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Process for the manufacture of non-genotoxic diacetylrhein (diacerein) and formulations comprising non-genotoxic diacetylrhein

A diacerein and non-gene technology, applied in the field of diacetylrhein, can solve problems such as inappropriate use of active ingredients

Inactive Publication Date: 2011-11-30
EVULTIS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] The presence of these impurities makes today's use of non-high purity diacerein inappropriate as an active ingredient in pharmaceutical preparations for human and veterinary use due to new requirements by the Health Agencies for genotoxic compounds

Method used

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  • Process for the manufacture of non-genotoxic diacetylrhein (diacerein) and formulations comprising non-genotoxic diacetylrhein
  • Process for the manufacture of non-genotoxic diacetylrhein (diacerein) and formulations comprising non-genotoxic diacetylrhein
  • Process for the manufacture of non-genotoxic diacetylrhein (diacerein) and formulations comprising non-genotoxic diacetylrhein

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Embodiment 1 (SEPABEADS SP207 and HP20 use of resin)

[0101] Preparation of Potassium Salt of Crude Diacerein

[0102] Suspend 50 g of crude diacerein containing about 500 ppm of genotoxic impurities in 750 ml of acetone and 50 ml of water, and add 25 ml of triethylamine diluted in 100 ml of acetone over a period of 3 hours under magnetic stirring, keeping pH does not exceed 7 until complete dissolution. The final solution obtained was treated with 32 g of potassium ethylhexanoate in 260 ml of acetone at 18°C. The salt-forming reagent was added over a period of 2 hours. A precipitate formed which, after filtration, was washed with 500 ml of acetone and dried under vacuum at 40° C. overnight.

[0103] Obtain 50 g of the potassium salt of diacerein.

[0104] Elution:

[0105] 15 g of this product were dissolved in 750 ml of water. After filtration under vacuum, the solution was diafiltered through 1.1 liters of SEPABEADS SP207 or DIAION HP20 A 4.5 cm-diam...

Embodiment 2

[0113] Embodiment 2 (use of DIAION HP2MG resin)

[0114] Preparation of Potassium Salt of Crude Diacerein

[0115] Suspend 50 g of diacerein containing about 500 ppm of genotoxic impurity in 750 ml of acetone and 50 ml of water and add 25 ml of triethylamine diluted in 100 ml of acetone over a period of 3 hours under magnetic stirring to maintain the pH Not more than 7 until completely dissolved. The resulting solution was treated with 32 g of potassium ethylhexanoate in 260 ml of acetone over a period of 2 hours. The resulting precipitate was filtered, washed with 500 ml of acetone and dried under vacuum at 40°C overnight.

[0116] Obtain 50 grams of diacerein potassium salt.

[0117] Elution:

[0118] Dissolve 25 grams of diacerein potassium salt in 1250 ml of water. After filtration under vacuum, the solution was diafiltered through 5.1 liters of DIAION HP2MG A 10.0 cm-diameter, 110 cm-high column (flow rate 20 ml / min).

[0119] DIAION HP2MG Typical characteristic...

Embodiment 3

[0126] 5 g of crude diacerein containing about 300 ppm of genotoxic impurity derivatives was dissolved in 40 mL of methanol, and 40 mL of water and 5 g of KOH were added under magnetic stirring. Heating to 60-65° C. is carried out in the presence of a condenser for 30 minutes; after this period, 35 ml of 6N HCL are added; dilution with about 35 ml of water is carried out and the solution is boiled for about 30 minutes. After cooling, the suspension was filtered under vacuum, the residue was washed with water and dried under vacuum to constant weight.

[0127] 4.5 g of rhein were thus obtained.

[0128] 2 g of rhein thus obtained were converted to the corresponding potassium salt as described in Example 1 for diacerein.

[0129] 2 g of the potassium salt of rhein were dissolved in 200 ml of water (final pH of the solution was 6.2). After filtration under vacuum, the solution was diafiltered through a solution containing 180 g of SEPABEADS SP207 7.5 cm-diameter, 10 cm-high...

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Abstract

The present invention is directed to a process for producing non-genotoxic Diacetylrhein (Diacerein), comprising: i) transformation of raw Diacerein (or raw Rhein), into a water-soluble salt; ii) adsorption of the salt Diacerein (or Rhein) solution on a hydrophobic resin; iii) washing with an appropriate solvent to eliminate the impurities (in particular the genotoxic impurities); iv) elution to recover Diacereinor Rhein; v) if the process is applied to Rhein, its transformation to Diacerein by acetylation; vi) acidification of purified Diacerein and its recovery, and drying.; The invention is also directed to non-genotoxic Diacerein obtained by the process of the invention, in which the total content of genotoxic impurities is below 1ppm, and suitable for the preparation of pharmaceutical formulations, in particular capsules, for human and veterinary use, in agreement with the current Health Authorities request.

Description

technical field [0001] The present invention relates to a new process for the preparation of diacetylrhein (diacerein) with high purity, in particular with low content of genotoxic impurities. These properties allow the use of non-genotoxic diacerein in pharmaceutical formulations for human and veterinary applications. Background technique [0002] Diacerein (chemical name: 1,8-diacetoxy-3-carboxyanthraquinone) is a molecule with anti-inflammatory activity (especially anti-free radical activity), and thus can be used in the prevention and treatment of various pathological conditions, Especially those case states that involve cartilage degeneration, such as arthritis and certain forms of osteoarthritis. [0003] Chemically, diacerein has the following structure: [0004] [0005] The raw materials for the preparation of diacerein are plant extracts derived from different plant species containing glycosilate-based anthraquinone structures; in particular, Senna or Aloe ext...

Claims

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Application Information

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IPC IPC(8): C07C51/47C07C66/02C07C69/157
CPCC07C51/47C07C67/56C07C51/412A61P39/06C07C66/02C07C69/017C07C69/16
Inventor A·马佐拉S·莫亚那
Owner EVULTIS SA
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