Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-25
2002-10-08
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06462202
ABSTRACT:
The present invention relates to a method for the production of solvent-free &agr;-lipoic acid.
&agr;-Lipoic acid (thioctic acid, 1,2-dithiolane-3-pentanoic acid) is a natural substance which occurs in the form of the R enantiomer in low concentrations in plant and animal cells. The physiological action of &agr;-lipoic acid, which was originally discovered as a growth factor, in hydrophilic and lipophilic media is as a coenzyme of the oxidative decarboxylation of &agr;-keto carboxylic acids (e.g. pyruvates) and as an antioxidant, and it is able to regenerate vitamin C, vitamin E, glutathione and coenzyme Q10. Racemic &agr;-lipoic acid is approved for the treatment of liver disorders and neuropathies (e.g. diabetic poly-neuropathies); its use as an effective inhibitor of the replication of HIV-1 viruses has been suggested (cf. Klin. Wochenschr. 1991, 69(15), 722-724). The racemate of &agr;-lipoic acid also displays cytoprotective, antiinflammatory and antinociceptive (analgesic) properties, and it has emerged for the pure optical isomers of &agr;-lipoic acid (R-&agr;-lipoic acid and S-&agr;-lipoic acid) that, in contrast to the racemate, the R enantiomer shows a predominantly antiinflammatory, and the S enantiomer shows a predominantly anti-nociceptive, profile of actions (cf. EP 0 812 590 A2).
The syntheses of crude racemic &agr;-lipoic acid and of enantiopure R- or S-&agr;-lipoic acid takes place by known methods or ones analogous thereto, as described or summarized, for example, in Crévisy et al., Eur. J. Org. Chem. 1998, 1949, Fadnavis et al., Tetrahedron Asym. 1998, 9, 4109, Dhar et al., J. Org. Chem. 1992, 57, 1699, Adger et al., J. Chem. Soc. Chem. Commun. 1995, 1563, Dasaradhi et al., J. Chem. Soc. Chem. Commun. 1990, 729, Gopalan et al., J. Chem. Soc. Perkin Trans. I 1990, 1897, Yadav et al., J. Sci. Ind. Res. 1990, 49, 400, Tolstikov et al., Bioorg. Khim. 1990, 16, 1670, Gopalan et al., Tetrahedron Lett. 1989, 5705.
The usual method for purifying crude &agr;-lipoic acid is recrystallization from solvents (e.g. from n-pentane, cyclohexane, methylcyclohexane, ethyl acetate) or mixtures of solvents (e.g. from ethyl acetate and hexane), as recommended, for example, in Brookes et al., J. Chem. Soc. Perkin Trans. 1 1988, 9, Segre et al., J. Am. Chem. Soc. 1957, 3503, Walton et al., J. Am. Chem. Soc. 1955, 77, 5144, Acker et al., J. Am. Chem. Soc. 1954, 76, 6483. The crystallized &agr;-lipoic acid is then filtered or centrifuged and subsequently dried by conventional methods. The crystalline &agr;-lipoic acid obtained in this way, which, however, contains residues of solvent, is finally processed further to the finished drug product.
An alternative additional method for purifying lipoic acid which has previously been recrystallized by a mixture of cyclohexane and ethyl acetate is, as proposed in DE 197 26 519 A1, a treatment of the crude material enriched in lipoic acid with liquid or supercritical carbon dioxide. Nevertheless, even the purified lipoic acid obtained in this way still has residual solvent contents of from 8 to 1030 ppm cyclohexane and 83 to 225 ppm ethyl acetate. In addition, the described method of treatment with liquid or supercritical carbon dioxide under a pressure in the range from 50 to 1000 bar is complicated and can be carried out only if appropriate safety measures are complied with.
As has emerged, residual solvent contents in &agr;-lipoic acid resulting from the production process cannot be completely precluded. According to the 4th International Conference on Harmonization (ICH 4), in the production of active ingredients for medicinal products, however, certain solvents must either be entirely avoided (class 1 solvents: with known or strongly suspected human carcinogenicity, with environment-endangering properties), or be limited to protect patients from possible adverse reactions (class 2 solvents: with non-genotoxic carcinogenicity in animals, with irreversible toxicity or reversible but significant toxicity). Where possible, less toxic solvents (class 3) should be used. This classification is moreover by no means exhaustive, and it is just as possible for new scientific findings about recommended limits to appear as for the classification of particular solvents to change. For example, there are tendencies to reduce even further the limit for the residual solvent content in &agr;-lipoic acid for medical approvals. Medicinal active ingredients and products ought never to contain residual solvent contents exceeding limits relevant to safety. However, even noncritical solvents such as, for example, acetic acid, which is permitted as food additive, may have an unpleasant effect on the odor or taste of an active ingredient or medicinal product. Since a residual solvent content cannot have therapeutic benefits, these solvents should generally be avoided as far as possible (or removed where appropriate) in order to comply with the requirements of GMP (Good Manufacturing Practice), product specifications and other quality characteristics. Suitable guidelines within the framework of the abovementioned ICH 4 are various policies, e.g. guideline Q3A, Impurities in New Active Substances; Q3B, Impurities in New Medicinal Products.
The present invention is therefore based on the object of designing a method for the production of solvent-free &agr;-lipoic acid not having the disadvantages of the known methods but making it possible to produce, in a simple manner, &agr;-lipoic acid which no longer contains any residual organic solvents.
This object has been achieved according to the invention by
a) dissolving the &agr;-lipoic acid to be purified in aqueous alkaline solution, or dissolving the salt thereof in water and adjusting an alkaline pH,
b) removing any solid impurities present from the aqueous solution from stage a),
c) adjusting the aqueous solution from stage a) or b) to a pH of from −1.0 to 5.0 with the aid of an acid and
d) isolating the precipitated &agr;-lipoic acid by known methods.
It has surprisingly emerged in this connection that not only is a solvent-free &agr;-lipoic acid obtained in this way but, in addition, typical impurities from the production process, such as, for example, 1,2,3-tri-thiane-4-valeric acid (6,8-epithioctic acid), are removed and thus the chemical purity of &agr;-lipoic acid is improved.
In the method of the invention, the &agr;-lipoic acid to be purified is dissolved in stage a) in aqueous alkaline solution expediently having a pH of from 7.5 to 16.0, preferably from 9.0 to 14.0. The alkaline solution may contain conventional bases in the form of hydroxides, carbonates and bicarbonates of alkali metals or alkaline earth metals (such as, for example, sodium, potassium, calcium and magnesium), ammonia or primary, secondary or tertiary amines (such as, for example, benzylamine, diisopropylamine, triethylamine).
The crude &agr;-lipoic acid employed in stage a) may in this connection have been produced by any method. The &agr;-lipoic acid may, for example, be produced by recrystallization using an organic solvent, or be crude &agr;-lipoic acid in the absence of organic solvents.
It is likewise possible to employ in the method of the invention both racemic &agr;-lipoic acid and an enantiopure R-(+)-&agr;-lipoic acid or S-(−)-&agr;-lipoic acid or any mixtures thereof. In place of free &agr;-lipoic acid it is also possible for a salt of &agr;-lipoic acid to be dissolved in water and subsequently made alkaline, e.g. with the bases already described, expediently to a pH of from 7.5 to 16.0, preferably 9.0 to 14.0
In a preferred embodiment, alkali metal (such as, for example, sodium or potassium) or alkaline earth metal salts (such as, for example, calcium or magnesium) of &agr;-lipoic acid are used thereby. However, it is also possible to employ other salts of &agr;-lipoic acid, in which case their cations may consist, in particular, of elements zinc, iron, copper, palladium, vanadium and selenium. It is also possible to employ as starting compounds salts of &agr;-lipoic acid with organic cations such as, for exa
Gruber Ansgar
Schuhbauer Hans
Winkler Stefan
Degussa - AG
Dentz Bernard
Fulbright & Jaworski L.L.P.
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