WO2010066687A2

WO2010066687A2 - Stabalized statin-comprising compositions

Info

Publication number: WO2010066687A2
Application number: PCT/EP2009/066546
Authority: WO
Inventors: De Ben Lange; Den Ronald Uil
Original assignee: Dsm Ip Assets B.V.
Priority date: 2008-12-11
Filing date: 2009-12-07
Publication date: 2010-06-17
Also published as: WO2010066687A3

Abstract

The present invention relates to a method for isolating a statin comprising spray drying a solution of said statin in an alcohol or precipitating said statin from said solution characterized in that two antioxidants are present in said solution or in that said antioxidants are added during said spray drying or during said precipitating. Furthermore there is provided a composition comprising a statin and 0.01% to 1% by weight of said composition of two antioxidants which are 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.

Description

STABILIZED STATIN-COMPRISING COMPOSITIONS

Field of the invention

The present invention relates to novel compositions comprising a statin and antioxidants and to a method for the preparation of such compositions.

Background of the invention

One of the main problems in the production of active pharmaceutical ingredients is to achieve and maintain the purity as required by governmental and health organizations. Unfortunately, several examples are known wherein impurities are responsible for highly detrimental side effects.

Impurities can result from the production process itself but can also occur after isolation of the final product. One particular type of impurity can occur both ways, namely the formation of oxidative degradation products. Such unwanted impurities can occur readily in the class of statins, compounds that are useful as inhibitors of the enzyme 3- hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and are thus useful hypolipidemic and hypocholesterolemic agents. For example, oxidative degradation of atorvastatin is known from WO 2006/008091 and the autooxidation of simvastatin has been described by G. B. Smith et al. (Tetrahedron (1993) 49, 4447-4462). A solution to the problem of autooxidation has been presented in WO 2006/008091 in terms of preparing and/or storing the relevant products in an inert atmosphere, i.e. an atmosphere devoid of oxygen such as nitrogen or one of the noble gases. As practical reasons such as handling or costs not always favor the use of an inert atmosphere, there is still a need for alternative means to avoid, diminish and/or revert oxidative degradation of statins. Summary of the invention

The present invention provides a method for isolating a statin comprising spray drying a solution of said statin in an alcohol or precipitating said statin from said solution characterized in that antioxidants are present in said solution or in that said antioxidants are added during said spray drying or during said precipitating. Furthermore there is provided a composition comprising a statin and 0.01 % to 1 % by weight of said composition of antioxidants which are 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

A comprehensive overview of the mechanisms of autooxidation of pharmaceuticals has been given by K. C. Waterman et al. (Pharm. Dev. Technol. (2002) 7, 1 -32). Several strategies to prevent or diminish autooxidation 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 statins such as atorvastatin, lovastatin, pravastatin, simvastatin and wuxistatin, isolation of the active pharmaceutical ingredients in the presence of small amounts of antioxidants resulted in products 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 the first aspect of the present invention, disclosed is a method for isolating a statin in the presence of antioxidants. In a first embodiment isolation is carried out by spray drying a solution of said statin in a solvent. For instance, a solution of atorvastatin is subjected to spray drying in the presence of antioxidants. 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, fert-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. The starting statin can be prepared through most known methods for example 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-[(phenylamino) 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.

Spray drying in the presence of a single antioxidant has been described in WO 2006/039441 and XP002540320 (STN Database accession no. 148: 106032) whereas compositionsd of statins and a single antioxidant have been reported in US 2003/220343, WO 2003/094923, US 2004/126423 and US 2007/202159. However the preparation of compositions comprising a statin and two or more antioxidants is novel and furthermore it has now surprisingly been established that combinations of two or more antioxidants 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 the context of the present invention, spray drying refers to a method of drying a liquid feed through a hot gas. Typically, this hot gas is air, but sensitive materials such as statins may be processed under oxygen-free conditions and an inert gas such as nitrogen gas is used instead. The liquid feed may be a solution, colloid or suspension. Advantageously, the process of spray drying is a one step rapid process and eliminates additional processing. As a non-limiting example liquid feed is pumped through an atomizer device that produces fine droplets into the main drying chamber. Atomizers may vary with rotary, single fluid, two-fluid, and ultrasonic nozzle designs. These different styles have different advantages and disadvantages depending on the application of the spray drying required. In some instances a spray nozzle may be used in place of an atomizer for a different dispersion rate. The hot drying gas may be passed as a co-current or counter-current flow to the atomizer direction. The co-current flow enables the particles to have a lower residence time within the system and the particle separator (typically a cyclone device) operates more efficiently. The counter-current flow method enables a greater residence time of the particles in the chamber and preferably is paired with a fluidized bed system.

In a second embodiment the feed solution, colloid or suspension may be sprayed into a partial vacuum. Since the boiling point of a solvent is the temperature at which the vapor pressure of the solvent is equal to the ambient pressure, reducing pressure has the effect of lowering the boiling point of the solvent which may be advantageous for the yield of the spray drying process and/or for the quality of the final product.

The solvent in which the statin and/or the antioxidants are dissolved prior to spray drying can be any solvent although preferred solvents are those in which the components in question have a solubility, at 20^QC, exceeding 0.5 g/L, preferably exceeding 1 g/L, more preferably exceeding 5 g/L, most preferably exceeding 10 g/L, still most preferably exceeding 50 g/L so that a solution can be obtained wherein the concentration of the statin is from 10 g/L to 300 g/L, preferably from 40 g/L to 150 g/L. Preferred solvents are alcohols such as methanol, ethanol, isopropanol and the like. The amount of antioxidants 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 solution prior to spray drying, preferably from 0.01 % w/w to 2% w/w, more preferably from 0.05% w/w to 1 % w/w. In a third embodiment, the antioxidants may be added to the solution prior to the spray drying process. Alternatively the antioxidants are added during the spray drying process; the latter approach 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 antioxidants. In a fourth embodiment it was found that amorphous atorvastatin could be prepared by precipitation at temperatures not exceeding 50^QC from a mixture of selected alcohols in the presence of antioxidants. 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 2005/0119493 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. The antioxidants 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. Suitable antioxidants are the same as outlined in the first embodiment.

In a fifth embodiment, the resultant precipitated and isolated or spray dried statin 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 statin, or re-mixing the resultant precipitated and isolated statin 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.

The embodiments described above are not limited to atorvastatin but also apply to other statins that are prone to oxidative degradation such as lovastatin, pravastatin, simvastatin and wuxistatin.

In a second aspect of the present invention, disclosed is a composition comprising a statin and at least two antioxidants. Preferably the statin is atorvastatin, lovastatin, pravastatin, simvastatin or wuxistatin and the antioxidants are carbohydrates, carotenoids, flavonoids, isoflavonoids, hydroxyacids, phenols, polyphenols, sulphite salts, terpene alcohols, thiourea, unsaturated acids or vitamins or mixtures 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, fert-butylhydroquinone, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and vitamin A.

Preferably the amount of antioxidants in the composition of the second aspect ranges from 0.005% w/w to 5% w/w relative to the amount of statin, preferably from 0.01 % w/w to 2% w/w, more preferably from 0.05% w/w to 1 % w/w. 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 two 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 of atorvastatin prepared according to the method of the present invention as detailed in Example 1 (B) and of the crystalline atorvastatin starting material (A). X-axis: 2-theta scale, Y-axis: Lin (counts). EXAMPLES

Example 1 Spray drying of atorvastatin from methanol

Crystalline atorvastatin (14 g) was dissolved in methanol (200 ml_) and spray dried (inlet temperature 66-69^QC, feed rate 3-4 ml/min, atomization air pressure 0.5-1 .0 kg/cm²) to give 10 g of amorphous atorvastatin with 99.4% HPLC purity (area%). XRD analysis of the product obtained revealed the full amorphous character as confirmed by the XRD spectrum given in Figure 1 . The stability of the resulting product was monitored for a period of three months (see Table 1 ).

Table 1 Stability data of atorvastatin (at 40^QC and 75% relative humidity)

Example 2

Spray drying of atorvastatin from methanol in the presence of citric acid and butylated hydroxyanisole

Crystalline atorvastatin (20 g) was dissolved in methanol (400 mL) and citric acid (0.1 g) and butylated hydroxy anisole (0.1 g) were added. The solution was spray dried under the conditions from Example 1 to give 15 g of amorphous atorvastatin with 99.1 % HPLC purity (area %). The stability of the resulting product was monitored for a period of three months (see Table 2).

Table 2 Stability data of (at 40^QC and 75% relative humidity)

Claims

1. Method for isolating a statin comprising spray drying a solution of said statin in an alcohol or precipitating said statin from said solution characterized in that two antioxidants are present in said solution or in that said antioxidants are added during said spray drying or during said precipitating.

2. Method according to claim 1 wherein said antioxidants independently are 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.

3. Method according to any one of claims 1 to 2 wherein said two antioxidants are a hydroxy acid and a phenol derivative.

4. Method according to any one of claims 1 to 3 wherein said antioxidants are present in said solution in an amount ranging from 0.01 % w/w to 1 % w/w relative to the amount of statin present in said solution.

5. Method according to any one of claims 1 to 4 wherein said statin is atorvastatin.

6. Composition comprising a statin and 0.01 % to 1 % by weight of said composition of two antioxidants which are 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. Composition according to claim 6 wherein said two antioxidants are a hydroxy acid and a phenol derivative.

8. Composition according to any one of claims 6 to 7 wherein said statin is atorvastatin.

9. Composition comprising a statin and 0.01 % to 1 % by weight of said composition of two antioxidants which are 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.

10. Use of a composition comprising a statin and 0.01 % to 1 % by weight of said composition of two antioxidants which are 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.