Amlodipine salt forms and processes for preparing them

Details Amlodipine salt forms and processes for preparing them Amlodipine salt forms and processes for preparing them

2002-11-20

2004-12-07

Desai, Rita (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S321000

Reexamination Certificate

active

06828339

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to amlodipine salt forms, including hydrate and anhydrate forms, and to processes for making amlodipine salt forms.
Pharmaceutical products with antianginal and antihypertensive properties are described in U.S. Pat. No. 4,572,909. An especially important compound among those disclosed is amlodipine, ±2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester. Amlodipine has the following structural formula.
This compound is used for the preparation of a medicament having calcium channel blocking activity that is useful, inter alia, in the management of hypertension, congestive heart failure and angina pectoris. The commercial product of amlodipine (NORVASCO® by Pfizer, Inc.) contains amlodipine besylate, which is described in U.S. Pat. No. 4,879,303 and corresponding EP 244 944. This patent discloses a single form of amlodipine besylate, namely a crystalline anhydrous besylate salt of amlodipine. This salt form is described as being non-hygroscopic; e.g., it does not form a hydrate. It is formed in the examples by combining either benzene sulphonic acid or ammonium benzenesulphonate with a slurry of amlodipine free base in industrial methylated spirits.
While the amlodipine salt form disclosed in U.S. Pat. No. 4,879,303 is suitable for a commercial product, it would be desirable to find other suitable salt forms of amlodipine. Further, it would be desirable to provide a process for making amlodipine besylate from an aqueous media instead of an organic solvent/slurry.
SUMMARY OF THE INVENTION
The present invention relates to salt forms of amlodipine. A first aspect of the invention relates to amlodipine besylate hydrates. Particular hydrate forms include monohydrate and dihydrate forms, but is not limited thereto.
Another aspect of the invention relates to amlodipine besylate anhydrates that differ from the known, commercially sold anhydrous amlodipine besylate as described in U.S. Pat. No. 4,879,303. In particular, anhydrous forms that do not exhibit a first melting point within the range of 201° C. to 205° C., unlike the known anhydrous form, are preferred.
Still another aspect of the present invention relates to an amorphous amlodipine besylate form and to pharmaceutical compositions containing the same.
A further aspect of the present invention relates to a crystalline pharmaceutical substance comprising a repeating lattice structure formed of the following molecules: (a) amlodipine, an ion thereof, or both; (b) benzene sulfonic acid, an ion thereof, or both; and (c) water.
The above novel compounds/substances of amlodipine can be used in pharmaceutical compositions generally in combination with at least one pharmaceutically acceptable excipient.
Another aspect of the present invention relates to an amlodipine besylate composition that contains at least one amlodipine besylate anhydrate and at least one amlodipine besylate hydrate. Such a composition may further contain a pharmaceutically acceptable excipient and, in such an embodiment, preferably contains the anhydrate and/or hydrate salts in a pharmaceutically effective amount. Similarly, the above novel compounds or a combination thereof, can be used to treat hypertension or angina in mammals by administering an effective amount of the amlodipine compound, e.g. amlodipine besylate hydrate, amlodipine besylate anhydrate, mixtures thereof, etc., to a mammal in need thereof.
Yet another aspect of the present invention relates to a process for forming an amlodipine besylate from an aqueous medium. In particular, the process comprises precipitating an amlodipine besylate from an aqueous solution. The formed solid salt can be a hydrate or anhydrate depending on the conditions employed.


REFERENCES:
patent: 4879303 (1989-11-01), Davison et al.
patent: 99/52873 (1999-10-01), None
patent: WO 03/101965 (2003-12-01), None
J. Rollinger, Doctoral Thesis “Polymorphism in Binary Systems—with special regard to antihypertensive drug substances,” 1999, University of Innsbruck, Innsbruck, Austria.
J. Rollinger and A. Burger, “Physico-Chemical Characterization of Hydrated and Anhydrous Crystal Forms of Amlodipine Besylate,” J. Thermal Analysis and Calorimetry, vol. 68, 2002, pp 361-372.

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