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

A technology for lercanidipine hydrochloride and lerca hydrochloride, which is applied in the directions of solution crystallization, medical preparations containing active ingredients, and drug combinations.

Inactive Publication Date: 2004-10-20
RECORDATIE IRELAND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 2

[0158] Embodiment 2 thick lercanidipine hydrochloride shape (A)

Embodiment 1

[0159] 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.

Embodiment 3

[0160] Embodiment 3 thick lercanidipine hydrochloride shape (B)

[0161] The organic phase finally obtained in Example 1 was heated under reflux (70-75° C.) and the water contained in the solution was removed with a DeanStark apparatus (Spaziani Rolando, Nettuno, Rome, Italy) until a K.F. value of about 2% was obtained. Thereafter the whole is distilled at atmospheric pressure up to 3 / 4 of the initial volume. Neoethyl acetate was added to bring the solution up to its original volume. The K.F. value at the end of the treatment was 0.9-1.1%. The final solution was cooled to 0-5 °C. A solid slowly precipitated, which was filtered. The solid thus obtained was suspended in ethyl acetate (350 g) and stirred at 60-65°C for 1 hour. The whole was cooled to 5-10°C, then filtered and dried in an oven at 70°C to obtain 133 g of crude lercanidipine hydrochloride (B), with a DSC peak of 131-135°C; 75% yield.

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Abstract

The invention is directed to novel crude forms and crystalline forms of lercanidipine hydrochloride, and to processes for the preparation of these forms. Pharmaceutical compositions comprising the novel crystalline forms also are contemplated.

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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IPC IPC(8): A61K31/44A61K31/4422A61P9/12B01D9/02C07D211/90
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 RECORDATIE IRELAND LTD
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