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Novel crude and crystalline forms of lercanidipine hydrochloride

a technology of lercanidipine and lercanidipine, which is applied in the field of new crude forms and crystalline forms of lercanidipine hydrochloride, can solve the problems of difficult industrial scale complex purification and isolation steps of lercanidipine from reaction mixtures, and low yield of desired products

Inactive Publication Date: 2005-09-01
RECORDATI IRELAND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides novel crude and crystalline forms of lercanidipine hydrochloride and methods for making them. These forms have different melting points and can be isolated from each other. The invention also provides pharmaceutical compositions comprising the different forms of lercanidipine hydrochloride and a carrier or diluent. The invention also provides methods of treating arterial hypertension and atherosclerotic lesions in arteries using the different forms of lercanidipine hydrochloride."

Problems solved by technology

A major disadvantage of the process of preparing lercanidipine, as it is described in U.S. Pat. No. 4,705,797, is that the disclosed cyclization reaction generates several by-products, which results in a lower yield for the desired product.
Moreover, the purification and isolation of lercanidipine from the reaction mixture is quite complex, since it requires numerous treatments with different solvents.
Finally, the purification and isolation steps are difficult to perform on an industrial scale because of the necessity of purifying the product by column chromatography.
However, the isolation of lercanidipine hydrochloride in crystalline form is again quite complex.
This raised issues as to whether assurances of purity and / or reproducibility can be made (e.g., to regulatory authorities) that the product is always the same.

Method used

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  • Novel crude and crystalline forms of lercanidipine hydrochloride
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  • Novel crude and crystalline forms of lercanidipine hydrochloride

Examples

Experimental program
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Effect test

example 1

Initial Preparation

[0149] Thionyl chloride (36 g) diluted in ethyl acetate (25 g) was slowly added to a solution of 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (90 g) prepared, e.g., as disclosed in German patent DE 2847 237, in dimethylformamide (115 g) and ethyl acetate (396 g), keeping temperature between −1 and +1° C. 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 mixture thus obtained. The whole was kept under stirring at the same temperature for 3 hours. The mixture was then heated to 20-25° C. and kept under stirring for 12 hours. Water (340 ml) was then added, the whole was stirred for 30 min and after settling the aqueous phase was discarded. The organic phase was washed again with water (340 ml).

example 2

Crude Lercanidipine Hydrochloride Form (A)

[0150] The organic phase obtained from Example 1 was then subjected to azeotropic distillation under vacuum at about 250 mmHg, without going above a temperature of 60° C. After removing about 50 ml of water, the solution was concentrated to about ⅓ of the initial volume in the same conditions of temperature and pressure and then brought to its initial volume with fresh ethyl acetate 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 whole was cooled to 5-10° C. and then filtered. The solid was dried in an oven at 70° C. 133 g of dry raw lercanidipine hydrochloride Form (A) was obtained (75% yield), DSC peak 150-152° C.

example 3

Crude Lercanidipine Hydrochloride Form (B)

[0151] The organic phase obtained at the end of Example 1 was heated under reflux (70-75° C.) and the water contained in the solution was removed with a Dean Stark apparatus (Spaziani Rolando, Nettuno, Rome, Italy) until a K.F. value of about 2% was obtained. The whole was then distilled at atmospheric pressure to reach ¾ of initial volume. The solution was brought to its initial volume by adding fresh ethyl acetate. The K.F. value at the end of this operation was 0.9-1.1%. The final solution was cooled to 0-5° C. A solid slowly precipitates 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., thus obtaining 133 g of crude lercanidipine hydrochloride Form (B), DSC peak 131-135° C.; 75% yield.

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Abstract

The invention describes novel lercanidipine crude Forms (A) and (B), novel lercanidipine hydrochloride crystalline Forms (I) and (II) obtained from said crude Forms, pharmaceutical, antihypertensive compositions containing as active agent at least one of the lercanidipine hydrochloride crystalline Forms (I) and (II) and methods of use thereof

Description

RELATED APPLICATIONS [0001] The present application is a divisional application of and claims the benefit of priority under 35 U.S.C. § 121 of prior application Ser. No. 10 / 214,386, filed Aug. 6, 2002, and claims priority under 35 U.S.C. 119 (e) of U.S. provisional application 60 / 367,789, filed Mar. 26, 2002 and priority under 35 U.S.C. 119 (a)-(d) of Italian patent applications MI 2001A 001726 and MI 2001A 001727, both filed Aug. 6, 2001. Each of the aforementioned applications is hereby incorporated herein by reference in its entirety.FIELD OF THE INVENTION [0002] 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 are also contemplated. BACKGROUND OF THE INVENTION [0003] Lercanidipine (methyl 1,1,N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate) i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor BONIFACIO, FAUSTOCAMPANA, FRANCESCOIASI, GIANLUCA DELEONARDI, AMEDEO
Owner RECORDATI IRELAND LTD
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