SI22255A - New polymorphs of statine salts and their application in pharmaceutical formulations - Google Patents

Abstract

The amorphous atorvastatin sodium and new polymorphs of forms I, II, III, IV and V as well as procedures for their preparation along with their integration into solid oral dosage forms are described.

Description

NEW STATIN SALT POLYMORPHS AND THEIR USE IN PHARMACEUTICAL FORMULATIONS

FIELD OF THE INVENTION

The invention relates to novel atorvastatin sodium salt polymorphs and to their incorporation into pharmaceutical compositions having improved stability and bioavailability, as well as to processes for their preparation.

BACKGROUND OF THE INVENTION

Atorvastatin is a member of a class of medicines called statins. Antiquities inhibit cholesterol biosynthesis by competitively inhibiting 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, which catalyzes the conversion of HMG-CoA to mevalonate, which defines the determining stage in cholesterol biosynthesis. Currently, the most therapeutically effective drugs available for the treatment of hyperlipidemia and hypercholesterolemia are both risk factors for arteriosclerosis and coronary heart disease.

Atorvastatin, [R- (R *, R *)] - 2- (4-fluorophenyl) -P, 5-dihydroxy-5- (1-methylethyl) -3-phenyl-4 [(phenylamino) carbonyl] -1 / N-pyrrole-1-heptanoic acid, its lactone form and its alkali and alkaline earth alkali salts are known in the art and the processes for the preparation of atorvastatin and its key intermediates are described in, for example, US Patents 5,003,080; 5,097,045; 5,103,024, 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,342,952, 5,397,792; 4,681,893; 5,273,995 and 5,298,627.

US Patent 5,273,995 describes monosodium, mono-potassium, chemical,

N-methylglucamine, hemi-magnesium, hemi-zinc and l-deoxy-1- (methylamino) D-glucitol (N-methylglucamine) salt of atorvastatin. Additionally, US patent 6583295 describes a series of amine salts of HMG-CoA reductase inhibitors that are used in the process of isolating and / or purifying these HMG-CoA reductase inhibitors. The tertiary butylamine and cyclohesylamine salt of atorvastatin are described.

WO 2005/105738 discloses atorvastatin salts with ammonia, benetamine, benzatin, dibenzylamine, diethylamine, L-lysine, morpholine, olamine, piperazine and 2-amino-2-methylpropan-1-ol, and novel crystalline forms of erbumine and atorvastatin sodium salts. The atorvastatin sodium salt polymorph was prepared from a mixture of acetonitrile and water, and gels were produced that were difficult to handle industrially since 6 days of stirring at room temperature were required to isolate the product. Furthermore, in the process of preparing the pharmaceutical dosage forms of acetonitrile, it is not very suitable to use a solvent for the preparation of pharmaceutically active compounds, since some of it remains in the pharmaceutically active compound as a residual solvent and for its toxicity.

WO 2006/0210216 describes novel polymorphs of atorvastatin potassium salt and its incorporation into solid oral dosage forms.

It is an object of the present invention to provide novel processes for the preparation of the atorvastatin sodium and hemi-magnesium salts more suitable for use on an industrial scale. It is further the object of the present invention to provide oral solid pharmaceutical dosage forms comprising the atorvastatin sodium and hemi-magnesium salts prepared according to the methods of the present invention.

Short description of the pictures

FIG. 1 shows a photograph and an X-ray powder diffraction pattern of Form I atorvastatin sodium.

FIG. 2 shows a photograph and an X-ray powder diffraction pattern of Form II atorvastatin sodium.

FIG. 3 shows a photograph and an X-ray powder diffraction pattern of Form III atorvastatin sodium.

FIG. 4 shows a photograph and an X-ray powder diffraction pattern of Form IV atorvastatin sodium.

FIG. 5 shows a photograph and an X-ray powder diffraction pattern of Form V atorvastatin sodium.

FIG. 6 shows a photograph and X-ray powder diffraction pattern of amorphous atorvastatin sodium.

Summary of the Invention

The present invention provides novel atorvastatin sodium salt polymorphs expressing improved solubility and improved characteristics, and processes for their preparation.

Another aspect of the present invention is a process for incorporating them into solid oral pharmaceutical dosage forms, together with conventional pharmaceutically acceptable excipients, diluents, carriers and / or additives.

DETAILED DESCRIPTION OF THE INVENTION

New atorvastatin sodium salt polymorphs are prepared by crystallization and / or precipitation or by complete removal of the solvent from the purified atorvastatin sodium solutions by freeze drying or spray drying.

Purified solutions of atorvastatin sodium can be obtained by hydrolysis of either tertiary butyl ester [R- (R *, R *)] - 2- (4-fluorophenyl) -P, 5-dihydroxy-5- (1-methylethyl) phenyl-4- [ (phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid, (atorvastatin tert-butyl ester) or atorvastatin lactone with aqueous sodium hydroxide or by neutralization of atorvastatin free acid with aqueous sodium hydroxide in a water-miscible solvent washing the mixture with a suitable water-immiscible solvent.

Aqueous sodium atorvastatin sodium solutions for the freeze-drying process are those containing water-miscible co-solvents which have a low temperature volatility and a relatively high melting point, e.g. 1,4-dioxane or tert-butanol. Aqueous suspensions of atorvastatin sodium not containing co-solvents or containing a small amount of co-solvents are also suitable.

Aqueous solutions of atorvastatin sodium, suitable for the spray drying process, are those containing water miscible co-solvents, e.g. aliphatic alcohols such as methanol, ethanol, isopropanol, tert-butanol; ketones such as acetone; ethers such as tetrahydrofuran or 1,4-dioxane; or mixtures of water, water miscible solvents and water miscible solvents such as a combination of water, alcohols, ketones, ethers, etc. Non-aqueous atorvastatin sodium solutions are also suitable for spray drying. The gas carrier may be selected from air, nitrogen or argon.

Formor I atorvastatin can be prepared by partially evaporating an aqueous solution of atorvastatin sodium containing a water miscible co-solvent, such as methanol, 1,4-dioxane or tert-butanol, optionally saturated with a solvent which is not it is mixed with water such as tert-butyl methyl ether to such a degree that the low melting point volatile solvents are completely removed and also that a gelatinous precipitate is formed. Subsequently, the remaining solvents are completely removed, preferably by freezing the suspension, followed by freeze-drying under high vacuum.

Formor II atorvastatin can be prepared by partially evaporating an aqueous solution of atorvastatin sodium containing a water miscible co-solvent such as tert-butanol or 1,4 dioxane optionally saturated with a water immiscible solvent such as tert -butylmethyl ether, to such a degree that the low melting point volatile solvents are completely removed while the precipitate does not expire. The remaining solvents are then completely removed from the resulting solution, preferably by freezing the solution, followed by freeze-drying under high vacuum.

Atorvastatin sodium Form III can be prepared by contacting Form II with moist air at temperatures from about 20 ° C to about 80 ° C.

Form IV atorvastatin can be prepared by a process comprising the hydrolysis of atorvastatin tertbutyl ester with sodium hydroxide in 20% to 50% in aqueous methanol, preferably in about 35% aqueous methanol, at elevated temperatures, preferably at the reflux temperature of the mixture . When the hydrolysis process is complete, the reaction solution is allowed to cool, preferably to room temperature, in order to carry out both precipitation and / or crystallization.

Formor V atorvastatin can be prepared by a process comprising concentrating atorvastatin sodium solution in 50% to 90% aqueous methanol, preferably in about 85% aqueous methanol, to about one-third of the original volume under reduced pressure and cooling the resulting solution to about 0 ° C to precipitate and / or crystallize.

Amorphous atorvastatin sodium can be prepared by spray-drying atorvastatin sodium solutions.

X-ray powder diffraction samples were obtained with a Philips PW3040 / 60 X'Pert PRO diffractometer; CuK _(X irradiation 1.541874.

The polymorphic form I of atorvastatin sodium salt is characterized by the following 2theta degrees: 4.3, 5.9, 8.7, 11.3, 12.2, 14.2, 19.0, 22.9 ± 0.2.

Polymorphic form II of atorvastatin sodium salt is characterized by the following 2-theta degrees: 5.3, 8.3, 18.3 ± 0.2.

The polymorphic form III of atorvastatin sodium salt is characterized by the following 2-theta degrees: 5.6, 8.4, 9.5, 14.4, 16.2,22.7 ± 0.2.

The polymorphic form IV of atorvastatin sodium salt is characterized by the following 2-theta degrees: 5.1, 5.7, 6.6, 8.5, 10.3, 13.4, and 18.8 ± 0.2.

The polymorphic form V of atorvastatin sodium salt is characterized by the following 2-theta degrees: 6.4, 8.1, 9.7, 10.5, 11.6, 18.9, 20.0 ± 0.2.

The constituents of the atorvastatin sodium salt may be solid, semi-solid or liquid. The solid form of the preparations includes powders, granules, tablets, capsules, sachets, suppositories and dispersible granules. Preferably, atorvastatin sodium is in tablet form, most preferably in the form of film-coated tablets.

A solid dosage form may be, for example, immediate release dosage form, rapid-fire dosage form, controlled release dosage form, lyophilized dosage form, delayed release dosage form, sustained release dosage form, pulsed release dosage form, mixed immediate release and controlled release or a combination of both. The solid dosage form of the present invention is preferably an immediate release dosage form that offers advantages in terms of bioavailability and stability of the active compound.

The atorvastatin sodium formulations of the invention can be prepared by well-known technological methods such as direct compression or wet granulation (with water or organic solvents, e.g., MeOH, EtOH, nPrOH, iPrOH or mixtures thereof with water), dry granulation or lyophilization.

The compositions of this invention provide a process for the production of tablets with acceptable content uniformity. For example, the relative standard deviation of uniformity in tablet content (and finally film-coated tablets) is less than 10%, preferably less than 5%, even more preferably less than 3%.

The compositions of the present invention also provide a free flow of compression mixtures suitable for compression into tablets and preferably for further film coating.

The compositions of the present invention comprise atorvastatin sodium salt, solvates and various polymorphs thereof and at least one excipient.

The excipients of the present invention are selected from the group of diluents / fillers, decomposers, binders, lubricants, gliders, stabilizers, solubilizates, sweeteners, flavorings, etc.

The excipients present in the composition of the invention may be diluents such as lactose in various forms (anhydrous, monohydrate, spray-dried lactose, etc.), microcrystalline cellulose (such as commercially available Avicel PH 101, Avicel PH 102 or Avicel PH 112 ), powdered cellulose, silicified microcrystalline cellulose, sucrose, fructose, dextrates, other sugars, such as mannitol, lactose tol, xylitol, sorbitol, sodium hydrogen phosphate, calcium carbonate, calcium lactate, or combined diluents. Starch such as pregelatinized starch can also be used as a diluent. Preferably the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate. Cellactose in combination with other diluents such as starches or microcrystalline cellulose is preferred for the direct compression process.

The composition of the invention may also include binders such as povidone, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose (comprising from 5 to 16% by weight hydroxypropyl groups), hydroxypropylmethyl cellulose, or other cellulose ethanol, cellulose ethanol, starch or polymethacrylate or a binder mixture. Preferably, the excipients include at least one binder selected from cellulose or derivatives thereof. If a wet granulation process is used, hydroxypropyl cellulose is preferably used.

Further, decomposers and / or super-decomposers such as starches (eg corn starch, potato starch), modified starches (sodium starch glycolate), modified cellulose (croscarmellose, i.e. cross-linked carboxymethyl cellulose sodium) cross-linked polyvinylpyrrolidine crouproylsprorolinylpyrrolidine pyrolinylsprorolinylpyrrolidine pyrolinylsprorolinylpyrrolidine may be present , microcrystalline cellulose, carboxymethyl cellulose sodium, Amberlite®, alginic acid, sodium alginate, guar gum, gelan gum, Xanthan SM® or calcium silicate. When used as a disintegrant, microcrystalline cellulose is preferably used in an amount of from 5 to 15 wt. %. Preferably, the excipients include at least one disintegrant or super-disintegrant selected from croscarmellose, crospovidone and microcrystalline cellulose. If necessary, a combination of two or more disintegrants, for example, croscarmellose sodium, crospovidone and microcrystalline cellulose may be used.

In addition, lubricants such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, macrogols may also be present as excipients. Preferably, the excipients include at least one lubricant selected from magnesium stearate, sodium stearyl fumarate or hydrogenated vegetable oil.

Excipients may have several functions, i.e. one excipient may be a diluent and, in addition, a binder, binder and decomposer, etc.

Optionally, surfactants may be included in the solid pharmaceutical formulation. Surfactants may be selected from the group of non-ionic or ionic surfactants or mixtures thereof. Suitable nonionic surfactants are selected from the group of alkylglucosides, alkilmaltozidov, alkiltioglukozidov, lauryl macrogolglycerides, polyoxyethylene alkylphenols, polyoxyethylene alkiletrov, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polioksietilenpolioksipropilen block copolymers, polyglyceryl fatty acids, polyoxyethylene glycerides, polyoxyethylene of vegetable oils, polyoxyethylene of hydrogenated vegetable oils, sterols and mixtures thereof. Preferred non-ionic surfactants are polyoxyethylene sorbitan fatty acid esters sold under the trade names Polysorbate or Tween.

Suitable ionic surfactants are selected from the group of fatty acid salts, bile salts, phospholipids, phosphoric acid esters, carboxylates, sulfates, sulfonates and mixtures thereof. A preferred ionic surfactant is sodium lauryl sulfate.

The pharmaceutical composition of the present invention may range from 0.1-5 wt. %, preferably 0.2-4 wt. % surfactant, most preferably 0.3-3%.

The pharmaceutical composition of the invention may also comprise a stabilizer. Alkalising agents or buffers, for example, alkali compounds or alkaline earth compounds, may be used as stabilizers. Alkali additives such as, for example, sodium hydroxide, sodium peroxide, sodium carbonate, sodium hydrogen carbonate, sodium phosphate, sodium hydrogen phosphate or sodium salts with organic acids (eg sodium citrate or sodium tartrate), potassium hydroxide, potassium peroxide, potassium hydroxide, potassium peroxide, potassium hydroxide, potassium peroxide potassium carbonate, potassium hydrogen carbonate, potassium phosphate, potassium hydrogen phosphate or potassium salts with organic acids (for example potassium citrate or potassium tartrate).

The composition typically comprises from 0.01 wt. % to 20 wt. %, preferably of 0.1 wt. % to 15 wt. % and most preferably of 0.2 wt. % to 10 wt. % alkali additive.

Preferably, the composition of the present invention contains the sodium or hemi-magnesium salt of atorvastatin as an active ingredient, optionally an alkali additive selected from the sodium and potassium compounds, and optionally exposed to an atmosphere comprising from 1 to 16 vol. % oxygen. Most preferably, the composition comprises atorvastatin sodium as the active ingredient, sodium hydroxide or sodium carbonate as an alkalinizing agent and is optionally exposed to an atmosphere comprising from 1 to 16 vol. % oxygen.

It is further preferred that the composition is present in the package, with blister or bottle preferred. So the composition in the package is formed. The package may be provided with means of trapping and removing free oxygen. Further, the composition is preferably incorporated into a substantially impermeable gas exchange material, such as in a package having an atmosphere with the required reduced oxygen content. The substantially impermeable gas exchange envelope is preferably selected from the group consisting of Al / Al blister, Al-polychloro-3-fluoroethylene homopolymer / PVC laminate blister or bottle.

Any suitable process for the preparation of pharmaceutical compositions, e.g. direct compression, wet or wet granulation, etc.

It is further understood that atorvastatin sodium includes various polymorphic (including amorphous) or / and pseudomorphic forms (hydrates or other solvates).

According to the present invention, the tablet cores are preferably coated. The lining may be of conventional materials used for film coating. Film coating formulations typically contain the following components: polymer (s), plasticizer (s), colorant (s) / opacifier (s), solvent (s) and, optionally, flavors, surfactants and waxes in smaller quantities. Cellulose derivatives such as cellulose ethers (hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose) or acrylic polymers and copolymers, high molecular weight polyethylene glycols, polyvinylpyrrolidone pyrrolidone pyrrolidone pyrrolidinol can be used as coating agents.

Hydroxypropyl cellulose or polyvinyl alcohol are preferably used as the coating polymers.

Commonly used plasticizers can be categorized into three groups: polyols (glycerol, propylene glycol, macrogols), organic esters (phthalate esters, dibutyl sebacate, citrate esters, triacetin) and oils / glycerides (castor oil, acetylated monoglycerides, cocacids, facacos.

Dyes / opacities can be selected from groups of organic dyes or inorganic dyes.

The combination of different materials from each group can be combined in a certain proportion. Film coating suspensions can be used to make commercially available ready-to-make preparations. Preferably, commercially available mixtures, such as various Opadry® (Colorcon) mixtures, are used.

The film coating dispersion can be prepared using various solvents such as water, alcohols, ketones, esters, chlorinated hydrocarbons, preferably water.

Further, the composition of the invention may also comprise a coating of waxy materials such as Gelucire. Gelucire coatings are especially effective in preventing the entry of environmental gases into tablet cores, either when used alone or in combination with carboxymethyl sodium cellulose (NaCMC) or polyvinyl alcohol (PVA) based coatings. Gelucir compositions are inert semi-solid waxy materials that are amphiphilic in nature and have varying physical characteristics. They are surface-active in nature and are dispersed or solubilized in aqueous media to form micelles, microscopic globules or vesicles. They are identified by their melting point / HLB value. The melting point is expressed in degrees Celsius and HLB (hydrophilic-lipophilic equilibrium) is a numerical dimension that ranges from 0 to about 20. The large Gelucire family of compositions is characterized by a wide melting range of about 33 ° C to 64 ° C and most commonly from about 35 ° C to about 55 ° C, and having a plurality of HLB values of about 1 to about 14, most typically from about 7 to about 14. For example, Gelucire 50/13 indicates a melting point of about 50 ° C and an HLB value of about 13. Gelucire 50/13 has been found to be particularly effective when coating the formulation of the invention. It consists of fatty acid esters (most of Ci ₆ and Cig) and glycerol, PEG esters and free PEG (lauryl macrogol glycerides).

The coatings may be applied by melting processes or solutions / dispersions in water or organic solvents may be used as coating suspensions.

Various technological processes, such as direct compression, dry granulation, wet granulation (with water or organic solvents), spray drying, freeze drying, etc., can be used for the preparation according to the invention.

If a direct compression process is used, it can be performed by (a) adding the active ingredient to the mixture of excipients and compressing or (b) mixing the active ingredient together with the excipients and compressing.

Solid dosage forms (e.g., tablet cores) may be optionally coated.

Optionally, the excipients may be treated prior to mixing with the active ingredient, for example, by wet granulation using either water or an organic solvent, or a mixture thereof, as fluid granulomas.

A suitable blending device in direct compression or, optionally, wet granulation as described above is conventional equipment used to mix the active ingredients, excipients or combination of the active ingredient (s) and excipients. In the case of wet granulation as described above, the equipment is selected from standard equipment, for example, a quick-rotating granulator or a vortex granulator.

The present invention is illustrated, but in no way limited, by the following examples:

Examples

Preparation of formor sodium atorvastine

Example 1

To a solution of 5.00 g of tertiary butyl ester [R- (R *, R *)] - 2- (4-fluorophenyl) N, O-dihydroxy 5- (1-methylethyl) phenyl-4 - [(phenylamino) carbonyl] - To a solution of 0.33 g of NaOH (8.25 mmol, 1.01 equivalent) in 30 mL of water was added 177-pyrrol-1-heptanoic acid (8.13 mmol) in 17 mL of methanol and 15 mL of tert-butylmethyl ether. The reaction mixture was heated at reflux for 21 hours, when the concentration of the starting compound was reduced to 2.3% as determined by HPLC, then cooled to room temperature and washed twice with tert-butyl methyl ether (1 x 30 mL, 1 x 10 mL). The lower aqueous phase was partially concentrated under reduced pressure to remove most of tert-butyl methyl ether and methanol. Due to the initial foaming, the pressure must be carefully controlled. The evaporation is stopped when the distillate is no longer collected in the recipient at 47 mbar and the water bath temperature is 38 ° C. The remaining gel was deep frozen using a liquid nitrogen bath and lyophilized on a Lio 5 (Kambic) freeze dryer as needed (approximately 1 day to obtain 4.59 g of Formor I sodium as powder containing 6.53% water by volume). Karl Fischet assay (91% yield) The product was 99.4% pure by HPLC analysis.

Example 2

To a solution of 5.00 g of tertiary butyl ester [R- (R *, R *)] - 2- (4-fluorophenyl) -β, b-dihydroxy 5- (1-methylethyl) phenyl-4 - [(phenylamino) carbonyl] - 177-pyrrol-1-heptanoic acid (8.13 mmol) in 17 mL of tert-butanol and 15 mL of tert-butylmethyl ether add a solution of 0.33 g of NaOH (8.25 mmol, 1.01 equivalent) in 30 mL of water . The cloudy mixture was heated at reflux for 21 hours when the concentration of the starting compound was reduced to less than 0.5% as determined by HPLC. The reaction mixture was cooled to room temperature and washed twice with tert-butyl methyl ether (1 x 20 mL, 1 x 10 mL). The lower aqueous phase was partially concentrated under reduced pressure to remove tert-butyl methyl ether. The pressure was gradually reduced and the evaporation was stopped at 70 mbar and the water bath temperature 38 ° C. The remaining gel was deep frozen using a liquid nitrogen bath and lyophilized on a Lio 5 (Kambic) freeze dryer as necessary (approximately 1 day) to obtain 4.67 g of Formor I sodium as powder containing 8.40% water according to Karl Fischey's analysis (91% yield). The product is more than 99.5% pure by HPLC analysis.

Preparation of formor sodium atorvastatin II

Example 3

Φ Φ

To a solution of 5.00 g of tertiary butyl ester [R- (R, R)] -2- (4-fluorophenyl) -N, O-dihydroxy 5- (1-methylethyl) phenyl-4- [(phenylamino) carbonyl] -177 -pyrrol-1-heptanoic acid (8.13 mmol) in 17 mL of 1,4-dioxane and 15 mL of tert-butylmethyl ether was added a solution of 0.33 g of NaOH (8.25 mmol, 1.01 equivalent) in 30 mL. water. The reaction mixture was heated at reflux for 21 hours when the concentration of the starting compound was reduced to less than 0.1% as determined by HPLC, then cooled to room temperature and washed twice with 10 mL of tert-butyl methyl ether. The lower aqueous phase was partially concentrated under reduced pressure to remove tert-butyl methyl ether. Due to the initial foaming, the pressure must be carefully controlled. The evaporation was stopped at 52 mbar and the water bath temperature was 35 ° C when distillation of 1,4-dioxane began. The resulting solution was deep-frozen using a liquid nitrogen bath and lyophilized on a Lio 5 (Kambic) freeze dryer as needed (approximately 1 day) to obtain 4.79 g of Form II sodium atorvastatin as a white powder containing 3.76% water according to Karl Fischer's analysis (97.7% yield). The product is more than 99.5% pure by HPLC analysis.

Example 4

To a solution of 40.0 g of tertiary butyl ester [R- (R *, R *)] - 2- (4-fluorophenyl) -N, 6-dihydroxy 5- (1-methylethyl) phenyl-4 - [(phenylamino) carbonyl] - 177-Pyrrol-1-heptanoic acid (65 mmol) in 136 mL of tert-butanol and 120 mL of tert-butylmethyl ether was added a solution of 2.6 g of NaOH (65 mmol, equivalent) in 240 mL of water. The reaction flask was washed with an argon stream for 10 minutes and the cloudy mixture was heated at reflux temperature under an inert atmosphere for 4 hours when the initial compound concentration was reduced to about 2% as determined by HPLC. The reaction mixture was cooled to room temperature and washed three times with tert-butylmethyl ether (1 x 160 mL, 1 x 100 mL). The lower aqueous phase was partially concentrated under reduced pressure to remove tert-butyl methyl ether. The pressure is gradually reduced and the evaporation is stopped when distillate no longer collects at 400 mbar and a water bath temperature of 45 ° C. The resulting solution was diluted with 150 mL of tert-butanol, then deep-frozen using a liquid nitrogen bath and lyophilized as necessary (approximately 1 day) to give the product as a white powder. This material was further dried in vacuo, first at room temperature for about 4 hours and then at 50 ° C for 18 hours to obtain 34.70 g of sodium atorvastatin form II containing 3.83% water by Karl Fischei analysis (88.4 % profit). The product is more than 99.5% pure by HPLC analysis.

Preparation of sodium atorvastite form III

Example 5

A sample of atorvastatin sodium form II (1 g) was maintained at 40 ° C and 75% relative humidity in an open container for 14 days. Form II sodium atorvastatin is obtained after XRPD analysis.

Preparation of sodium atorvastatin Form IV

Example 6

To a mixture of 10.00 g of tertiary butyl ester [R- (R *, R *)] - 2- (4-fluorophenyl) -N, O-dihydroxy-5 (1-methylethyl) phenyl-4 - [(phenylamino) carbonyl ] - 1/7-pyrrol-1-heptanoic acid (16.26 mmol) in 34 mL of methanol was added a solution of 0.68 g of NaOH (17.0 mmol, 1.05 equivalent) in 60 mL of water. The mixture was heated at reflux for several hours until all the solid material had dissolved. The resulting solution was allowed to cool to room temperature and maintained at this temperature overnight. The solid was then filtered off and air-dried to give 5.60 g (ca. 59%) of sodium atorvastatin Form IV. The product is more than 99% pure by HPLC analysis.

Preparation of sodium atorvastatin Form V

Example 7

A mixture of 80.0 g of atorvastatin chemical salt (0.069 mol), 1500 mL of water, 900 mL of tetrahydrofuran and 100 mL of 5% hydrochloric acid solution was stirred at room temperature until a clear solution was obtained. The mixture was extracted with ethyl acetate, the combined extracts were dried with sodium sulfate and concentrated. The oily residue (ca. 87 g) was dissolved in 800 mL of methanol, then a solution of 6.0 g of NaOH (0.15 mol) in 150 mL of water was added and the mixture was heated at reflux for several hours. After cooling to room temperature, the resulting solution was partially concentrated and cooled in an ice bath. The solid was then filtered off and air-dried to give Form V sodium atorvastatin.

Preparation of amorphous atorvastatin sodium

Example 8

525 mL of tert-butyl methyl ether washed solution of atorvastatin sodium (0.138 M, 72.5 mmol) prepared according to Example 1 was spray dried on a Buchi 190 mini spray dryer using nitrogen as a drying gas under the following conditions: inlet temperature 130- 135 ° C, outlet temperature 58-62 ° C, nitrogen flow approx. 750 mL / min. The solid was collected and further dried in a vacuum oven for 3 days at room temperature and for 6 hours at 50 ° C. 29.87 g of amorphous atorvastatin sodium is obtained as a white powder containing 1.97% water by Karl Fischei's analysis (70% yield). The product is more than 99.5% pure by HPLC analysis.

Preparation of film-coated tablets (granulation in fluidized bed layers with organic solvent)

Example 9:

Component Amount per tablet / mg 1 atorvastastin Na 41,6 2 NaOH 2.0 3 sodium lauryl sulfate 8.0 4 hydroxypropyl cellulose 12,0 5 methanol about 0.3 6 lactose monohydrate 223,4 7 microcrystalline cellulose 70,0 8 croscarmellose sodium 20,0 9 crospovidone 20,0 10 magnesium stearate 3.0 In total 400

Sodium hydroxide is dissolved in methanol and atorvastatin sodium, sodium lauryl sulfate as well as hydroxypropyl cellulose are added. The resulting granular mixture (in the form of an opalescent solution) was sprayed onto lactose in a vortex granulator. The resulting granulate is dried and sieved and mixed with components 7 to 11 and compressed into tablets using round, slightly biconvex seals.

The resulting tablet cores were further coated with Opardy II HP (3% w / w coating) and optionally with Gelucire 50/13 (2%, lava macrogol glycerides) as the second layer. The tablets are packed in aluminum bags under reduced partial pressure of oxygen (3X% v / v oxygen, 10% v / v oxygen, 15% v / v oxygen).

The oxygen content of the blisters is measured using a mass spectrometer. An injection needle is used to sample the atmosphere in the blister. The process involves the removal of a single blister foil from a pharmaceutical pack containing atorvastatin tablets. A small amount of silicone sealant is applied to the top of the blister to form air permeable seal. Once dry, insert the needle into the sealant, taking care not to pierce the blister. The needle is then evacuated to remove any air / oxygen contamination before being inserted directly into the blister cavity, then headspace analysis is performed using a mass spectrometer and the oxygen concentration is calculated from the measured excess O2 + / N14N15 + ions.

Example 10:

Component Amount per tablet / mg 1 atorvastastin Na 41,6 2 NaOH 2.0 3 sodium lauryl sulfate 8.0 4 hydroxypropyl cellulose 12,0 5 methanol about 0.3 6 lactose monohydrate 223,4 7 microcrystalline cellulose 70,0 8 croscarmellose sodium 20,0 9 crospovidone 20,0

10 stearyl fumarate 3.0 In total 400

Sodium hydroxide is dissolved in methanol and atorvastatin sodium, sodium lauryl sulfate as well as hydroxypropyl cellulose are added. The resulting granular mixture (in the form of an opalescent solution) was sprayed onto lactose in a vortex granulator. The resulting granulate is dried and sieved and mixed with components 7 to 11 and compressed into tablets using round, slightly biconvex seals.

The resulting tablet cores were further coated with Opardy II HP (3% w / w coating) and optionally with Gelucire 50/13 (2% lauryl macrogol glycerides) as the second layer. The tablets are packed in aluminum bags under reduced oxygen partial pressure (3-4% v / v oxygen, 10% v / v oxygen, 15% v / v oxygen).

Example 11:

Component Amount per tablet / mg 1 atorvastastin Na 41,6 2 NaOH 2.0 3 sodium lauryl sulfate 8.0 4 hydroxypropyl cellulose 12,0 5 methanol about 0.3 6 lactose monohydrate 223,4 7 microcrystalline cellulose 70,0 8 croscarmellose sodium 20,0 9 crospovidone 20,0 10 hydrogenated vegetable oil 3.0 In total 400

Sodium hydroxide is dissolved in methanol and atorvastatin sodium, sodium lauryl sulfate as well as hydroxypropyl cellulose are added. The resulting granular mixture (in the form of an opalescent solution) was sprayed onto lactose in a vortex granulator. The resulting granulate is dried and sieved and mixed with components 7 to 11 and compressed into tablets using round, slightly biconvex seals.

The resulting tablet cores were further coated with Opardy II HP (3% w / w coating) and optionally with Gelucire 50/13 (2% lauryl macrogol glycerides) as the second layer. The tablets are packed in aluminum bags under reduced oxygen partial pressure (3-4% v / v oxygen, 10% v / v oxygen, 15% v / v oxygen).

Direct compression

Example 12:

Component Amount per tablet / mg 1 atorvastatin Na 41,6 2 At ₂ CO ₃ 18,0 3 sodium lauryl sulfate 8.0 4 Cellactose 80 213,4 5 microcrystalline cellulose (Avicel PH 102) 100,0 6 croscarmellose sodium 16.0 7 magnesium stearate 3.0 In total 400

Atorvastatin Na is first mixed with Na ₂ CO ₃ and sodium lauryl sulfate; mix other excipients except magnesium stearate. Finally, magnesium stearate is added and the compression mixture is compressed into cores. These cores are further coated with Opadry II HP (3% w / w coating).

The tablets are packed in aluminum bags under reduced oxygen vapor pressure.

Example 13:

Component Amount per tablet / mg 1 atorvastatin Na 41,6 2 sodium lauryl sulfate 8.0 4 Cellactose 80 219,4 5 microcrystalline cellulose (Avicel PH 102) 112,0 6 croscarmellose sodium 16.0 7 magnesium stearate 3.0 In total 400

Atorvastatin First mixed with lauryl sulfate sodium; other excipients other than magnesium stearate are mixed. Finally, magnesium stearate is added and the compression mixture is compressed into cores. These cores are further coated with Opadry II HP (3% w / w coating).

The tablets are packed in aluminum bags under reduced partial pressure of oxygen.

Example 14:

Component Amount per tablet / mg 1 atorvastatin Na 41,6 2 At ₂ CO ₃ 18,0 3 sodium lauryl sulfate 8.0 4 Cellactose 80 213,4 5 microcrystalline cellulose (Avicel PH 102) 100,0 6 croscarmellose sodium 16.0 7 stearyl fumarate 3.0 In total 400

Atorvastatin Na is first mixed with Na ₂ CO ₃ and sodium lauryl sulfate; other excipients other than stearyl fumarate are mixed. Finally, stearyl fumarate is added and the compression mixture is compressed into cores. These cores are further coated with Opadry II HP (3% w / w coating).

The tablets are packed in aluminum bags under reduced partial pressure of oxygen.

Example 15:

Component Amount per tablet / mg 1 atorvastatin Na 41,6 2 sodium lauryl sulfate 8.0 4 Cellactose 80 219,4 5 microcrystalline cellulose (Avicel PH 102) 112,0 6 croscarmellose sodium 16.0 7 stearyl fumarate 3.0 In total 400

Atorvastatin First mixed with lauryl sulfate sodium; other excipients other than stearyl fumarate are mixed. Finally, stearyl fumarate is added and the compression mixture is compressed into cores. These cores are further coated with Opadry II HP (3% w / w coating).

The tablets are packed in aluminum bags under reduced partial pressure of oxygen.

Example 16:

Component Amount per tablet / mg 1 atorvastatin Na 41,6 2 At ₂ CO ₃ 18,0 3 sodium lauryl sulfate 8.0 4 Cellactose 80 213,4 5 microcrystalline cellulose (Avicel PH 102) 100,0

6 croscarmellose sodium 16.0 7 hydrogenated vegetable oil 3.0 In total 400

Atorvastatin Na is first mixed with Na ₂ CO 3 and sodium lauryl sulfate; mix other excipients except hydrogenated vegetable oil. Finally, hydrogenated vegetable oil is added and the compression mixture is pressed into the cores. These cores are further coated with Opadry II HP (3% w / w coating).

The tablets are packed in aluminum bags under reduced partial pressure of oxygen.

Example 17:

Component amount per tablet / mg 1 atorvastatin Na 41,6 2 sodium lauryl sulfate 8.0 4 cellactose 80 219,4 5 microcrystalline cellulose (Avicel PH 102) 112,0 6 croscarmellose sodium 16.0 7 hydrogenated vegetable oil 3.0 In total 400

Atorvastatin First mixed with lauryl sulfate sodium; mix other excipients except hydrogenated vegetable oil. Finally, hydrogenated vegetable oil is added and the compression mixture is pressed into the cores. These cores are further coated with Opadry II HP (3% w / w coating).

The tablets are packed in aluminum bags under reduced partial pressure of oxygen.

Claims (21)

PATENT APPLICATIONS A new polymorphic form I sodium salt of atorvastatin, characterized in that the X-ray powder diffraction pattern comprises the following 2-theta 'values measured using CuKa irradiation: 4.3, 5.9, 8.7, 11.3, 12.2, 14.2, 19.0, 22.9 ± 0.2. 2. A new polymorphic form II of the sodium salt of atorvastatin, characterized in that the X-ray powder diffraction pattern contains the following 2-theta values modified using CuKa irradiation: 5.3, 8.3, 18.3 ± 0.2. 3. A new polymorphic form III of the atorvastatin sodium salt, characterized in that the X-ray powder diffraction pattern contains the following 2-theta values measured using CuKa irradiation: 5.6, 8.4, 9.5, 14.4, 16 , 2, 22.7 ± 0.2. 4. A new polymorphic form IV of the atorvastatin sodium salt, characterized in that the X-ray powder diffraction pattern contains the following 2-theta values modified using CuKa irradiation: 5.1, 5.7, 6.6, 8.5, 10 , 3, 13.4 and 18.8 ± 0.2. 5. A new polymorphic form V of the atorvastatin sodium salt, characterized in that the X-ray powder diffraction pattern contains the following 2-theta values modified using CuKa irradiation: 6.4, 8.1, 9.7, 10.5, 11 , 6, 18.9, 20.0 ± 0.2. 6. The amorphous sodium salt of atorvastatin. 7. New forms I, II, III, IV and V and the amorphous form of the atorvastatin sodium salt according to any one of claims 1 to 6 in the form of its hydrate or solvate. The atorvastatin sodium solvate or hydrate of claim 7, wherein said solvate is obtained from a solvent selected from the group consisting of water, alcohols, ketones and / or ethers. 9. A process for the preparation of atorvastatin sodium form I, comprising: i. ) partial evaporation of an aqueous solution of atorvastatin sodium containing a water miscible solvent which is optionally saturated with a water immiscible solvent to such a degree that the low melting point volatile solvents are completely removed and also that a gelatinous precipitate forms, and ii. ) complete removal of residual solvents. A process according to claim 9, characterized in that the water miscible co-solvent is methanol, 1,4-dioxane or tert-butanol and optionally the water miscible solvent is tert-butyl methyl ether. Process according to claim 9, characterized in that the complete removal of the remaining solvents is achieved by freezing the suspension, followed by freeze-drying under high vacuum. 12. A process for the preparation of atorvastatin sodium form II, comprising: i. ) partial evaporation of an atorvastatin sodium aqueous solution containing a water miscible co-solvent optionally saturated with a water miscible solvent to such a degree that the low melting volatile solvents are completely removed while must not expire, and ii. ) complete removal of residual solvents. A process according to claim 12, characterized in that the water miscible co-solvent is 1,4 dioxane or tert-butanol and is optionally a water miscible solvent tert-butyl methyl ether. Process according to claim 12, characterized in that the complete removal of the remaining solvents is achieved by freezing the suspension, followed by freeze-drying under high vacuum. 15. A process for the preparation of atorvastatin sodium form III, comprising contacting the atorvastatin sodium form II in contact with moist air at temperatures from about 20 ° C to about 80 ° C. 16. A process for the preparation of atorvastatin sodium form IV, comprising: i. ) hydrolysis of atorvastatin tert-butyl ester with sodium hydroxide in 20% to 50% aqueous methanol, preferably in 35% aqueous methanol at elevated temperatures, preferably at the reflux temperature of the mixture, and ii. cooling the reaction solution, preferably to room temperature, in order to carry out both precipitation and / or crystallization. 17. A process for the preparation of atorvastatin sodium form V, comprising: i. ) concentrating the atorvastatin sodium solution in 50% to 90% aqueous methanol, preferably in about 85% aqueous methanol, to about one-third of the original volume under reduced pressure; and ii. ) cooling the resulting solution to about 0 ° C in order to carry out both precipitation and / or crystallization. 18. A process for the preparation of amorphous atorvastatin sodium comprising spray drying of atorvastatin sodium solutions. A pharmaceutical formulation comprising as an active ingredient a member selected from amorphous sodium atorvastatin, sodium atorvastatin, form I, sodium atorvastatin, form II, sodium atorvastatin, form III, sodium atorvastatin, form IV or sodium hydrate, atorvate, form atorvastatin or a solvate thereof according to any one of claims 1 to 7, together with conventional pharmaceutically acceptable excipients, diluents, carriers and / or additives. The pharmaceutical formulation of claim 19 in the form of tablets, pills, dispersible granules, capsules, powders, lozenges or suppositories. 21. Use of a member selected from amorphous sodium atorvastatin, sodium atorvastatin, form I, sodium atorvastatin form II, sodium atorvastatin, form III, sodium atorvastatin, form IV or sodium atorvastatin, form V, or any hydrate or solvate thereof Claims 1 to 7, for the preparation of a pharmaceutical formulation useful for the treatment of hypercholesteremia or hyperlipidemia.