Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-27
2003-02-11
Fan, Jane (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
06518288
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel compound, to processes for preparing it and to its use in treating medical disorders. In particular the present invention relates to novel acid addition salts of amlodipine.
2. Description of the Related Arts
Calcium channel blockers (calcium antagonists) are useful in treating cardiac conditions including angina and/or hypertension. Dicarboxylate-dihydropyridine derivatives are generally known to possess calcium channel blocking activity. For example, EP 089 167 and corresponding U.S. Pat. No. 4,572,909 disclose a class of 2-amino group-3,5-dicarboxylate dihydropyridine derivatives as being useful calcium channel blockers. These patents identify that one of the most preferred compounds is 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine. This compound, which is now commonly known as amlodipine, has the following formula:
Amlodipine exhibits good bioavailability and has a long half-life in the body. While a variety of acid addition salts are mentioned in these patents as being potentially suitable, including fumarates, the maleate salt is identified as the most preferred acid addition salt. However, the commercial product of amlodipine (NORVASC by Pfizer) uses amlodipine besylate (benzene sulfonate) and not amlodipine maleate. Indeed, subsequent patents EP 244 944 and corresponding U.S. Pat. No. 4,879,303 indicate that the besylate salt provides certain advantages over the known salts including good formulating properties. Apparently, amlodipine maleate suffered from tabletting and stability problems so as to cause a switch during development to the besylate salt. (See “Review of Original NDA” for NDA# 19-787 of Oct. 10, 1990, obtainable from FDA under Freedom of Information Act). The stability and tabletting issues/causes are not publicly disclosed in the information available from the FDA.
SUMMARY OF THE INVENTION
The present invention relates to fumarate salts of amlodipine. In particular, one aspect of the invention relates to an acid addition salt of amlodipine with fumaric acid. Another aspect of the invention relates to amlodipine fumarate in a crystalline state. A preferred form of amlodipine fumarate is amlodipine hemifumarate.
The invention also relates to a process, which comprises contacting amlodipine free base or a salt thereof with fumaric acid or its ammonium salt in the presence of a solvent to form amlodipine fumarate.
Further aspects of the invention include a method for treating or preventing angina or hypertension which comprises administering to a patient in need thereof an effective amount of amlodipine fumarate as well as to a pharmaceutical composition for use in the treatment and/or prevention of angina or hypertension that comprises an effective amount of amlodipine fumarate together with a pharmaceutically acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a novel salt of amlodipine that does not comprise problems associated with the maleate salt and is a suitable equivalent to the besylate salt. According to the present invention there is provided an acid addition salt of amlodipine with fumaric acid, i.e. amlodipine fumarate.
Fumaric acid, unlike maleic acid, exists in a trans configuration. It has now been discovered that a problem with the formation and/or stability of amlodipine maleate is the potential for the amine nitrogen of amlodipine to react with the double bond of the maleic acid to form an amlodipine aspartate of the following formula.
This reaction is a Michael-type addition. The present invention avoids the formation of amlodipine aspartate by selecting a different salt anion. In particular, although both maleic acid and fumaric acid contain a carbon double bond, the Michael-type addition is prevented from occurring with fumaric acid because of this acid's trans configuration. Accordingly an aspartate derivative can not be formed with fumaric acid and this particular impurity/stability issue now known to be associated with amlodipine is avoided.
Amlodipine fumarate as used herein means any acid addition salt formed by reacting/combining fumaric acid with amlodipine; e.g. any salt comprised of amlodipine cations and fumaric acid anions. For instance, solid as well as dissolved forms are included as are crystalline and amorphous forms. Further, the ratio of amlodipine to fumaric acid is not required to be 1:1, although such is included, in order to be an amlodipine fumarate compound. For example, a preferred amlodipine fumarate has a ratio of 2:1, which corresponds to a hemifumarate. These and other specific ratios of amlodipine to fumaric acid are all embraced by the single generic term “amlodipine fumarate.” The crystal forms can be anhydrates, hydrates, solvates, etc. Further, it should be understood that the compound can exist as one of two enantiomers due to the presence of a chiral center on the 1,4-dihydropyridine ring. The forms may be separated e.g., by crystallisation or chromatography of the amlodipine free base or a salt thereof with an optically active acid, and converted to the corresponding fumarate salt. The individual enantiomers as well as mixtures thereof are likewise all embraced by the singular expression “amlodipine fumarate.”
Amlodipine fumarate can be prepared by contacting amlodipine (as the free base) or its acid addition salt other than the fumarate, with fumaric acid or its ammonium salt in a suitable solvent, preferably with both the fumaric acid and amlodipine being fully dissolved therein. Generally the amlodipine fumarate is precipitated out of the solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution or by adding a contrasolvent, i.e. a liquid miscible with the solvent in which the amlodipine fumarate is less soluble.
The amlodipine or salt thereof to be used in making the present invention can be obtained by methods well known in the art including those described in the above-mentioned patents as well as in U.S. Pat. No. 4,572,909. Another useful synthesis scheme for making amlodipine or salts thereof in good yields and purity via a phthalimidoamlodipine intermediate is also described in commonly-owned provisional application serial No. 60/258,613 filed Dec. 29, 2000, the entire contents of which are incorporated herein by reference, and in commonly-owned U.S. patent application Ser. No. 09/809,351, filed on Mar. 16, 2001 and entitled “Process for Making Amlodipine, Derivatives Thereof, and Precursors Therefor,” the entire contents of which are incorporated herein by reference. Fumaric acid and ammonium salts thereof are well known per se and are readily available to the worker skilled in the art.
Solvents useful for carrying out the salt reaction include water, alcohol such as methanol or ethanol, ketone such as acetone or methyl isobutyl ketone, ester such as ethylacetate, ether such as diethylether or tetrahydrofuran, nitrile such as acetonitrile, dipolar aprotic solvents such as dimethylsulfoxide or dimethylformamide, hydrocarbons such as hexane or toluene and mixtures thereof. Preferred solvents are those wherein the reactants are more soluble than the amlodipine fumarate product. In this way, the salt forming reaction is accompanied by spontaneous precipitation of the produced fumarate salt out of the solution. Examples are alcohols such as ethanol and isopropanol, esters such as ethyl acetate, and hydrocarbons such as toluene.
The precipitated fumarate salt may be isolated in a solid state by conventional methods such as filtration or centrifugation, optionally followed by washing and/or drying and may be purified by crystallization, for example at elevated temperature in an appropriate solven
Benneker Franciscus B. G.
Lemmens Jacobus M.
Peters Theodorus H. A.
Picha Frantisek
Fan Jane
Synthon BV
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