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Methanesulfonic acid cinepazide crystal form and preparation method

A technology of cinepazide and methanesulfonic acid, applied in the field of medicine, can solve the problems of unstable chemical properties, increased content of cis isomers, etc., and achieve the effects of improving safety and reducing cis isomers

Active Publication Date: 2012-04-25
BEIJING SIHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Its solubility in water is greater than that of cinepazide maleate, and its stability is also better than that of cinepazide maleate. It is especially suitable for making injections and meets the dosage form of cinepazide. The impact on the drug safety of the mesylate salt has been reduced, but the problem of drug safety still exists. The raw material cinepazide mesylate is an amorphous powder with unstable chemical properties. Its structure has a cis-trans isomerism Double bond, during long-term storage, the content of its cis-isomer will increase significantly, and this cis-isomer has greater toxicity, which brings certain risks to clinical application

Method used

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  • Methanesulfonic acid cinepazide crystal form and preparation method
  • Methanesulfonic acid cinepazide crystal form and preparation method
  • Methanesulfonic acid cinepazide crystal form and preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1 cinepazide mesylate raw material

[0042] 1.1 Preparation of raw materials

[0043] According to the preparation method of the patent application "New medicinal salt of cinepazide and its preparation method" (application number: 200710096248.2), the white crystalline powder is precipitated by cooling.

[0044] 1.2 XRD-powder diffraction pattern

[0045] See figure 1 , showing that the raw material prepared by the above-mentioned patent is an amorphous crystal powder.

[0046] 1.3 Solubility experiment

[0047] Solvents capable of dissolving cinepazide mesylate include: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, DMF, water, ethylene glycol monomethyl ether, dichloro Methane, chloroform, acetonitrile, nitromethane, DMSO. Among them, water, methanol, nitromethane, ethylene glycol monomethyl ether, and DMSO have excellent solubility, while others are average. Solvents that cannot dissolve cinepazide mesylate include: t...

Embodiment 2

[0048] Example 2 Cinepazide mesylate crystal form I

[0049] 2.1 Preparation method

[0050] Cinepazide mesylate in dichloromethane, chloroform, nitromethane, DMF, methanol / ether, dichloromethane / ether, methanol / methyl tert-butyl ether, DMF / ether, ethylene glycol monomethyl The crystals in ether / diethyl ether and ethylene glycol monomethyl ether / acetonitrile are all crystal forms I.

[0051] Method 1 (taking dichloromethane as an example): Add 0.5g of cinepazide mesylate to 25mL of dichloromethane under light-proof conditions, heat slightly to dissolve, stir for 1 hour, filter, and keep standing for three A few days later, the solvent was evaporated to dryness, and the solid was crushed, left to dry at room temperature for 6 hours, and samples were collected to obtain cinepazide mesylate crystal form I.

[0052] Method 2 (taking DMF / diethyl ether as an example): Add 0.7g of cinepazide mesylate to 20mL of DMF under dark conditions, dissolve, stir for 30min, add the solution d...

Embodiment 3

[0063] Example 3 Cinepazide mesylate crystal form II

[0064] 3.1 Preparation method

[0065] Cinepazide mesylate in methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, acetonitrile, nitromethane / acetonitrile, DMSO / carbon tetrachloride / diethyl ether Crystallized as Form II.

[0066] Method 1 (taking methanol as an example): Add 2g of cinepazide mesylate to 5mL of methanol under light-shielding conditions, heat slightly to help dissolve, stir for 0.5h, filter, and keep it standing for about 23 days. Volatilized to dry up, collected samples, and obtained cinepazide mesylate crystal form II.

[0067] Method 2 (taking DMSO / carbon tetrachloride / diethyl ether as an example): Add 1 g of cinepazide mesylate to 15 mL of DMSO under dark conditions, dissolve, stir for 30 minutes, and add the solution dropwise to 150 mL of carbon tetrachloride In a mixed solvent with 100 mL of diethyl ether, white solid crystals were precipitated, filtered by suction, dried ...

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Abstract

The invention relates to a 'methanesulfonic acid cinepazide crystal form and preparation method', which belongs to chemical and pharmaceutical field. In the invention, the methanesulfonic acid cinepazide crystal form I, II, III are prepared, the solubility of the three crystal forms in water is larger than that of amorphous materials, and the crystal form is particularly suitable for the injection; compared with the amorphous materials, the chemical stability of the crystal form is better, and the crystal form is beneficial for the storage and the transportation of the pharmaceutical production and bulk drug, meanwhile, the drug safety is increased, especially for the crystal form II, the cis-isomer under the high temperature and high humidity is correspondingly reduced, meanwhile, the invention provides safety insurance for the drug clinical application.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a crystal form of cinepazide mesylate and a preparation method thereof. Background technique [0002] Cinepazide maleate is the maleate salt of cinepazide, and the dosage form listed in China is mainly injection. Cinepazide maleate has the dual effects of dilating cerebral blood vessels and promoting nutrient metabolism of nerve cells. It has been used in the treatment of cardiovascular and cerebrovascular diseases in China in the past two years. Cinepazide maleate is a calcium ion channel blocker, which relaxes vascular smooth muscle by preventing Ca2+ from transmembrane entering into smooth muscle cells, and dilates cerebrovascular, coronary and peripheral blood vessels, thereby relieving vasospasm, reducing vascular resistance, increasing Blood flow can enhance the effect of adenosine and cyclic adenosine monophosphate (cAMP), reduce oxygen consumption, inhibit c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/18A61K31/496A61P9/00A61P9/12
Inventor 车冯升
Owner BEIJING SIHUAN PHARMA