The present invention relates to a method of resolving racemic amlodipine into its R-(+) and S-(xe2x88x92) enantiomers by precipitation with tartaric acid.
The synthesis of racemic amlodipine (3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate) and its activity as an inhibitor of calcium channels is described in U.S. Pat. No. 4,572,909 to Campbell et al. Results of in vitro tests to determine calcium antagonist activity of amlodipine enantiomers against calcium-induced constriction of potassium-depolarized rat aorta is described in Arrowsmith et al., J. Med. Chem., (1986) 29, 1696-1702. The authors allege that the (xe2x88x92) stereoisomer is twice as active as the racemic mixture in antagonizing calcium-induced constriction. The S absolute configuration is the (xe2x88x92) optical rotatory form. Goldmann, J. Med. Chem., (1992)35, 3341-44. Desirability of optically pure S-(xe2x88x92)-amlodipine for treatment of hypertension and angina is described in U.S. Pat. No. 6,057,344.
Although R-(+)-amlodipine appears to have little activity as a calcium channel blocker, it is not pharmacologically inert, but rather it is a potent inhibitor of smooth muscle cell migration. WO 95/05822 (now U.S. Pat. No. 6,080,761) to Chahwala et al. Ideally, the preferred mode of using amlodipine would be the administration of the S-(xe2x88x92) enantiomer substantially free of the R-(+) enantiomer. U.S. Pat. No. 6,057,344 to Young. Nonetheless, there is presently no amlodipine product that contains S-(xe2x88x92)-amlodipine substantially free of the R-(+) enantiomer. See, for example, NORVASC(copyright), the active ingredient of which is racemic amlodipine besylate.
Methods of producing enantiomerically pure amlodipine have concentrated on methods of resolving the racemate, i.e., methods of separating the enantiomers of a racemic mixture of amlodipine or an intermediate in the synthesis of amlodipine by stereoselective precipitation. Such methods are known. See EP 331 315 A2 to Arrowsmith (resolution of an amlodipine intermediate by cinchonidine).
Spargo described a method of resolving racemic amlodipine by forming a precipitate in a dimethylsulfoxide (DMSO) solvent by addition of D- or L-tartaric acid. WO 95/25722 (now U.S. Pat. No. 6,046,338). The resultant precipitate consists of amlodipine:tartrate:DMSO in a 2:1:2 ratio, which is termed an amlodipine hemitartrate DMSO monosolvate.
Spargo optionally allowed for the presence of a co-solvent in an amount that is preferably between 0.2% and 6% the volume of DMSO. Suitable co-solvents are taught to include dimethylacetamide, dimethylformamide (DMF), acetonitrile and tetrahydrofuran (THF). Spargo further describes a method of secondarily processing the amlodipine hemitartrate DMSO monosolvate to obtain crystalline amlodipine free base by a process of extraction of the amlodipine hemitartrate DMSO monosolvate in dichloromethane (DCM) with aqueous NaOH to remove the tartrate followed by precipitation with hexane.
However, the use of DMSO renders the method of Spargo unsuitable for large-scale (kilogram) routine production of enantiomeric amlodipine. FDA guidelines point out that DMSO residual concentrations above 0.5% would only be acceptable upon convincing justification. Guidance for Industry IMPURITIES: RESIDUAL SOLVENTS, FDA, September 1999, page 9. Accordingly, there is an art-recognized need for commercially acceptable large-scale methods of resolving amlodipine.
In one aspect, the invention is directed to a method of optically enriching racemic amlodipine, comprising precipitating amlodipine hemitartrate dimethylacetamide monosolvate from a solution comprising amlodipine and either D- or L-tartaric acid, whereby the amlodipine hemitartrate dimethylacetamide monosolvate precipitate is enriched for one enantiomer of amlodipine. In certain embodiments, the ratio of the two enantiomers of amlodipine in the precipitate is at least 8:1, preferably at least 9:1, or even at least 20:1. In certain embodiments, the method includes heating a slurry or solution of amlodipine and tartaric acid, e.g., to a temperature above 35xc2x0 C., preferably above 45xc2x0 C. or even above 55xc2x0 C., such as between 35 and 100xc2x0 C., preferably between 50 and 90xc2x0 C., even more preferably between 60 and 80xc2x0 C. In certain such embodiments, the elevated temperature is maintained for at least 30 min., preferably at least 60 min. or even more than 2 hours. In certain embodiments, the resolution is performed on a scale of more than 1 kg of amlodipine, preferably at least 10 kg or even more than 100 kg of amlodipine.
In another aspect, the invention is directed to a crystalline composition comprising S-(xe2x88x92)-amlodipine D-hemitartrate DMAC monosolvate or, alternatively, R-(+)-amlodipine L-hemitartrate DMAC monosolvate, wherein at least 80% of the amlodipine in the crystalline composition is the predominant enantiomer. Preferably at least 90% of the amlodipine in the crystalline composition is the predominant enantiomer. More preferably at least 97% of the amlodipine in the crystalline composition is the predominant enantiomer. Most preferably at least 99% of the amlodipine in the crystalline composition is the predominant enantiomer.
In yet another embodiment, the invention is directed to solid pharmaceutical dosage forms comprising an optically active amlodipine or a pharmaceutically acceptable salt or hydrate thereof, and a carrier matrix, and to methods for manufacturing such dosage forms. In certain preferred embodiments, at least 80% of the optically active amlodipine in the dosage form is S-(xe2x88x92)-amlodipine, preferably at least 90%, or even 95% or more.