the alcohol solution, a white solid was precipitated. After stirring overnight, the solid was centrifuged and dried in vacuo at 50° C. to obtain 67.56 mg of a white solid, with a yield of 66%.

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Abstract

The invention relates to a vonoprazan organic acid or inorganic acid salt crystal form as well as preparation method, and particularly relates to an L-malate crystal form, a dihydric phosphate crystalform, a hydrochloride crystal form, a succinate crystal form, a semi-L-tartrate crystal form, a sulfate crystal form, a hydrosulfate crystal form and a mesylate crystal form. The problem that vonoprazan L-malate and the like easily absorbs moisture is solved, the vonoprazan organic acid or inorganic acid salt crystal form has good stability and is convenient to store and transport. The obtained vonoprazan L-malate crystal form and the dihydric phosphate crystal form are compared with a fumarate crystal form and an acetate crystal form, the solubility in the water is higher, and support is provided for research of new preparations.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical crystal forms, in particular to a vonoprazan organic acid or inorganic acid salt crystal form and a preparation method thereof, in particular to a vonoprazan L-malate crystal form and a preparation method thereof. Background technique [0002] Vonoprazan fumarate is a new class of inhibitors of potassium ion competitive acid blockers, which has a strong and long-lasting inhibitory effect on gastric acid secretion. At the same time, in the last step of gastric acid secretion by gastric parietal cells, it also has an early termination effect on gastric acid secretion by inhibiting the binding of potassium ions to hydrogen ions and proton pumps. However, the compound has poor water solubility, and its oral bioavailability in rats is only 10%, which limits the effect of the compound on suppressing acid and treating gastric acid-related diseases. [0003] At present, there have been many litera...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12C07C59/245C07C51/43
CPCC07B2200/13C07D401/12
Inventor 余睿刘启冉徐仲军周玉宝吴鸿辉
Owner HANGZHOU ZHONGMEI HUADONG PHARMA
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