Title of Invention	ALPHA-LIPOIC ACID HAVING A NOVEL MODIFICATION.
Abstract	THE INVENTION RELATES TO A THIOCTIC ACID HAVING A PREDOMINANAT CONTENT OF ONE ENANTIOMER AND NEW MODIFICATION, IN WHICH THE X-RAY POWDER DIFFRACTOGRAMS HAVE A CHARACTERISTIC REFLECTION IN THE RANGE 23.4 TO 22.7 DEGREE 2THETA(CU), WHICH SHIFTS IN THE DIRECTION OF SMALLER ANGULAR VALUES WITH INCREASING ENANTIOMER CONTENT.

Full Text

Alpha-lipoic acid having a novel modification Alpha-lipoic acid is used in pharmaceutical formulations for oral administration both in infusion solutions and in solid pharmaceutical formulations. For this, synthetically produced, racemic DL-alpha-lipoic acid, which is also referred to as RS-thioctic acid, is employed. One enantiomer of alpha-lipoic acid, R-thioctic acid, occurs as a natural substance in virtually all animal and plant cells. As a coenzyme in the oxidative decarboxylation of alpha-keto acids (e.g. pyruvic acid), R-thioctic acid is of essential importance. Thioctic acid is pharmacologically active and has anti-inflammatory and antinociceptive (analgesic) as well as cytoprotective properties. An important medical indication is the treatment of diabetic polyneuropathy. Furthermore, thioctic acid is used in cosmetics and for nutritional supplementation, e.g. on account of its antioxidative action. The use of R-thioctic acid appears particularly advantageous here, since this is present in naturally identical form (see also EP 0 572 922 A1), and is only incorporated into the pyruvate dehydrogenase complex as a cofactor in natural form (Oehring et al., Biol. Chem. Hoppe-Seyler 373, 333-335, 1992). According to more recent results (Baur et al., Klin. Wochenschr. 1991, 69(15), 722-4), thioctic acid may possibly gain importance in the control of the illness caused by HIV-1 and HTLV-IIIB viruses. In the pure optical isomers of thioctic acid (R and S form, i.e. R-thioctic acid and S-thioctic acid), unlike the racemate, the R enantiomer mainly has antiinflammatory activity and the S enantiomer mainly antinociceptive activity (see also EP 0 427 247 A2). To achieve a selective action, the preparation and use of the pure enantiomers is therefore of great importance. For the specific preparation of the pure enantiomers, R- or S-thioctic acid, a number of processes are known which as a rule include an enantioselective synthesis step for the production of a suitable chiral precursor or intermediate. All processes known hitherto require a high synthetic outlay, or efforts to deplete the undesired enantiomer, and have hitherto not facilitated use on the industrial scale. The melting range of the pure enantiomers of thioctic acid (47 to 49°C) is lower compared with the racemic compound (58-61°C). In the preparation of solid pharmaceutical formulations, which as a rule proceeds under compression or compaction, the use of pressure on the material is indispensable, so that on the one hand warming and on the other hand melting of the thioctic acid takes place. Concentrated solutions of thioctic acid or its melts polymerize immediately and can no longer be converted into a crystalline form by cooling. In the case of pure enantiomers of thioctic acid, this effect is strongly pronounced on account of the lower melting point. For therapeutic use of the pure enantiomers, which is desirable per se, the use of basic salts was proposed (see also EP 702 953 A2). The object of the present invention is to prepare thioctic acid which contains the desired enantiomer in enriched form, and at the same time, on the other hand, to discover a modification or form which, on account of its physical properties, behaves during processing as largely as possible like racemic thioctic acid. If, in the preparation of thioctic acid by a suitable synthetic preparation process, one enantiomer is enriched, but still not completely, surprisingly, during crystallization from suitable solvents, thioctic acid is obtained which contains the prevailing enantiomer enriched, but does not behave like the corresponding solid mixtures of the crystalline racemate with pure crystalline R- or S-thioctic acid. The novel modification formed shows an X-ray powder diffractogram which does not correspond to those of the racemate, the pure enantiomers or mixtures thereof. The present invention relates to thioctic acid having a predominant content of one enantiomer, preferably having an enantiomer ratio of 60:40 to 97:3, which is present in a novel modification. In Figures 1 and 2, the typical X-ray diffractogram recordings of racemic RS-thioctic acid and of pure R-thioctic acid, which are known from the literature, are shown. Furthermore, Figures 3 to 5 show X-ray powder diffractograms which originate from crystallized thioctic acid which is prepared from solutions of thioctic acid enriched in pure enantiomers. In Figure 3, a thioctic acid having a content of R enantiomer of 66% and 34% S enantiomer is illustrated, in Figure 4 with a content of R enantiomer of 76% and 24% S enantiomer and in Figure 5 a thioctic acid having a content of R enantiomer of 95% with 5% S enantiomer. Surprisingly, the thioctic acid according to the invention exhibits a melting range of 48 to 59°C, which differs from the expected eutectic melting range of 44 to 48°C. Furthermore, it facilitates preferred pharmaceutical processing and has a better temperature stability compared with the pure enantiomer. The crystallization of the thioctic acid can be performed in a suitable organic solvent. Examples of organic solvents which can also contain water are, inter alia, aliphatic hydrocarbons having a carbon chain length of between 3 and 10 carbon atoms, aromatic hydrocarbons which are liquid, esters of aliphatic or cycloaliphatic carboxylic acids having 2 to 6 carbon atoms and aliphatic or cycloaliphatic alcohols having 1 to 6 carbon atoms, aliphatic or cycloaliphatic alcohols having 1 to 6 carbon atoms, ethers and glycol ethers or homogeneous mixtures of the solvents mentioned. Particularly preferred solvents are ethyl acetate, hexane, cyclohexane, pentane, heptane, diisopropyl ether, toluene, ethanol and their homogeneous mixtures. The purity and composition of the thioctic acids obtained was determined by means of analysis on a chiral HPLC column. The melting ranges were determined by means of differential scanning calorimetry (DSC) with a heating rate of 2°K/min. The present invention makes it possible to make the enantiomers of thioctic acid accessible for various applications in enriched form, which can be obtained crystalline and pure in a simple and economical manner from solutions thereof. The invention is illustrated in greater detail by the following examples. Example 1 41.2 g of racemic thioctic acid were dissolved in a mixture of 960 ml of cyclohexane and 240 ml of ethyl acetate at 40°C and 12.0 g (100 mmol) of S-(-)-a-methylbenzylamine were then slowly added dropwise. The mixture was then cooled to 25°C, and the precipitate was filtered off with suction and washed with cyclohexane-ethyl acetate mixture. 660 ml of water were added to the filtrate and a pH of 1-1.5 was set at room temperature using about 10% strength hydrochloric acid. The phases were separated and the aqueous phase was extracted a further time with 60 ml of cyclohexaneethyl acetate mixture. The combined organic phases were distilled in vacuo to about 1/5 of the original volume. The distillation residue obtained was cooled to -5 to -10°C and stirred for crystallization. The precipitate was filtered off, washed and dried. 20.4 g of thioctic acid in the new modification were obtained as a first crystallizate. The content of R-(+)-thioctic acid was 69.0%. Example 2 A solution which contained 20.0 g of R-(+)-thioctic acid and 5.0 g of S-(-)-thioctic acid in a mixture of 225 ml of cyclohexane and 25 ml of ethyl acetate was cooled from 35 to 40°C to -5 to -10°C, and the crystals were filtered and dried. 17.3 g of thioctic acid in the new modification were obtained as a first crystallizate. The content of R-(+)-thioctic acid was 75.6% with a melting range of 4 9 to 54°C. Example 3 A solution which contained 11.7 g of R-(+)-thioctic acid and 5.0 g of S-(-)-thioctic acid in a mixture of 225 ml of cyclohexane and 25 ml of ethyl acetate was cooled from 35 to 40°C to -5 to -10°C, and the crystals were filtered and dried. 12.0 g of thioctic acid in the new modification were obtained as a first crystallizate. The content of R-(+)-thioctic acid was 65.8% with a melting range of 54 to 58°C. Example 4 A solution which contained 95.0 g of R-(+)-thioctic acid and 5.0 g of S-(-)-thioctic acid in a mixture of 225 ml of cyclohexane and 25 ml of ethyl acetate was cooled from 35 to 40°C to -5 to -10°C, and the crystals were filtered and dried. 87.1 g of thioctic acid in the new modification were obtained as a first crystallizate. The content of R-(+)-thioctic acid was 93.5% with a melting range of 45 to 47°C. Example 5 A solution which contained 4.0 g of R-(+)-thioctic acid and 16.0 g of S-(-)-thioctic acid in 80 ml of diisopropyl ether was cooled from 35 to 40°C to -5 to -10°C, and the crystals were filtered and dried. 14.5 g of thioctic acid in the new modification were obtained as a first crystallizate. The content of S-(-)-thioctic acid was 75.8% with a melting range of 50 to 56°C. Example 6 A solution which contained 16.6 g of R-(+)-thioctic acid and 3.4 g of S-(-)-thioctic acid in 80 ml of diisopropyl ether was cooled from 35 to 40°C to -5 to -10°C, and the crystals were filtered and dried. 13.5 g of thioctic acid in the new modification were obtained as a first crystallizate. The content of R-(+)-thioctic acid was 78.8% with a melting range of 48 to 54°C. Example 7 A solution which contained 17.5 g of R-(+)-thioctic acid and 2.5 g of S-(-)-thioctic acid in a mixture of 200 ml of n-hexane and 57 ml of ethyl acetate was cooled from 35 to 40°C to -5 to -10°C, and the crystals were filtered and dried. 13.5 g of thioctic acid in the new modification were obtained as a first crystallizate. The content of R-(+)-thioctic acid was 82.6% with a melting range of 47 to 52°C. Example 8 A solution which contained 19.5 g of R-(+)-thioctic acid and 0.5 g of S-(-)-thioctic acid in a mixture of 24 ml of toluene and 6 ml of n-heptane was cooled from 35 to 40°C to -5 to -10°C, and the crystals were filtered and dried. 13.0 g of thioctic acid in the new modification were obtained as a first crystallizate. The content of R-(+)-thioctic acid was 94.5% with a melting range of 45 to 48°C. Example 9 A solution which contained 3.0 g of R-(+)-thioctic acid and 7.0 g of S-(-)-thioctic acid in a mixture of 135 ml of cyclohexane and 15 ml of ethyl acetate was cooled from 35 to 40°C to -5 to -10°C, and the crystals were filtered and dried. 8.5 g of thioctic acid in the new modification were obtained as a first crystallizate. The content of S-(-)-thioctic acid was 67.8% with a melting range of 53 to 58°C. We Claim: 1. Thioctic acid having a predominant content of one enantiomer and new modification, characterized in that the X-ray powder diffractograms have a characteristic reflection in the range 23.4 to 22.7° 2theta(Cu), which shifts in the direction of the smaller angular values with increasing enantiomer content. 2. Thioctic acid as claimed in claim 1, wherein an enantiomer content of R- of S-thioctic acid of 60 to 97% is present. 3. Thioctic acid as claimed in claims 1 and 2, wherein a melting range of 48 to 59°C is present. The invention relates to a thioctic acid having a predominant content of one enantiomer and new modification, in which the X-ray powder diffractograms have a characteristic reflection in the range 23.4 to 22.7° 2theta(Cu), which shifts in the direction of smaller angular values with increasing enantiomer content.

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00195-cal-1999-assignment.pdf

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