Novel crude and crystalline forms of lercanidipine hydrochloride
AssigneeRecordati Ireland Limited
InventorsFausto Bonifacio, Francesco Campana, Gianluca Delasi, Amedeo Leonardi
Life of this patent
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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
Claims53
1-26. (Cancelled)
Isolated lercanidipine hydrochloride crystalline Form (II), which has an X-ray diffraction pattern, at wavelength Kα, as shown in FIG. 12.
29-36. (cancelled)
(original) a method of producing lercanidipine hydrochloride crystalline Form (II), which has an x-ray diffraction pattern, at wavelength Kα, as shown in FIG. 12, the method comprising the steps of:
- d″) adding acetonitrile to lercanidipine hydrochloride and heating the mixture thus obtained to form a solution;
- e″) cooling of the solution of step d″) and stirring until the concentration of lercanidipine hydrochloride dissolved in the crystallization solvent is ≦2%;
- and
- f″) recovering the solid of step e″) and drying said solid to produce the lercanidipine hydrochloride Form (II).
43-50. (Cancelled)
A method of producing lercanidipine hydrochloride crystalline Form (II), which has an X-ray diffraction pattern, at wavelength K, as shown in FIG. 12, which comprises:
- d″′) adding ethanol or isopropanol with a water content below 10% by weight to lercanidipine hydrochloride and refluxing to produce a solution;
- e″′) cooling the solution and stirring until the concentration of lercanidipine hydrochloride dissolved in the crystallization solvent is <2%;
- and
- f′″) recovering the solid produced in step e″′) to produce lercanidipine hydrochloride Form (II).
A method of producing the lercanidipine hydrochloride crystalline Form (II), which has an x-ray diffraction pattern, at wavelength Kα, as shown in FIG. 12, which comprises:
- d″″) dissolving crude lercanidipine hydrochloride or lercanidipine hydrochloride crystalline Form (I) in a protic polar or an aprotic dipolar solvent containing up to 50% by weight of water to produce a solution;
- e″″) stirring the solution of step d″″) until the concentration of lercanidipine hydrochloride dissolved in the crystallization solvent is ≦2%;
- and
- f″″) recovering the solid of step e″″) to produce lercanidipine Form (II).
An antihypertensive pharmaceutical composition comprising (1) a predetermined content of lercanidipine hydrochloride crystalline Form (II) or a combination of lercanidipine hydrochloride crystalline Form (I) and lercanidipine hydrochloride crystalline Form (II) comprising a predetermined content of each crystalline form, 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 treating a subject with hypertension, coronary heart disease or congestive heart failure the method comprising administering a therapeutically effective amount of lercanidipine hydrochloride crystalline Form (II) or a combination of lercanidipine hydrochloride crystalline Forms (I) and (II) having a predetermined content in each of said Form I and II 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 therapeutically effective amount of lercanidipine hydrochloride crystalline Form (II) or a combination of lercanidipine hydrochloride crystalline Forms (I) and (II) having a predetermined content in each of said Form I and II 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 (II) or a combination of lercanidipine hydrochloride crystalline Forms (I) and (II) having a predetermined content in each of said Form I and II to a subject in need of such treatment.
An antihypertensive composition comprising predetermined amounts of lercanidipine hydrochloride crystalline Form (I) and lercanidipine hydrochloride crystalline Form (II).
A lercanidipine hydrochloride of crystalline Form II exhibiting essentially the following X-ray diffraction data:
- 22 Relative D (Å) Intensity (I/Io) 9.3 35 6.0 45 5.49 65 4.65 52 4.27 74 3.81 41 3.77 100 3.58 44 3.54 29
A lercanidipine hydrochloride crystalline polymorphic form (Form II) having a melting point determined by differential scan calorimetry of 207-211° C.
A lercanidipine hydrochloride crystalline polymorphic form (Form II) having the Infrared spectrum (IR) as a KBr powder which shows absorption bands at 3183, 2684, 1705, 1675, 1526, 1350, 1402 and 1380 cm−1.
A lercanidipine hydrochloride crystalline polymorphic form (Form II) having a 13C-NMR solid phase spectrum which exhibits peaks at 6168.1, 166.6, 151.9, 121.9, 104.0, 102.8, 79.0, 66.0, 58.0, 49.7, 48.8, 44.3, 40.5, 29.8, 27.6, 23.5, 19.6 and 18.3 ppm.
A composition comprising lercanidipine hydrochloride wherein at least 90% of its lercanidipine hydrochloride content is Form II.
A pharmaceutical formulation comprising lercanidipine hydrochloride Form II which has at least one of the following pharmacokinetic profile feature when administered to a human as a 10 mg tablet;
- an AUCo-t (ng. h/ml) of about 10.36;
- a Cmax (ng/ml) of about 3.22;
- and a tmax of about 2.50.
Dependencies are inferred from the claim text.