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Conivaptan-hydrochloride novel crystal form and preparation method thereof

A conivaptan hydrochloride and crystal form technology, applied in the field of medicinal chemistry, can solve the problems of environmental protection, poor economy, difficult recovery of solvents, and low crystal form purity, and achieve high solubility and bioavailability, low production cost, The effect of meeting the requirements of medicine

Active Publication Date: 2014-01-08
BEIJING COLLAB PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the crystallization and crystal form preparation methods adopted in Japanese patents JP2001002678 and JP2002087962 use mixed solvents, the operation is complicated, the solvent is not easy to recover, the crystal form has low purity, and the preparation process is environmentally friendly and economical.

Method used

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  • Conivaptan-hydrochloride novel crystal form and preparation method thereof
  • Conivaptan-hydrochloride novel crystal form and preparation method thereof
  • Conivaptan-hydrochloride novel crystal form and preparation method thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0036] Preferably, the method for preparing the new crystal form of cornivatan hydrochloride specifically includes

[0037] Step a) Dissolve the crude cornivatan hydrochloride in anhydrous methanol by heating to dissolve it, decolorize the activated carbon, filter, and evaporate the filtrate to dryness;

[0038] Step b) Add acetonitrile, reflux, cool, filter, and dry the filtrate.

[0039] Wherein, the ratio of the mass of the crude cornivatan hydrochloride to the volume of the anhydrous methanol in step a) is preferably 1 g: 10 mL to 15 mL, more preferably 1 g: 10 mL. That is, it is preferable to add 10 mL to 15 mL of anhydrous methanol per 1 g of crude cornivatan hydrochloride, more preferably to add 10 mL of anhydrous methanol.

[0040] The preparation method of the new crystal form of cornivatan hydrochloride according to the present invention Step a) The crude cornivatan hydrochloride is dissolved in anhydrous methanol and heated to dissolve the crude cornivatan hydrochloride. Th...

Embodiment 1

[0052] Example 1: Preparation of new crystal form of Cornivatan Hydrochloride

[0053] 1g of crude cornivatan hydrochloride is dissolved in 12mL of anhydrous methanol, heated to 35~40℃ in a water bath to dissolve it, add 0.06g activated carbon to enter, keep stirring and decolorize for 20min, filter, and the filtrate will be evaporated to dryness under vacuum at 35~40℃ with water pump; Add 25mL of acetonitrile, heat and reflux for 5 hours with rapid stirring, cool to about 15°C, and filter after stirring for 1 hour. The filter cake is dried to constant weight by oil pump at 60°C to obtain 0.694g of white solid powder with a yield of 69.4%. After HPLC analysis, the total amount of related substances in the obtained product was 0.065%, and the maximum single impurity was 0.046% (area normalization method).

[0054] Using the Japanese Rigaku D / max-2550 powder X-ray diffractometer, the test parameters are: copper target, tube flow 150mA, tube pressure 40kV, scanning speed 8° / min, step ...

Embodiment 2

[0057] Example 2: Preparation of new crystal form of Cornivatan Hydrochloride

[0058] 20g of the crude Cornivatan Hydrochloride is dissolved in 200mL of anhydrous methanol, heated to 35-40℃ in a water bath to dissolve it, add 1.0g activated carbon into it, keep stirring and decolorize for 30min, filter, the filtrate will be evaporated to dryness under vacuum at 35-40℃ with water pump; 400mL of acetonitrile was added, heated to reflux with rapid stirring for 5 hours, cooled to about 15°C, filtered for 1 hour, and the filter cake was dried to constant weight under a 60°C oil pump under reduced pressure to obtain 14.672g of white solid powder with a yield of 73.36%. After HPLC analysis, the total amount of related substances in the product obtained was 0.067%, and the maximum single impurity was 0.042% (area normalization method).

[0059] The product was analyzed with a Japanese Rigaku D / max-2550 powder X-ray diffractometer and a Swiss Mettler DSC1 thermal analyzer, and the results ...

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Abstract

The invention relates to the field of medicinal chemistry, and discloses a conivaptan-hydrochloride novel crystal form and a preparation method of the conivaptan-hydrochloride novel crystal form. The conivaptan-hydrochloride novel crystal form is single in crystal form, high in purity, good in stability, high in solubility and bioavailability, capable of restraining arginine vasopressin V1a and V2 receptors, and capable of being used for preparing medicine for treating hyponatremia. The preparation method of the conivaptan-hydrochloride novel crystal form is simple to operate, avoids complex and fussy crystallization processing conditions, enables solvents to be recycled, is low in production cost, and is suitable for industrial production. Products meet medicinal standards and good in stability.

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new crystal form of cornivatan hydrochloride and a preparation method thereof. Background technique [0002] Cornivatan hydrochloride is a non-peptide dual inhibitor of arginine vasopressin (AVP) V1a and V2 receptors. The FDA first approved Astellas Pharma US’s Cornivatan Hydrochloride on December 29, 2005, with the trade name Vaprisol, as a 20mg / 4mL injection. Its indications are mainly used for hyponatremia with normal blood volume (often Accompanied in the treatment of patients with abnormal secretion of antidiuretic hormone syndrome, hypothyroidism, hypoadrenal glands or lung diseases) and treatment of hospitalized patients with hypervolemic hyponatremia. In 2007, the FDA approved Cornivatan to increase the indication-hypervolemic hyponatremia. In 2008, it approved the addition of a new dosage form of -20mg / 100mL large infusion. [0003] The chemical name of Cornivatan Hydroch...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/55A61P3/12
CPCC07D487/04
Inventor 张宪美谈敦潮孟月垒孙志国赵大龙王珂
Owner BEIJING COLLAB PHARMA
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