Novel solvate and crystalline forms of lercanidipine hydrochloride
AssigneeRecordati Ireland Limited
InventorsAmedeo Leonardi, Gianluca De Iasi, Fausto Bonifacio
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Abstract
The invention describes new solvates of lercanidipine hydrochloride with organic solvents, new lercanidipine hydrochloride crystalline Forms (III) and (IV) obtained from said solvates, pharmaceutical and antihypertensive compositions containing as active agent at least one of the lercanidipine hydrochloride crystalline Forms (III) and (IV) and methods of use thereof.
Claims88
A solvate of lercanidipine hydrochloride comprising lercanidipine hydrochloride and an organic solvent, wherein the solvent is selected from the group consisting of methylene chloride, acetone, anisole, tetrahydrofuran, terbutyl methyl ether, isopropanol, 2-butanol, heptane, methyl ethyl ketone, and ethyl acetate.
Isolated lercanidipine hydrochloride crystalline form (III), having an X-ray diffraction image, at wavelength Kα, expressed by the following Table:
- 42 d (Å) Relative intensity (%) Angle (° 2 θ) 11.5 39 7.7 9.1 38 9.7 9.0 37 9.8 8.0 50 11.0 6.6 48 13.5 5.58 57 15.9 5.49 34 16.1 5.13 43 17.3 4.09 63 21.7 3.92 43 22.7 3.72 100 23.9 3.60 85 24.7 3.47 31 25.6
Isolated lercanidipine hydrochloride crystalline form (IV), having an X-ray diffraction image, at wavelength Kα, expressed by the following Table:
- 43 d (Å) Relative intensity (%) Angle (° 2 θ) 7.9 71 11.2 6.9 53 12.7 5.21 57 17.0 5.13 46 17.3 4.73 66 18.8 4.69 95 18.9 4.53 53 19.6 4.40 81 20.2 4.34 43 20.4 3.99 44 22.2 3.89 52 22.8 3.77 100 23.6 3.69 35 24.1
An antihypertensive pharmaceutical composition comprising (1) a first lercanipidine form selected from the group consisting of lercanidipine hydrochloride crystalline Form (III), lercanidipine hydrochloride crystalline Form (IV) and combinations thereof, each crystalline form having a predetermined content;
- and (2) at least one component selected from the group consisting of a pharmaceutically acceptable carrier or diluent, a flavorant, a sweetener, a preservative, a dye, a binder, a suspending agent, a dispersing agent, a colorant, a disintegrant, an excipient, a lubricant, a plasticizer, and an edible oil.
A method of making a lercanidipine hydrochloride solvate comprising:
- (i) mixing lercanidipine crystalline Form (I), lercanidipine crystalline Form (III), crude lercanidipine form (A), crude lercanidipine form (B), crude lercanidipine form (C) or a lercanidipine hydrochloride-methylene chloride solvate with an organic solvent to form a solvate of lercanidipine hydrochoride and said organic solvent;
- and
- (ii) isolating the solvate formed in step (i),
- with the proviso that step (i) does not consist of mixing a lercanidipine hydrochloride-methylene chloride solvate with the organic solvent methylene chloride.
A method for preparing lercanidipine hydrochloride crystalline Form (III), comprising the removal of solvent from a lercanidipine hydrochloride solvate by evaporation under vacuum or in a nitrogen stream to form said crystalline Form (III).
A method for preparing lercanidipine hydrochloride crystalline Form (IV), comprising removal of acetone from a lercanidipine hydrochloride-acetone solvate by evaporation under vacuum or in a nitrogen stream.
A method for preparing a solvate lercanidipine hydrochloride-methyl ethyl ketone, comprising the steps of:
- (i) mixing lercanidipine hydrochloride crystalline Form (I) with methyl ethyl ketone to obtain a solution;
- (ii) optionally cooling the solution and continue stirring to produce the solvate lercanidipine hydrochloride-methyl ethyl ketone, and
- (iii) isolating the solvate of step (ii).
A method of treating a subject with arterial hypertension, the method comprising administering a therapeutically effective amount of lercanidipine hydrochloride crystalline Form (III), lercanidipine hydrochloride crystalline form (IV), or combinations thereof to a subject in need of such treatment.
A method of treating or preventing atherosclerotic lesions in arteries in a subject, which comprises administering a herapeutically effective amount of lercanidipine hydrochloride crystalline Form (III), lercanidipine hydrochloride crystalline Form (IV), or combinations thereof having a predetermined content in each of said Form (III) and (IV) to a subject in need of such treatment.
A method of treating or preventing heart failure in a subject, which comprises administering a therapeutically effective amount of lercanidipine hydrochloride crystalline Form (III), lercanidipine hydrochloride crystalline Form (IV), or combinations thereof having a predetermined content in each of said Form (III) and (IV) to a subject in need of such treatment.
An antihypertensive composition comprising predetermined amounts of lercanidipine hydrochloride crystalline Form (III) and lercanidipine hydrochloride crystalline Form (IV).
Dependencies are inferred from the claim text.