WO2009106909A1

WO2009106909A1 - Process for the purification of diacerein

Info

Publication number: WO2009106909A1
Application number: PCT/IB2008/000450
Authority: WO
Inventors: Guido Di Napoli; Alessandro Di Napoli
Original assignee: Laboratoire Medidom S.A.
Priority date: 2008-02-29
Filing date: 2008-02-29
Publication date: 2009-09-03
Also published as: AR072244A1

Abstract

There is provided a process for the purification of crude diacerein, wherein diacerein is crystallized from 1-methyl-2-pyrrolidone, or a mixture of 1-methyl-2- pyrrolidone and a co-solvent.

Description

PROCESS FOR THE PURIFICATION OF DIACEREIN

The present invention relates to a process for the purification of diacerein.

Diacerein is a known therapeutically-active compound having anti-arthritic, antiinflammatory, antipyretic and analgesic activity, most known for use in the treatment for arthritic diseases.

Diacerein may be prepared by a number of known processes. The most widely known process for preparing diacerein comprises acetylation of aloin to obtain acetylbarbaloin followed by chromic oxidation of the acetyl derivative to obtain diarcerein (R. Robinson and G. L. Simonsen, Journal of the Chemical Society, Transactions, 95, 1909, 1085-1095).

As an alternative to preparing diacerein from aloin by the acetylation of aloin to acetylbarbaloin, there have been proposed in the literature processes for the preparation of diacerein starting from aloe-emodin. For example, there has been described the preparation of diacerein by oxidation of aloe-emodin with hexavalent chromium ("Sostanze Farmaceutiche", Italian translation and review by R. Longo, OEMF, Milan, 1998, P. 596, of "Pharmazeutische Wirkstoffe, Synthesen, Patente and Anwedungen", George Thieme Verlag, Stuttgart-New York, 1982-1987).

An alternative process for preparing diacerein from aloe-emodin is disclosed in EP0928781 , whereby aloe-emodin is oxidized to rhein with a salt of a nitrous acid in an acid reaction medium. The rhein so-obtained is then acetylated, e.g. with an acetic anhydride, to give diacerein.

Diacerein obtained according to the known processes, contains undesired accompanying aloe-emodin impunities (aloe-emodin and mono-, di-, tri-acetate derivatives thereof) resulting from incomplete oxidation. Aloe-emodin is defined as a cathartic compound and is known to have mutagenic properties. Other impurities derive from degradation of diacerein, to monoacetyl rhein (I and II) and rhein, the protection of the hydroxyl groups by acetylation being reversible, due to hydrolysis in basic medium. Diacerein rapidly undergoes deacetylation in even slightly basic medium, and the basicity induced by the diacerein salt (alkaline metal salt) is sufficient to cause some deacetylation, with the consequent formation of mono-acetyl impurities, on dissolution of diacerein salts in aqueous solution. Rhein is also used as starting material or intermediate in diacerein preparation in some processes (e.g. FR 2,508,798, EP 0 928 78).

Furthermore, diacerein obtained by a chromic oxidation process contains residual chromium compound impurities and must be subjected to purification processes to obtain diacerein free from any traces of chromium, in view of the very-high toxicity and carcinogenicity of chromium compounds.

In order to reach a purity of pharmaceutical grade, crude diacerein obtain by known processes must be subjected to subsequent purification processes for obtaining diacerein substantially free from impurities, and more particularly free from aloe-emodin and free from any traces of chromium.

Purification of crude diacerein to remove or reduce to a minimum the content of aloe-emodin and of chromium residues is known to be particularly critical.

A number of processes have been proposed in the literature for purifying crude diacerein.

EP0636602 describes two procedures for the purification of diacerein obtained by the acetylation of aloin to acetylbarbaloin, followed by chromic oxidation of the acetylated product to obtain crude diacerein: (1) salification with triethylamine in methylene chloride, release of diacerein by acidification with hydrochloric acid, followed by a crystallization from 2-methoxyethanol, and finally a crystallization from N₁N dimethylacetamide, (2) three successive crystallizations from N, N dimethylacetamide, followed by re-crystallization from ethanol. An aloe-emodin content of lower than 70 ppm is reported.

WO96/24572 describes a process whereby diacerein is purified by salification with a tertiary amine, comprising the steps of (a) forming a suspension of diacerein in a mixture of an organic solvent and water, (b) adding a tertiary amine (triethylamine), (c) adding an alkaline metal or alkaline-earth metal acid salt, (d) performing hydrolysis in a weakly acidic medium, and (e) recovering the purified diacerein by filtration. A similar process is described in WO98/56750 wherein diacerein is salified with a tertiary amine, and then the sodium salt of diacerein is precipitated by addition of 2-sodium ethylhexamoate in acetone/isopropanol solution. Finally the sodium salt is converted to diacerein by hydrolysis with an aqueous acid.

WO01/96276 describes a process for the purification of diacerein by crystallization from acetic anhydride or an acetic anhydride/acetic acid mixture, optionally with the addition of ethylenediaminetetraacetic acid to remove chromium impurities, followed by washing with acetic acid and water. According to WO01 /96276 the resulting purified diacerein has a purity of least 99.8%, contains less than 70 ppm aloe-emodin and not more than 15 ppm of chromium. In a similar process reported in WO00/68179 an additional purification step is described whereby the crystallized diacerein is then dissolved in acetone/triethylamine, to form the triethalamyne salt, and finally diacerein is precipitated by addition of aqueous phosphoric acid.

A process for the purification of diacerein to low levels of aloe-emodin content is described in WO2004/050601 , whereby an aqueous-organic solution of a salt of diacerein with a weak organic base (triethylamine, tributylamine) is subject to extraction with a water immiscible or sparingly water-miscible solvent (toluene, butyl acetate or methylene chloride), followed by recovery of diacerein by acidification of the salt solution with hydrochloric or phosphoric acid, and then crystallization of the diacerein from acetic anhydride/acetic acid. According to WO2004/050601 diacerein may be obtained with an aloe-emodin content of lower than 100 ppm, reportedly lower than 5 ppm aloe-emodin with repeated extractions.

A similar process is described in WO2005/028412 wherein triethylamine is added to crude diacerein dissolved in acetone/water to adjust to a pH of 6.6-7.2, and the extraction solvent is toluene. Diacerein having an average purity of 99,17%, and an aloe-emodin content of 7-10 ppm and a chromium content of 20-25 ppm is reported.

Known processes for purifying crude diacerein suffer from several drawbacks in that they are often complex with multiple steps, and/or use toxic solvents or reagents, and/or require the use of large quantities of solvents and/or reagents with the associated economic and environmental drawbacks.

It is an object of the invention to provide a process for the purification of diacerein with a high degree of purity.

It would be advantageous to provide a process for the purification of diacerein to very low aloe-emodin content. It would be further advantageous to provide a process by which purified diacerein may be obtained with low content of monoacetyl rhein and rhein impurities, and very low chromium content.

It would be advantageous to provide a process for the purification of diacerein to high purity, which is simple, economic, and suitable for application on an industrial scale. It would be further advantageous to provide a process which minimizes waste of solvents and/or reagents with the associated economic and environmental benefits.

It has now been surprisingly found that diacerein with a high purity, can be easily and advantageously obtained by crystallization from 1-methyl-2-pyrrolidone (NMP) or a mixture of 1-methyl-2-pyrrolidone and an organic co-solvent, in a process which may be advantageously applied on an industrial scale.

Objects of the present invention are obtained by a process for the purification of crude diacerein according to claim 1.

Other objects and advantages of the present invention will be apparent from the claims and from the following detailed description, examples and accompanying drawing.

Figure 1 shows a flow-chart schematic representation of a process for the purification of diacerein according to one embodiment of the present invention.

In the process of the present invention crude diacerein is purified by crystallization from 1-methyl-2-pyrrolidone (NMP) alone or the presence of one or more co- solvents).

The crude diacerein may be prepared by any known process, for instance by acetylation of aloin followed by chromic oxidation of the acetylated aloin, as described by Robinson, or alternatively by oxidation of aloe-emodin or aloe- emodin triacetate, using a chromic oxidation systems as described by George Thieme Verlag or a chromium-free oxidation process such as described in EP0928781 , and acetylation of rhein to obtain diacerein.

As co-solvent any suitable organic solvent or mixture of organic solvents may be envisaged. Suitable organic solvents include ketones, aromatic hydrocarbons, esters, ethers, alcohols, acetic acid and aromatic hydrocarbons. Advantageously, as a co-solvent there may be used one or more organic solvents selected from the group consisting of 2-butanone (methyl ethyl ketone, MEK), methyl isobutyl ketone (MIBK)₁ acetone, cyclohexanone, toluene, xylene, ethyl and n-butyl acetates, tetrahydrofuran, dimethoxyethane, 1 ,4-dioxane, methanol, ethanol, isopropanol, acetic acid, perchloroethylene, dichloromethane and 1 ,2-dichloroethane. More preferably the co-solvent is a ketone, particularly 2-butanone, methyl isobutyl ketone, acetone or cyclohexanone.

In a preferred embodiment of the present invention, as the solvent for the crystallization is used 1-methyl-2-pyrrolidone (NMP) alone, or a mixture of 2- butanone (MEK) and 1-methyl-2-pyrrolidone (NMP).

Preferably 2-10 parts w/w 1-methyl-2-pyrrolidone may be used with respect to diacerein for purification step, advantageously from about 4 to about 6 parts w/w.

The ratio of 1-methyl-2-pyrrolidone to organic co-solvent in the solvent system for crystallization is preferably from 1 :0 to 1 :4 w/w.

In the present process, diacerein is preferably dissolved in the solvent system by heating, for example to a temperature ranging from 40 to 110 ⁰C. The solvent system may be pre-heated before addition of the crude diacerein, for instance to a temperature ranging from 10 to 110 ⁰C, and preferably heating is continued to maintain a temperature from 40 to 110 ⁰C, advantageously around 80 ⁰C, during the dissolution of the crude diacerein. Alternatively, crude diacerein may be added to the solvent system and then the diacerein/solvent mixture heated to a temperature between 40 to 110 °C, preferably around a 80 ⁰C to dissolve the diacerein.

Precipitation of the crystallized diacerein is achieved by cooling the diacerein/solvent solution, to a temperature from 0 to 30 ⁰C. Preferably the diacerein/solvent solution is cooled to a temperature between 0 to 5 ⁰C. The cooling may be maintained for a time, for instance, 0.5 to 5 hours to maximize crystallization.

The crystallized diacerein product may be separated by filtration, and the solvent (1-methyl-2-pyrrolidone alone or in a mixture with a co-solvent) may be easily recovered by conventional methods, e.g. by distillation, and may be re-used. According to one preferred embodiment of the present invention, the crystallization from 1-methyl-2-pyrrolidone, or a mixture of1-methyl-2-pyrrolidone and a co-solvent, may be repeated one or more times. The repetition of the crystallization purification step allows the content of impurities in the purified diacerein to be minimized.

In a preferred embodiment of the invention, crude diacerein is subjected to three or more successive crystallizations from 1-methyl-2-pyrrolidone or 1-methyl-2- pyrrolidone and a co-solvent, more preferably from 4 to 10, for instance from 4 to 6 successive crystallizations. The number of successive crystallizations required to obtain the desired level of purity depends, amongst others, on the level of purity of the initial crude diacerein. Usually around 4 successive crystallizations, is sufficient.

According to one embodiment of the invention the purification of diacerein is carried out using a "waterfall" process whereby the mother liqueur filtrate containing the crystallization solvent(s), obtained in the filtration of the purified diacerein product after completion of one crystallization step, is re-used as crystallization solvent in the purification of a subsequent batch of diacerein, without first being subject to any treatment or solvent extraction, as illustrated in figure 1 , with reference to Examples 1 to 3.

The re-use of the mother liqueurs, obtained in the filtration of the precipitated diacerein product of a crystallization step, in this way is particularly advantageous for application of the process on an industrial scale since the need to use new solvents at each crystallization, and/or for purification of each new batch of crude diacerein to the purified is avoided. Advantageously, the mother liqueurs can be re-used without the need for any additional treatment or solvent recovery steps, such as filtration and distillation processes for extraction of the crystallization solvents. The use of solvent is minimized, with associated economic and environmental advantages, and the process is simple and easily used on an industrial scale.

In this embodiment of the invention, fresh solvent is preferably used in a final crystallization step (n) in a series of successive crystallization (1 to n), whereas mother liqueurs obtained from crystallization steps in the purification of a previous batch of diacerein are used in the first crystallization steps (1 to n-1). "Fresh" solvents 1-methyl-2-pyrrolidone and optionally co-solvent may be obtained easily by solvent recovery from mother liqueurs, for example the mother liqueurs obtained after the first crystallization step in series of successive crystallizations, by conventional methods, i.e. filtration and distillation.

The diacerein precipitate may advantageously be washed with a ketone, such as for instance acetone or 2-butanone, or an alcohol, such as ethanol or isopropanol, and water to remove any residual 1-methyl-2-pyrrolidone. This solvent treatment may be carried out at a temperature ranging from 0 ⁰C to reflux, for example at a temperature from 0 to 80 ⁰C.

The determination of impurity content may be carried out by conventional methods, e.g. HPLC methods. Particularly determination of aloe-emodin content is carried out by HPLC with external standard method.

According to the process of the present invention diacerein may be obtained with good yield and a high purity suitable for pharmaceutical applications. The diacerein produced according to the present invention has a purity of at least 99.5% percent, for example 99.5% to 99.9%, normally at least 99.7%, and contains less than 0.1%, e.g. 0% to 0.1%, usually 0.05% or less, of individual impurities monoacetylated rhein (I and II) and rhein. According to the process of the present invention, purified diacerein may be obtained with a content of less than 3 ppm of aloe-emodin and its derivatives (mono-, di- and tri-acetylated aloe- emodin). Where the process of the invention is used to purify diacerein produced by processes involving chromic oxidation, the process of the present invention allows diacerein having a chromium content of less than 2 ppm to be obtained.

The process according to the present invention is economical since the crystallization solvent may be re-used or recycled, and inexpensive reagents and solvents may be used in the process. Moreover the process is easy to carry out on an industrial scale.

Embodiments of the invention are further illustrated by the following non-limiting examples:

EXAMPLES

Materials Solvents and starting materials used in the following purification process examples 1 to 3 are as specified below:

- 1-methyl-2-pyrrolidone (NMP) from Panreac, Spain. Purity: 99% (minimum).

- methyl ethyl ketone (also referred to as 2-butanone or MEK) from Panreac, Spain. Purity: 99.5 % (minimum). - crude diacerein from Laboratoire Medidom, Switzerland. Purity 94.30% assay (monoacetyl rhein I - 0.42%, monoacetlyl rhein Il - 0.74%, others - 0.8%)

For HPLC analysis:

- Methanol HPLC gradient from Panreac, Spain. - Water HPLC from Panreac, Spain.

- Instrument: Agilent 1100 with DAD detector

- Conditions: Column: XBridge C18 (from Waters) (250 x 4 mm, 5 μm)

Injection volume: 10 μl Temperature : 35 ⁰ C Flow: 0.8 ml

- Buffer: Water at pH 2 with Formic Acid (Aldrich 99.5%)

- Gradient:

- Detector 254 nm

Example 1 Step 1.1

248 g of 1-methyl-2-pyrrolidone (NMP) and 250 g of methyl ethyl ketone (MEK) fresh solvents (referred to as S in figure 1) were poured into a flask, and the mixture heated to 80 ⁰C. 45 g of crude diacerein, was added to the solvent mixture and stirred maintaining temperature at around 80 ⁰C, for five minutes to dissolve the diacerein. The resulting solution was then filtered maintaining the temperature and the filter washed with 20 g boiling MEK. The solution was then cooled to 2 ⁰C over 1.5 hours whereby a yellow solid was precipitated, and was maintained at 3 ⁰C for 3 hours. The precipitated solid was filtered and washed with 15 g MEK at 20 ⁰C. 59.8 g of humid diacerein product was obtained (referred to as C1.1). Weight loss was determined at 16.9% by thermobalance (70⁰C for 10 minutes) and NMP content was quantified by HPLC (22.1%). The humid product corresponded to 38.7 g of dry diacerein.

Solvents NMP and MEK were recovered from the mother liqueurs by distillation.

Step 1.2

Considering the weight and % NMP in C1.1 (59.3 g humid C1.1 corresponding to 38.4 g of diacerein) the solvents to be added were calculated (6 parts MEK and 5.33 parts NMP). 205.3 g of NMP and 23Og of MEK (S) were poured into the flask. The mixture was heated to 80 ⁰C and C1.1 was added and stirred for 5 minutes until dissolution. The solution was then cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated, and was maintained at 3°C for 3 hours. The solid was filtered and washed with MEK (15 g) at 20 ⁰C. The mother liqueurs (referred to as ML 1.2) were retained and used for purification of a second batch of diacerein (see example 2, step 2.1).

54.0 g of humid diacerein was obtained (referred to as C1.2). Weight loss (18.5%) was determined by thermobalance (70⁰C for 10 minutes) and NMP content (23.1%) quantified by HPLC. The humid product corresponded to 33.8 g of dry diacerein.

Step 1.3

Considering the weight and % NMP in C1.2, the solvents to be added were calculated (6 parts MEK and 5.33 parts NMP). For 53.4 g humid C1.2 corresponding to 33.5 g of diacerein, 178 g of NMP and 201 g of MEK (S) were poured into the flask. The mixture was heated to 80⁰C and C1.2 was added and stirred for 5 minutes until dissolutions, 3 g more NMP was added. The solution was cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated, and was maintained at 3 ⁰C for 3 hours. The solid precipitate was filtered and washed with MEK (15 g) at 20 ⁰C. The mother liqueurs (referred to as ML1.3) were retained and used for purification of a second batch of diacerein (see Example 2, Step 2.2). 45.4 g of humid diacerein was obtained (referred to as C1.3). Weight loss (12.0%) was determined by thermobalance (70⁰C for 10 minutes) and NMP content (22.0%) quantified by HPLC. The humid product corresponded to 31.2 g of dry diacerein.

Step 1.4

Considering the weight and % NMP in C1.3, the solvents to be added were calculated (6 parts MEK and 5.4 parts NMP). For 44.79 humid C1.3, corresponding to 30.7 g of diacerein, 165.5 g of NMP and 184 g of MEK (S) were poured into the flask. The mixture was heated to 80 ⁰C and C1.3 was added with stirring for 5 minutes until dissolution. The solution was cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated, and was maintained at 3 ⁰C for 3 hours. The solid precipitate was filtered and washed with MEK (15 g) at 20 ⁰C. The mother liqueurs (referred to as ML1-4) were retained and used in purification of a second batch of diacerein (see Example 2, Step 2.3). 42.8 g of humid diacerein was obtained (referred to as C1.4). Weight loss (13.0%) was determined by thermobalance (70°C for 10 minutes) and NMP content (24.0%) was quantified by HPLC. The humid product corresponded to 28.3 g of dry diacerein.

Step 1.5

280 g of MEK was poured into the flask and C1.4 (42.25 g) was added. The mixture was refluxed for one hour and then was cooled at room temperature. The solid was filtered and washed with fresh MEK. The solid product was dried at 70 ⁰C. 27.8 g of pure diacerein was obtained as a yellow solid.

Overall yield for batch of Example 1 , 65% percent corresponding to 29.2 g of pure diacerein.

Diacerein purity 99.70% determined by HPLC, total impurities less than 0.20% (monoacetyl rhein Il - 0.07%, monoacetyl rhein I - below detection limit, others - 0.03%) determined by HPLC. Aloe-emodin content 2 ppm, determined by HPLC.

Diacerein purity and content of individual impurities was determined by HPLC using apparatus, solvents, buffers and conditions as described above. Samples were as follows: Standard = 25 mg of diacerein (99.50%, assay) in 50 ml THF, test = 25 mg of diacerein in 50 ml of THF. Standard / test sample were injected for HPLC and the areas compared. Impurities were calculated related to diacerein area.

Aloe-emodin content was determined at ppm level by HPLC with external standard, using as standard 10mg of aloe emodin 99% assay, dissolved in 100 ml of methanol and then diluted to 1 :250 with methanol. For the sample was used 100mg of purified diacerein, purified according to example 1 , was dissolved in 10ml of 0.5M sodium hydroxide, stirred for 30 minutes and extracted three times with chloroform (3 x 35ml), then dried over celite, filtered and evaporated to dryness under vacuum. Residue was dissolved with 1ml methanol. The aloe standard and the sample were injected for HPLC, using apparatus and conditions as described above, and the areas compared. Detection limit 0.4ppm.

Example 2

Step 2.1

ML 1.2 [450 g (205 g NMP, 245 g MEK)] was poured into a flask and an additional

NMP (42 g) (S) was added to give 248 g of NMP and 270 g of MEK for the purification of 45 g of crude diacerein as in Example 1. The solvent mixture was heated to 80 ⁰C and 45g crude diacerein was added with stirring for 5 minutes until dissolution. The resulting solution was filtered maintaining the temperature and the filter was washed with boiling MEK (27 g). The solution was cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated and then was maintained at 3 ⁰C for 3 hours. The solid precipitate was filtered and washed with MEK (15 g) at 20 ⁰C. 62.7 g of humid diacerein was obtained (referred to as C2.1). Weight loss (16.1%) was determined by thermobalance (70⁰C for 10 minutes) and NMP content (22.4%) was quantified by HPLC. The humid product corresponded to 408 g of dry diacerein.

Solvent NMP and MEK were recovered from the mother liqueurs by distillation.

Step 2.2

Considering the weight and % NMP in C2.1 , the solvents to be added were calculated (6 parts MEK and 5.33 parts NMP). ^' For 62.0 g humid C2.2 corresponding to 40.4 g of diacerein, 215.3 g of NMP and 242 g of MEK were calculated. ML1.3 [394 g (consisting of 181 g NMP and 216 g MEK)] was poured into a flask and 34 g of NMP and 26 g of MEK (S) were added to complete the required quantities. The solvent mixture was then heated to 80 ⁰C. C2.1 was added with stirring for 5 minutes until dissolution. NMP (9 g) was added. The solution was cooled to 2 °C over 1.5 hours, whereby a yellow solid was precipitated and was maintained at 3 ⁰C for 3 hours. The solid precipitate was filtered and washed with MEK (15 g) at 20 ⁰C. The mother liqueurs (referred to as ML2.2) were retained and used in purification of a third batch of diacerein (see Example 3, Step 3.1). 62.1 g of humid diacerein was obtained (referred to as C2.2). Weight loss (18.0 %) was determined by thermobalance (70⁰C for 10 minutes) and then NMP content (23.7 %) quantified by HPLC. The humid product corresponded to 38.9 g of dry diacerein.

Step 2.3

Considering the weight and % NMP in C2.2, the solvents to be added were calculated (6 parts MEK and 5.33 parts NMP). For 61.2 g humid C2.2, corresponding to 38.3 g of diacerein, 204 g of NMP and 230 g of MEK were calculated. ML1.4 [363 g (consisting of 165.5 g NMP and 25 197.5 g MEK)] was poured into a flask and 38.5 g of NMP and 33 g of MEK (S) were added to complete the calculated quantities. The solvents mixture was heated to 80 ⁰C. C2.2 was added with stirring for 5 minutes until dissolution. NMP (10 g) was added. The solution was cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated and was maintained at 3 °C for 3 hours. The solid precipitate was filtered and washed with MEK (15 g) at 20 ⁰C. The mother liqueurs (referred to as ML2.3) were retained and used in the purification of a third batch of diacerein (see Example 3, Step 3.2). 65.5 g of humid diacerein was obtained (referred to as C2.3). Weight loss (25.5 %) was determined by thermobalance (70⁰C for 10 minutes) and NMP content (22.0 %) was quantified by HPLC. The humid product corresponded to 38.0 g of dry diacerein.

Step 2.4

Considering the weight and % NMP in C2.3, the solvents to be used were calculated (6 parts MEK and 5.4 parts NMP). Starting humid C2.3 was 64.8 g which corresponded to 37.6 g of diacerein, 204 g of NMP and 226 g of MEK (S) were poured into the flask. The mixture was heated to 80 ⁰C and C2.3 was added with stirring for 5 minutes until dissolution. NMP (7.5 g) was added. The solution was cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated and was maintained at 3 ⁰C for 3 hours. The solid precipitate was filtered and washed with MEK (15 g) at 20 ⁰C. The mother liqueurs (referred to as ML2.4) were retained and used in purification of a third batch of diacerein (see Example 3 Step 3.3). 51.7 g of humid diacerein was obtained (referred to as C2.4). Weight loss (17.5 %) was determined by thermobalance (70⁰C for 10 minutes) and NMP content (20.2 %) quantified by HPLC. The humid product corresponded to 34.1 g of dry diacerein.

Step 2.5

340 g of MEK was poured into a flask and C2.4 (51.1 g) was added. The mixture was refluxed for one hour and then cooled to room temperature. The solid was filtered and then washed with fresh MEK. The product was dried at 70 ⁰C. 33.6 g of pure diacerein was obtained as a yellow solid.

Diacerein purity 99.70% determined by HPLC, total impurities less than 0.20% (monoacetyl rhein Il - 0.08%, monoacetyl rhein I - below detection limit, others - 0.05%) determined by HPLC. Aloe-emodin content 2 ppm determined by HPLC with external standard.

Overall yield of batch 2 was 78.7%, corresponding to 35.4 g of pure diacerein.

Example 3

Step 3.1

ML2.2 [478 g (224 g NMP, 254 g MEK)] was poured into a flask and then additional NMP (24 g) (S) was added to complete to 248 g of NMP for purification of 45 g of crude diacerein as in Example 1. The solvent mixture was heated to 80 ⁰C. 45g crude diacerein was added and the mixture stirred for 5 minutes until dissolution. The resulting solution was filtered maintaining the temperature, and the filter was washed with boiling MEK (20 g). The solution was cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated, and was maintained at 3 ⁰C for 3 hours. The solid precipitate was filtered and washed with MEK (15 g) at 20 ⁰C. 64.7 g of humid diacerein was obtained (referred to as C3.1). Weight loss (16.5 %) was determined by thermobalance (70⁰C for 10 minutes) and NMP content (21.6 %) quantified by HPLC. The humid product corresponded to 42.4 g of dry diacerein.

Solvent NMP and MEK can be recovered from mother liqueurs.

Step 3.2

Considering the weight and % NMP in C2.1 , the solvents to be added were calculated (6 parts MEK and 5.33 parts NMP). For 63.9 g humid C2.2, corresponding to 41.8 g of diacerein, 223 g of NMP and 251 g of MEK were calculated. ML2.3 [448 g (consisting of 214 g NMP and 224 g MEK was poured into a flask and 9 g of NMP and 26 g of MEK (S) were added to complete the required quantities. The solvent mixture was heated to 80 ° C. C3.1 was added with stirring for 5 minutes until dissolution. NMP (20 g) was added. The solution was cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated, and was maintained at 3 ⁰C for 3 hours. The solid was filtered and washed with MEK (15 g) at 20 ⁰C. The mother liqueurs (referred to as ML3.2) were retained for use in the purification of a subsequent batch of diacerein. 65.5 g of humid diacerein was obtained (referred to as C3.2). Weight loss (21.7 %) was determined by thermobalance (70⁰C for 10 minutes), and NMP content (24.9 %) was quantified by HPLC. The humid product corresponded to 38.5 g of dry diacerein.

Step 3.3

Considering the weight and % NMP in C3.2, the solvents to be used were calculated (6 parts MEK and 5.33 parts NMP). For 64.5 g humid C3.2, corresponding to 38.0 g of diacerein, 202.5 g of NMP and 228 g of MEK were calculated. ML2.4 [456 g (consisting of 211 g NMP and 244 g MEK] was poured into a flask. The solvents mixture was heated to 80° C. C3.2 was added with stirring for 5 minutes until dissolution. NMP (18 g) (S) was added. The solution was cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated, and was maintained at 3 ⁰C for 3 hours. The solid was filtered and washed with MEK (15 g) at 20 ⁰C. The mother liqueurs (referred to as ML3.3) were retained for use in purification of a subsequent batch of diacerein. 59.2 g of humid diacerein was obtained (referred to as C3.3). Weight loss (18.0%) was determined by thermobalance (70⁰C for 10 minutes) and NMP content (21.8 %) was quantified by HPLC. The humid product corresponded to 38 g of dry diacerein.

Step 3.4 Considering the weight and % NMP in C2.4, the solvents to be used were calculated (6 parts MEK and 5.4 parts NMP). For 58.5 g humid C2.3, corresponding to 37.6 g of diacerein, 204 g of NMP and 226 g of MEK (S) were poured into a flask. The mixture was heated to 80 ⁰C and C3.3 was added with stirring for 5 minutes until dissolution. NMP (8.0 g) was added. The solution was cooled to 2 ⁰C over 1.5 hours, whereby a yellow solid was precipitated and was maintained at 3 ⁰C for 3 hours. The solid precipitate was filtered and washed with MEK (15 g) at 20 °C. The mother liqueurs (referred to as ML2.4) were retained for use in purification of a subsequent batch of diacerein. 53.6 g of humid diacerein was obtained (referred to as C3.4). Weight loss (18.5%) was determined by thermobalance (70⁰C for 10 minutes) and NMP content (21.6 %) quantified by HPLC. The humid product corresponded to 34.3 g of dry diacerein.

Step 3.5

340 g of MEK was poured into a flask and C3.4 (53.0 g) was added. The mixture was refluxed for one hour and then was cooled to room temperature. The solid was filtered and washed with fresh MEK. The product was dried at 70 ⁰C. 33.9 g of pure diacerein was obtained as a yellow solid.

Diacerein purity 99.70% determined by HPLC, total impurities less than 0.20% (monoacetyl rhein Il - 0.09%, monoacetyl rhein I - below detection limit, others - 0.06%) determined by HPLC. Aloe-emodin content 2 ppm determined by HPLC with external standard. Overall yield of batch 3 was 79.3%, corresponding to 35.7 g of pure diacerein.

Claims

1. A process for the purification of crude diacerein, wherein diacerein is crystallized from 1-methyl-2-pyrrolidone, or a mixture of 1-methyl-2- pyrrolidone and a co-solvent.

2. A process according to claim 1 wherein diacerein is crystallized from 1- methyl-2-pyrrolidone alone.

3. A process according to claim 1 wherein the co-solvent is one or more organic solvents selected from the group, consisting of 2-butanone, methyl isobutyl ketone, acetone, cyclohexanone, toluene, xylene, ethyl or n-butyl acetates, tetrahydofuran, dimethoxyethane, 1 ,4-dioxane, methanol, ethanol, isopropanol, acetic acid, perchloroethylene, dichloromethane or 1- 2-dichloroethane.

4. A process according to claim 3 wherein diacerein is crystallized from a solvent consisting of a mixture of 1-methyl-2-pyrrolidone and 2-butanone.

5. A process according to any one of claims 1 to 4 wherein diacerein is dissolved in 2-10 parts w/w of 1-methyl-2-pyrrolidone, optionally in the presence of a co-solvent.

6. A process according to any one of claims 1 to 5 wherein the ratio of 1- methyl-2-pyrrolidone to co-solvent is from 1 :0 to 1 :4 w/w.

7. A process according to claim 6 wherein 1-methyl-2-pyrrolidone and a co- solvent are used in a ratio from 10:1 to 1 :2 w/w.

8. A process according to any one of the claims 1 to 7 wherein diacerein is dissolved in 1-methyl-2-pyrrolidone or a mixture of 1-methyl-2-pyrrolidone and a co-solvent, at a temperature of from 40 to 110 °C and diacerein is precipitated by cooling to a temperature of from 0 to 30 ⁰C.

9. A process according to any one of claims 1 to 8 wherein diacerein is purified by successive crystallizations from 1-methyl-2-pyrrolidone or a mixture of 1-methyl-2-pyrrolidone and a co-solvent.

10. A process according to claim 9 or 10 wherein diacerein is purified by 4 to 6 successive crystallizations from 1-methyl-2-pyrrolidone or a mixture of 1- methyl-2-pyrrolidone and a co-solvent.

11. A process according to any one of claims 1 to 10 wherein a mother liqueur from one crystallization step is re-used as solvent in the purification of a separate batch of diacerein.

12. A process according to any one of claims 1 to 11 wherein diacerein is obtained having a purity of 99.5% or more, and a total content of alόe- emodin and mono-,di-,th-acetyl derivatives thereof of 0 to 3 ppm.

13. A process according to any one claim 1 to 12 wherein diacerein is obtained having a content of individual impurities monoacetyl rhein (I and II) and rhein of less than 0.1%.

14. A process according to any one of claims 1 to 13 wherein the crude diacerein is prepared by a chromic oxidation process, and wherein diacerein is obtained having a chromium content of 0 to 2 ppm.