WO2010066846A2

WO2010066846A2 - Method for the isolation of atorvastatin

Info

Publication number: WO2010066846A2
Application number: PCT/EP2009/066852
Authority: WO
Inventors: De Ben Lange; Henricus Leonardus Marie Elsenberg
Original assignee: Dsm Ip Assets B.V.
Priority date: 2008-12-11
Filing date: 2009-12-10
Publication date: 2010-06-17
Also published as: WO2010066846A3

Abstract

The present invention relates to a method for isolating atorvastatin comprising mixing at a temperature not exceeding 50ºC a solution of atorvastatin in methanol and/or ethanol and/or n-propanol with isopropanol and/or n-butanol and/or sec-butanol and/or tert-butanol and/or a linear or branched C5-alcohol and/or a linear or branched C6-alcohol and/or a linear or branched C7-alcohol, followed by isolating the precipitate thus obtained, optionally in the presence of one or more antioxidants.

Description

METHOD FOR THE ISOLATION OF ATORVASTATIN

Field of the invention

The present invention relates to a method of isolating amorphous atorvastatin by precipitation and to stabilized amorphous atorvastatin compositions.

Background of the invention

Atorvastatin ([R-(T^ /?^*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1 -methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-1 /-/-pyrrole-1 -heptanoic acid hemi calcium salt) is a pharmaceutical ingredient useful as an inhibitor of the enzyme 3-hydroxy-3- methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and thus useful as a hypolipidemic and hypocholesterolemic agent. Many polymorphic forms of atorvastatin, including the amorphous form, are known. The amorphous form of atorvastatin exhibits, in a number of drugs, different dissolution characteristics leading to different bioavailability patterns that may be favorable in some therapeutic indications. There are several problems associated with the production of amorphous atorvastatin. One is that the amorphous form is not always produced consistently in the sense that often mixtures of crystalline and amorphous material are obtained. Another problem is that, compared to crystalline atorvastatin, amorphous atorvastatin is relatively unstable and thus prone to the formation of unwanted impurities. In US 6,247,740 a process is disclosed involving dissolution of crystalline atorvastatin in a non hydroxylic solvent followed by removal of the solvents under a temperature of about 90^QC. However, the requirement of high temperatures is believed to be a major cause for the occurrence of degradation which becomes particularly pronounced in large scale manufacturing. In US 7,230,120 a process is disclosed wherein removal of a single hydroxylic solvent was accomplished by freeze drying or spray drying. Indeed freeze drying avoids the use of high temperatures and spray drying limits the use of high temperatures to short residence times but both technologies require the use of expensive and energy consuming additional equipment. In US 6,528,660 a process is disclosed wherein amorphous atorvastatin is obtained by dissolving the crystalline form in a non hydroxylic solvent which mixture is subsequently contacted with a non polar hydrocarbon anti solvent. Although this approach avoids the use of high temperatures, it has as drawback that relatively large amounts of residual non hydroxylic solvent (0.6%-0.7%) remain in the end product, as confirmed for instance in WO 2006/045018, thereby limiting the maximal attainable purity to about 99%.

In WO 2006/045018 the problem of high temperatures during isolation was also addressed, this time by suggesting to remove solvent by spray drying, rapid vacuum evaporation or thin film evaporation from a solvent mixture comprising of an alcohol and a ketone or ester, but again the advocated technologies require expensive and energy consuming equipment.

The majority of the above documents describe alternative procedures for preparing amorphous atorvastatin. Although some address and solve the problem of lack of consistency and others that of the use of elevated temperatures during isolation, the problem of the relative unstability of amorphous atorvastatin on the other hand has not been adequately recognized or addressed in the above publications leaving ample room for further improvement.

Summary of the invention

The present invention provides a method for isolating atorvastatin comprising mixing at a temperature not exceeding 50^QC a solution of atorvastatin in a first solvent with a second solvent followed by isolating the precipitate thus obtained, characterized in that said first solvent is methanol and/or ethanol and/or n-propanol and that said second solvent is isopropanol and/or n-butanol and/or sec-butanol and/or tert-butanol and/or a linear or branched C5-alcohol and/or a linear or branched C6-alcohol and/or a linear or branched C7-alcohol. Furthermore the present invention provides a composition comprising atorvastatin and 0.01 % to 1 % by weight of said composition of an antioxidant which is a carbohydrate, a carotenoid, a flavonoid, an isoflavonoid, a hydroxyacid, a phenol, a polyphenol, a sulphite salt, a terpene alcohol, thiourea, an unsaturated acid or a vitamin. Detailed description of the invention

In the first aspect of the present invention, it was found that amorphous atorvastatin could be prepared by precipitation at temperatures not exceeding 50^QC from a mixture of selected alcohols. Surprisingly the precipitation method of the first aspect of the invention leads to an unprecedented increase in the purity of atorvastatin. Hence, a method is disclosed for isolating atorvastatin comprising mixing at a temperature not exceeding 50^QC a solution of atorvastatin in a first solvent which is methanol and/or ethanol and/or n-propanol with a second solvent in which atorvastatin has a lower solubility than in the first solvent. Methanol is particularly suited as a first solvent since it results in atorvastatin of reproducible amorphous consistency, since it is a solvent that is easy to recover and also since it is cheap. Preferred second solvents are alcohols such as isopropanol, n-butanol, sec-butanol, tert-butanol, linear or branched C5-alcohols (such as 1 -pentanol, 2-pentanol, 3-pentanol, 1 -methyl-1 -butanol, 2-methyl-1 -butanol, 3-methyl-1 -butanol, 1 ,1 -dimethyl-1 -propanol, 1 ,2-dimethyl-1 -propanol), linear or branched C6-alcohols (such as 1 -hexanol, 2-hexanol, 3-hexanol, 1 -methyl-1 -pentanol, 2-methyl-1 -pentanol, 3-methyl-1 -pentanol, 4-methyl-1 -pentanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol, 2-methyl-3-pentanol, 1 ,1 -dimethyl-1 -butanol, 1 ,2-dimethyl-1 - butanol, 1 ,3-dimethyl-1 -butanol, 2,2-dimethyl-1 -butanol, 2,3-dimethyl-1 -butanol, 3,3- dimethyl-1 -butanol, 3,3-dimethyl-2-butanol, 2,2,3-trimethyl-1 -propanol) and linear or branched C7-alcohols; Even higher alcohols may be employed although for practical reasons generally only those having a melting point below 25^QC are suitable. The preferred second solvent is isopropanol. After precipitation of atorvastatin, preferably in amorphous state, the product may be isolated, for instance by centrifugation, filtration, sedimentation and the like. As stated, the temperature at which the precipitation is carried out should not exceed 50^QC. Preferably precipitation is carried out at temperatures ranging from 0^QC to 40^QC, most preferably ranging from 20^QC to 30^QC. Dependent on the subsequent steps, the isolated precipitate may be dried using standard drying techniques at temperatures ranging from 20^QC to 100^QC, preferably ranging from 30^QC to 80^QC, most preferably ranging from 40^QC to 60^QC as at this range significant degradation could not be established.

The solvents of the present invention have a clear advantage over those suggested in the prior art. In US 2005/01 19493 a mixture of dichloromethane and diisopropyl ether is suggested and in US 6,613,916 a mixture of alcohols and diethyl ether is suggested. From a safety and environmental point of view these solvents should be avoided, moreover since traces residual solvent are difficult to remove completely and some of the suggested prior art solvents are toxic and/or poisonous.

Moreover, it has surprisingly and unpredictably been found that of the wide range of solvents available to the skilled artisan, the mixture of selected alcohols of the present invention successfully solves one of the main problems encountered in preparing pharmaceutically active ingredients, namely the occurrence of unwanted side-products. Thus, precipitation of atorvastatin from the mixture of selected alcohols of the present invention resulted in substantial lowering of side-products in the final product. For instance, when precipitating atorvastatin from a solution in methanol with isopropanol, the amount of atorvastatin ketal could be lowered from 0.08% (w/w) to 0.06% (w/w) or even to 0.05% (w/w) and still more remarkably the amount of atorvastatin lactone could be lowered from 0.23% (w/w) to 0.10% (w/w) or even to 0.05% (w/w). Such levels of decrease in impurities through precipitation techniques have hitherto not been established in prior art documents.

The starting solution comprising atorvastatin can be obtained from any known method of preparing atorvastatin, for instance as described in US 5,003,080, US 5,097,045, US 5,103,024, US 5,124,482, US 5,149,837, US 5,155,251 , US 5,216,174, US 5,245,047, US 5,248,793, US 5,280,126, US 5,397,792 or US 5,342,952. Preferably, atorvastatin is prepared as its calcium salt, i.e., [R-(R^*, R^*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1 -methylethyl)-3-phenyl-4-[(phenyl- amino)carbonyl]-1 H-pyrrole-1 -heptanoic acid calcium salt (2:1 ). The calcium salt is desirable since it enables atorvastatin to be conveniently formulated in, for example, tablets, capsules, lozenges, powders, and the like for oral administration. In a first embodiment, the resultant precipitated and isolated atorvastatin of the method of the present invention is treated with a third solvent. Such treatment is referred to as washing and may comprise leading said third solvent over or through a layer of precipitated and isolated atorvastatin, or re-mixing the resultant precipitated and isolated atorvastatin in said third solvent followed by isolation of the solid materials. In many cases the effect of said treatment with a third solvent is that the purity of the end product further increases. Preferred third solvents are the same as mentioned above as second solvent. In individual cases, the third solvent can be a different solvent from the second solvent, which has the advantage that a wide variety of impurities can be removed by choosing from a wide variety of solvents, but can also be the same solvent as the second solvent which has the advantage that it simplifies solvent recovery. The preferred third solvent is isopropanol.

In a second embodiment, the precipitation method as outlined above, is carried out in the presence of an antioxidant. Suitable antioxidants are carbohydrates, carotenoids, flavonoids and isoflavonoids, hydroxyacids, phenols, polyphenols, sulphite salts, terpene alcohols, thiourea or derivatives thereof, unsaturated acids and vitamins and derivatives thereof. In particular the following compounds have been proven useful as antioxidant in the context of the present invention: ascorbic acid, ascorbyl palmitate, bis hydroxyanisole, butylated hydroxyanisole, butylated hydroxytoluene, β-carotene, γ-carotene, δ-carotene, caffeic acid, chlorogenic acid, cinnamic acid, citric acid, coumaric acid, cyanidin, delphinidin, 2,6-diisopropylphenol, 2,6-di-fert-butyl-4-methylphenol, ellagic acid, epicatechin, erythorbic acid, fumaric acid, gallic acid, geraniol, θ-hydroxy^S^δ-tetramethylchroman^-carboxylic acid, kaempferol, lycopene, malvidin, mannitol, myricetin, peonidin, petunidin, proanthocyanidins, propyl galate, quercetin, resveratrol, sodium ascorbate, sodium erythorbate, sodium metabisulphite, sodium sulphite, tartaric acid, ferf-butylhydroquinone, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and vitamin A. Salts of the above compounds may also be employed within the context of the present invention. Incorporation of an antioxidant has the advantage that stability can be further extended. The amount of antioxidant used according to the method of the present invention ranges from 0.005% w/w to 5% w/w relative to the amount of atorvastatin present in the first solvent, preferably from 0.01% w/w to 2% w/w, more preferably from 0.05% w/w to 1% w/w. The antioxidant may be added to the solution of atorvastatin in the first solvent, to the second solvent or to the optional third solvent. The latter two approaches may have additional advantages, for instance in that, when required, solvents different from the solvent wherein the atorvastatin is dissolved, may be used for dissolving the antioxidant.

A comprehensive overview of the mechanisms of auto oxidation of pharmaceuticals has been given by K. C. Waterman et al. (Pharm. Dev. Technol. (2002) 7, 1-32). Several strategies to prevent or diminish auto oxidation are also suggested, such as for instance addition of chelating agents, elimination of contact with metals, the use of acids and buffers, antioxidants, sacrificial reductants, peroxide quenchers and specific packaging technologies. Specific compounds for which such approaches might be successful are however not mentioned. Indeed in WO 2006/008091 it is suggested for the case of statins to apply the use of an inert atmosphere while the same document advocates that addition of certain compounds such as antioxidants to prevent or diminish oxidative degradation will not lead to favorable results.

Nevertheless, in spite of the above it was surprisingly found that, in the case of atorvastatin, isolation of the active pharmaceutical in the presence of small amounts of antioxidants resulted in a product that can be isolated in the purity as required by governmental organizations and also retain this degree of purity for long periods of time, such as multiple years.

In a third embodiment it has been established that combinations of two or more antioxidants may surpisingly display antioxidative effects that surpass those of the individual components. Succesful examples in this respect are combinations comprising a hydroxy acid and a phenol derivative, such as for instance the combinations citric acid and bis hydroxyanisole, citric acid and butylated hydroxyanisole, citric acid and butylated hydroxytoluene, citric acid and 2,6-diisopropylphenol, citric acid and 2,6-di-tert-butyl-4- methylphenol, tartaric acid and bis hydroxyanisole, tartaric acid and butylated hydroxyanisole, tartaric acid and butylated hydroxytoluene, tartaric acid and 2,6-diisopropylphenol and tartaric acid and 2,6-di-tert-butyl-4-methylphenol.

In a second aspect of the present invention, disclosed is a composition comprising atorvastatin and an antioxidant. Preferably the antioxidant is a carbohydrate, a carotenoid, a flavonoid, an isoflavonoid, a hydroxyacid, a phenol, a polyphenol, a sulphite salt, a terpene alcohol, thiourea, an unsaturated acid or a vitamin. In particular the following compounds have been proven useful as antioxidant in the context of the present invention: ascorbic acid, ascorbyl palmitate, bis hydroxyanisole, butylated hydroxyanisole, butylated hydroxytoluene, β-carotene, γ-carotene, δ-carotene, caffeic acid, chlorogenic acid, cinnamic acid, citric acid, coumaric acid, cyanidin, delphinidin,

2,6-diisopropylphenol, 2,6-di-fert-butyl-4-methylphenol, ellagic acid, epicatechin, erythorbic acid, fumaric acid, gallic acid, geraniol, 6-hydroxy-2,5,7,8-tetramethyl- chroman-2-carboxylic acid, kaempferol, lycopene, malvidin, mannitol, myricetin, peonidin, petunidin, proanthocyanidins, propyl galate, quercetin, resveratrol, sodium ascorbate, sodium erythorbate, sodium metabisulphite, sodium sulphite, tartaric acid, ferf-butylhydroquinone, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and vitamin A. Preferably the amount of antioxidant in the composition of the second aspect ranges from 0.005% w/w to 5% w/w relative to the amount of atorvastatin, preferably from 0.01 % w/w to 2% w/w, more preferably from 0.05% w/w to 1 % w/w.

In one embodiment of the second aspect the composition comprises at least two antioxidants. Preferably said at least two antioxidants are a hydroxy acid such as citric acid or tartaric acid and a phenol derivative such as bis hydroxyanisole, butylated hydroxyanisole, butylated hydroxytoluene, 2,6-diisopropylphenol or 2,6-di-tert-butyl-4- methylphenol. One of the most preferred combinations is citric acid and butylated hydroxyanisole.

In a third aspect of the present invention, the composition comprising one or more antioxidants of the second aspect may be used for the manufacture of a hypocholesterolemic medicament. The antioxidants of the present invention prevent unwanted oxidation of the active ingredient and are of a non-toxic nature.

Legend to the Figures

Figure 1 is the XRD spectrum (Type: 2Th/Th locked - Start: 5.000° - End: 60.140° - Step: 0.007° - Step time: 123 s - Temp.: 25°C (Room) - Time Started: 17 s - 2-Theta:

5.000° - Theta: 2.500° - Chi: 0.00° - Phi:) of atorvastatin prepared according to the method of the present invention as detailed in Example 1 . X-axis: 2-theta scale, Y-axis:

Lin (counts).

EXAMPLES

Example 1

Precipitation of amorphous atorvastatin from a methanol/isopropanol mixture using mechanical stirring

Atorvastatin (15 g) was dissolved in methanol (6O g) at 30^QC under stirring for 20 min after which a clear solution was obtained. Some solvent was removed from the solution thus obtained by evaporation at 35^QC under reduced pressure until the weight of the remaining solution was 36±1 g. In another container, isopropanol (18O g) was charged and stirred at 20^QC under an atmosphere of nitrogen. The atorvastatin-containing solution in methanol was added drop wise to the isopropanol under vigorous mechanical stirring during a period of 30 min while the temperature was maintained at 20^QC. After completion of the addition, stirring was continued for another 60 min at 20^QC after which the formed precipitate was isolated by filtration under a nitrogen atmosphere. The precipitate so obtained was washed with isopropanol (3 x 25 g) under a nitrogen atmosphere and the washed precipitate was dried in a vacuum oven at 50^QC to give 14 g of amorphous atorvastatin (93% yield). XRD analysis of the product obtained revealed the full amorphous character as confirmed by the XRD spectrum given in Figure 1 . The procedure as outlined above was repeated twice with reproducible results. The composition of the atorvastatin starting material, the amorphous end product and the atorvastatin remaining in the mother liquor was analyzed by HPLC and the results are given in Table 1 .

Table 1 HPLC assay of atorvastatin (ATV) in %

Example 2

Precipitation of amorphous atorvastatin from a methanol/isopropanol mixture using revolving container

Example 1 was repeated however without mechanical stirring but using a rotary evaporator. The results were similar.

Example 3 Influence of temperature on the solution of atorvastatin in methanol

A solution of atorvastatin in methanol was prepared in the same concentration as in Example 1 . It was established that formation of atorvastatin methyl ester and atorvastatin lactone was faster above 40^QC. The same solution was kept at 60^QC and samples were analyzed after different time intervals. The results are given in Table 2.

Table 2 HPLC assay of atorvastatin (ATV) in methanol solution at 60^QC in %

Claims

1. Method for isolating atorvastatin comprising mixing at a temperature not exceeding 50^QC a solution of atorvastatin in a first solvent with a second solvent followed by isolating the precipitate thus obtained, characterized in that said first solvent is methanol and/or ethanol and/or n-propanol and that said second solvent is isopropanol and/or n-butanol and/or sec-butanol and/or tert-butanol and/or a linear or branched C5-alcohol and/or a linear or branched C6-alcohol and/or a linear or branched C7-alcohol.

2. Method according to claim 1 further comprising contacting said precipitate after said isolating with a third solvent.

3. Method according to claim 2 wherein said third solvent is the same as said second solvent.

4. Method according to any one of claims 1 to 3 wherein said second solvent is isopropanol.

5. Method according to any one of claims 1 to 4 wherein an antioxidant is added to said atorvastatin solution in said first solvent and/or to said second solvent and/or to said third solvent.

6. Method according to claim 5 wherein said antioxidant is a carbohydrate, a carotenoid, a flavonoid, an isoflavonoid, a hydroxyacid, a phenol, a polyphenol, a sulphite salt, a terpene alcohol, thiourea, an unsaturated acid or a vitamin.

7. Method according to any one of claims 5 to 6 wherein at least two antioxidants are present.

8. Method according to claim 7 wherein said at least two antioxidants are a hydroxy acid and a phenol derivative.

9. Method according to any one of claims 5 to 8 wherein the amount of said antioxidant or antioxidants is ranging from 0.01 % w/w to 1 % w/w relative to the amount of atorvastatin present in said solution in said first solvent.

10. Composition comprising atorvastatin and 0.01 % to 1 % by weight of said composition of an antioxidant which is a carbohydrate, a carotenoid, a flavonoid, an isoflavonoid, a hydroxyacid, a phenol, a polyphenol, a sulphite salt, a terpene alcohol, thiourea, an unsaturated acid or a vitamin.

11 . Composition according to claim 10 wherein at least two antioxidants are present.

12. Composition according to claim 1 1 wherein said at least two antioxidants are a hydroxy acid and a phenol derivative.

13. Composition comprising atorvastatin and 0.01 % to 1 % by weight of said composition of an antioxidant which is a carbohydrate, a carotenoid, a flavonoid, an isoflavonoid, a hydroxyacid, a phenol, a polyphenol, a sulphite salt, a terpene alcohol, thiourea, an unsaturated acid or a vitamin for use as a medicament.

14. Use of a composition comprising atorvastatin and 0.01 % to 1 % by weight of said composition of an antioxidant which is a carbohydrate, a carotenoid, a flavonoid, an isoflavonoid, a hydroxyacid, a phenol, a polyphenol, a sulphite salt, a terpene alcohol, thiourea, an unsaturated acid or a vitamin for the manufacture of a hypocholesterolemic medicament.