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Methanesulfonic acid cinepazide crystal form III and preparation method thereof

A technology for cinepazide and cinepazide dihydrate, which is applied in the field of crystal forms of cinepazide mesylate and its preparation, and can solve the problems of increased cis isomer content, unstable chemical properties and the like , to achieve the effect of reducing cis isomers and improving safety

Active Publication Date: 2012-02-15
BEIJING SIHUAN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Its solubility in water is larger than that of cinepazide maleate, and its stability is also better than that of cinepazide maleate. 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 III and preparation method thereof
  • Methanesulfonic acid cinepazide crystal form III and preparation method thereof
  • Methanesulfonic acid cinepazide crystal form III and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1 cinepazide mesylate raw material

[0043] 1.1 Preparation of raw materials

[0044] According to the preparation method of the patent application "New medicinal salt of cinepazide and its preparation method" (application number: 200710096248.2), a self-colored crystalline powder is precipitated by cooling.

[0045] 1.2 XRD-powder diffraction pattern

[0046] See figure 1 , showing that the raw material prepared by the above-mentioned patent is an amorphous crystal powder.

[0047] 1.3 Solubility experiment

[0048] 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 inclu...

Embodiment 2

[0049] Example 2 Cinepazide mesylate crystal form I

[0050] 2.1 Preparation method

[0051] 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.

[0052] 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.

[0053] 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

[0064] Example 3 Cinepazide mesylate crystal form II

[0065] 3.1 Preparation method

[0066] 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.

[0067] 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.

[0068] 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 III and a preparation method thereof, and belongs to the field of chemical pharmaceutics. The water solubility of the prepared methanesulfonic acid cinepazide crystal form III is higher than that of an amorphous material, and the methanesulfonic acid cinepazide crystal form III is particularly suitable for injection, has higher chemical stability than the amorphous material, facilitates production of medicines, and storage and transportation of raw material medicines, improves the safety of the medicines and provides safe guarantee for clinical application of the medicines.

Description

[0001] This application is a divisional application of the invention patent application with the invention name "cinepazide mesylate crystal form and its preparation method" and application number 2008102278637. technical field [0002] 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 [0003] 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 periphera...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/185C07C309/04C07C303/44A61K31/496A61P9/00
Inventor 车冯升
Owner BEIJING SIHUAN PHARMA
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