Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation

A technology of lercanidipine hydrochloride and lercadipine hydrochloride, applied in solution crystallization, medical preparations containing active ingredients, drug combinations, etc.

Inactive Publication Date: 2009-01-07
RECORDATI IRELAND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This raises the question of whether guarantees of purity and / or reproducibility (e.g. regulatory agencies) are sufficient to make the product always the same

Method used

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  • Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation
  • Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation
  • Novel crystalline polymorphic forms of lercanidipine hydrochloride and process for their preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0157]The following examples for the preparation of lercanidipine hydrochloride crude forms (A) and (B) and crystalline forms (I) and (II), as well as DSC analysis and solubility, stability and hygroscopicity tests are now disclosed for illustrative rather than limiting purposes. Results; Bioavailability tests of the new crystalline form also disclosed.

[0158] Embodiment 1 initial preparation

[0159] Thionyl chloride (36 g) diluted in ethyl acetate (25 g) was slowly added to 2,6-dimethyl-5-methoxycarbonyl-4-( 3-Nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (90 g in a solution of dimethylformamide (115 g) and ethyl acetate (396 g)). A solution of 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol (84 g) in ethyl acetate (72 g) was slowly added to the resulting mixture middle. The whole mixture was kept stirring at the same temperature for 3 hours. The mixture was then heated to 20-25°C and kept under stirring for 12 hours. After this time water (340ml) was adde...

Embodiment 2

[0160] Embodiment 2 thick lercanidipine hydrochloride shape (A)

Embodiment 1

[0161] The organic phase obtained in Example 1 was then azeotropically distilled under a vacuum of about 250 mmHg at a temperature not exceeding 60°C. After removing about 50 ml of water, the solution was concentrated under the same temperature and pressure conditions to about 1 / 3 of the original volume and then neoethyl acetate was added to the original volume until the K.F. value (Karl Fisher value) was about 0.10-0.15% . The final suspension was cooled to 0-5°C. The solid was filtered, suspended in ethyl acetate (350 g), and stirred at 60-65°C for 1 hour. The bulk was cooled to 5-10°C and then filtered. The solid was dried in a 70°C oven. 133 g of dry crude lercanidipine hydrochloride (A) was obtained (75% yield), with a DSC peak of 150-152°C.

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Abstract

The present invention describes new lercanidipine hydrochloride crude forms (A) and (B), new lercanidipine hydrochloride crystal forms (I) and (II) obtained from said crude forms, containing at least one lercanidipine hydrochloride crystal form ( I) and (II) antihypertensive pharmaceutical compositions as active agents and methods of use thereof.

Description

field of invention [0001] The present invention relates to new crude and crystalline forms of lercanidipine hydrochloride, and processes for the preparation of these forms. Pharmaceutical compositions containing said new crystalline form are also related. Background of the invention [0002] Lercanidipine (1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)pyridine-3,5-dicarboxylate) is a highly lipophilic dihydropyridine calcium antagonist with long duration of action and high vascular selectivity. The mechanism of its antihypertensive activity is attributed to a direct relaxing effect on vascular smooth muscle, thereby reducing the total peripheral resistance. The recommended starting dose of lercanidipine as monotherapy is 10 mg per day by the oral route and, if necessary, a drug titration of 20 mg per day. Lercanidipine is rapidly absorbed after oral administration and Peak plasma levels occur after 2-3 hours. Elimination is...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90A61K31/44A61P9/12A61K31/4422B01D9/02
CPCC07D211/90A61P9/00A61P9/12
Inventor F·博尼法斯欧F·卡姆帕纳G·德艾斯A·莱昂纳迪
Owner RECORDATI IRELAND LTD
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