EP2049479A2 - Polymorphs of atorvastatin sodium and magnesium salts - Google Patents

Polymorphs of atorvastatin sodium and magnesium salts

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Publication number
EP2049479A2
EP2049479A2 EP07728152A EP07728152A EP2049479A2 EP 2049479 A2 EP2049479 A2 EP 2049479A2 EP 07728152 A EP07728152 A EP 07728152A EP 07728152 A EP07728152 A EP 07728152A EP 2049479 A2 EP2049479 A2 EP 2049479A2
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EP
European Patent Office
Prior art keywords
atorvastatin
hemi
sodium
magnesium
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07728152A
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German (de)
French (fr)
Inventor
Vesna Kroselj
Matej Smrkolj
Renata Osolnik
Jaroslav Tihi
Rok Zupet
Anton Stimac
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KRKA dd
Original Assignee
KRKA Tovarna Zdravil dd
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Publication date
Application filed by KRKA Tovarna Zdravil dd filed Critical KRKA Tovarna Zdravil dd
Publication of EP2049479A2 publication Critical patent/EP2049479A2/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the invention relates to new polymorphs of atorvastatin sodium and magnesium salts and their inclusion into pharmaceutical compositions which have an improved stability and bioavailability, as well as processes for their preparation.
  • Atorvastatin is a member of the class of drugs called statins.
  • Statins suppress cholesterol biosynthesis by competitively inhibiting 3-hydroxy-3-methyl-glutaryl- coenzyme A reductase which catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. They are currently the most therapeutically effective drugs available for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease.
  • Atorvastatin [R-(R * , R * )]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(1-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid, its lactone form and its alkali and earth alkali salts are known in the art, and processes for the preparation of atorvastatin and its key intermediates are disclosed in, for example, the United States 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 discloses the mono sodium, mono-potassium, hemi-calcium, N- methylglucamine, hemi-magnesium, hemi-zinc, and the 1-deoxy-1-(methylamino)-D- glucitol (N-methylglucamine) salts of atorvastatin.
  • US patent 6,583,295 discloses a series of amine salts of HMG-CoA reductase inhibitors which are used in a process for isolation and/or purification of these HMG-CoA reductase inhibitors. The tertiary butylamine and cyclohexylamine salts of atorvastatin are disclosed.
  • WO 2005/105738 discloses atorvastatin salts with ammonium, benethamine, benzathine, dibenzylamine, diethylamine, L-lysine, morpholine, olamine, piperazine, and 2-amino-2-methylpropan-1-ol and novel crystalline forms of the erbumine and sodium salt of atorvastatin.
  • the atorvastatin sodium salt polymorph was prepared from a mixture of acetonitrile and water, which process resulted in formation of gels. These gels, however, were difficult to handle from the industrial point of view as 6 days of stirring at ambient temperature were necessary in order to be able to isolate the product.
  • acetonitrile is not a very suitable solvent for the preparation of pharmaceutically active compounds as some of it remains in the pharmaceutically active compound as residual solvent. This is very disadvantageous as acetonitrile is a harmful solvent.
  • WO 2006/0210216 describes new polymorphs of atorvastatin potassium salt and their inclusion into solid oral dosage forms.
  • WO 2006/117761 discloses an atorvastatin hemi-magnesium salt, prepared from an alkali metal salt by contacting it with an organic or inorganic magnesium salt in the presence of a hydroxylic solvent.
  • WO 2007/020413 describes the preparation of atorvastatin sodium crystalline forms prepared from a mixture of an alcohol and a ketone.
  • the object of the present invention is to provide novel polymorphs of the sodium and hemi-magnesium salts of atorvastatin and processes for their preparation which are very suitable for use on an industrial scale.
  • a further object of the present invention is to provide pharmaceutical compositions including these polymorphs, in particular solid oral dosage forms .
  • Fig. 1 shows photographs and the X-ray powder diffraction pattern of Form I atorvastatin sodium according to the invention.
  • Fig. 2 shows photographs and the X-ray powder diffraction pattern of Form Il atorvastatin sodium according to the invention.
  • Fig. 3 shows photographs and the X-ray powder diffraction pattern of Form III atorvastatin sodium according to the invention.
  • Fig. 4 shows photographs and the X-ray powder diffraction pattern of Form IV atorvastatin sodium according to the invention.
  • Fig. 5 shows photographs and the X-ray powder diffraction pattern of Form V atorvastatin sodium according to the invention.
  • Fig. 6 shows photographs and the X-ray powder diffraction pattern of amorphous atorvastatin sodium according to the invention.
  • Fig. 7 shows the X-ray powder diffraction pattern of Form I atorvastatin hemi- magnesium according to the invention.
  • Fig. 8 shows the X-ray powder diffraction pattern of Form Il atorvastatin hemi- magnesium according to the invention.
  • Fig. 9 shows the X-ray powder diffraction pattern of Form III atorvastatin hemi- magnesium according to the invention.
  • Fig. 10 shows the X-ray powder diffraction pattern of Form IV atorvastatin hemi- magnesium according to the invention .
  • Fig. 11 shows the X-ray powder diffraction pattern of Form V atorvastatin hemi- magnesium according to the invention.
  • Fig. 12 shows the X-ray powder diffraction pattern of Form Vl atorvastatin hemi- magnesium according to the invention.
  • Fig. 13 shows the X-ray powder diffraction pattern of Form VII atorvastatin hemi- magnesium according to the invention.
  • Fig. 14 shows the X-ray powder diffraction pattern of Form VIII atorvastatin hemi- magnesium according to the invention.
  • Fig. 15 shows the X-ray powder diffraction pattern of Form IX atorvastatin hemi- magnesium according to the invention.
  • Fig. 16 shows the X-ray powder diffraction pattern of amorphous atorvastatin hemi- magnesium according to the invention. Summary of the invention
  • new polymorphs and amorphous forms of the sodium and hemi-magnesium salt of atorvastatin are provided, which have improved solubility and other beneficial characteristics, and processes for their preparation.
  • compositions including them and in particular solid oral pharmaceutical dosage forms comprising also conventional pharmaceutically acceptable excipients, such as diluents, carriers, and/or other additives.
  • novel polymorphs of atorvastatin sodium salt are prepared by crystallization and/or precipitation or by complete removal of the solvent from purified solutions of atorvastatin sodium by means of freeze-drying or spray-drying.
  • atorvastatin sodium Purified solutions of atorvastatin sodium are available through hydrolysis of either [R- (R * ,R * )]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(1-methylethyl)phenyl-4-[(phenylamino)- carbonyl]-1H-pyrrole-1-heptanoic acid tertiary butyl ester (atorvastatin te/t-butyl ester) or atorvastatin lactone with aqueous sodium hydroxide, or neutralization of atorvastatin free acid with aqueous sodium hydroxide in a water miscible solvent, followed by washing the mixture with a suitable water-immiscible solvent.
  • Aqueous solutions of sodium atorvastatin suitable for the freeze drying procedure are those containing water miscible co-solvents of reasonable volatility at low temperatures and a relatively high melting point, e.g. 1 ,4-dioxane or te/t-butanol.
  • Aqueous suspensions of atorvastatin sodium containing no or small amount of co- solvents are also applicable.
  • Aqueous solutions of sodium atorvastatin suitable for the spray-drying procedure are those containing water miscible co-solvents, e.g. aliphatic alcohols, such as methanol, ethanol, isopropanol, te/t-butanol; ketones such as acetone; ethers such as tetrahydrofuran or 1 ,4-dioxane; or the mixtures of water, water miscible and water immiscible solvents, such as the combination of water, alcohols, ketones, ethers, etc.
  • Non-aqueous solutions of atorvastatin sodium are also suitable for spray drying.
  • the gas carrier for the spray drying may be selected from air, nitrogen, or argon.
  • Atorvastatin sodium Form I may be prepared by partial evaporation of an aqueous solution of atorvastatin sodium containing a water miscible co-solvent, such as methanol, 1 ,4-dioxane or te/t-butanol, optionally being saturated with a water immiscible solvent, such as te/t-butyl methyl ether, to such a degree that volatile, low melting co-solvents are completely removed, and also that gelatinous precipitate is formed.
  • the residual solvents are then removed completely, preferably by freezing the suspension, followed by freeze drying under high vacuum.
  • Atorvastatin sodium Form Il according to the invention may be prepared by partial evaporation of an aqueous solution of atorvastatin sodium containing a water miscible co-solvent, such as te/t-butanol or 1 ,4-dioxane, optionally being saturated with water immiscible solvent, such as te/t-butyl methyl ether, to such a degree that volatile, low melting co-solvents are completely removed, while precipitation should not take place.
  • the residual solvents from the resulting solution are then removed completely, preferably by freezing the solution, followed by freeze drying under high vacuum.
  • Atorvastatin sodium Form III may be prepared by contacting Form Il with humid air at temperatures from about 20 0 C to about 80 0 C.
  • Atorvastatin sodium Form IV may be prepared by a process which comprises hydrolysis of atorvastatin tert-butyl ester with sodium hydroxide, in 20% to 50% (v/v) aqueous methanol, preferably in about 35% (v/v) aqueous methanol, at elevated temperatures, preferably at the reflux temperature of the mixture. After the hydrolysis procedure is complete, the reaction solution is allowed to cool, preferably to room temperature, in order to effect precipitation and/or crystallization.
  • Atorvastatin sodium Form V may be prepared by a process which comprises concentrating a solution of atorvastatin sodium in 50% to 90% (v/v) aqueous methanol, preferably in about 85% (v/v) aqueous methanol, to about one third of the original volume under reduced pressure, and cooling of the resulting solution to about 0 0 C in order to effect precipitation and/or crystallization.
  • Amorphous form atorvastatin sodium according to the invention may be prepared by spray-drying of solutions of atorvastatin sodium.
  • Atorvastatin hemi-magnesium salts are prepared by crystallization and/or precipitation.
  • Atorvastatin hemi-magnasium salt may be prepared from a solution of atorvastatin sodium salt by addition of a magnesium organic or inorganic salt, e.g. as is disclosed in Example 9.
  • a magnesium organic or inorganic salt e.g. as is disclosed in Example 9.
  • Primarily Form I or Form Il of atorvastatin hemi-magnesium is formed which upon drying transforms into other polymorphic forms, in particular into Form II.
  • Atorvastatin hemi-magnesium salt Form Il may be prepared by dissolving atorvastatin Mg in a solvent from the group comprised of acetone, ethanol, methanol, 1-butanol or 2-butanol, at an elevated temperature between 30 0 C to the reflux temperature, cooling to room temperature and adding water in an amount between 5 to 50 ml/ 1g of atorvastatin Mg, and/or hydrocarbon solvent, such as e.g. pentane, hexane, heptane or cyclohexane.
  • a solvent from the group comprised of acetone, ethanol, methanol, 1-butanol or 2-butanol
  • Atorvastatin hemi-magnesium salt Form III may be prepared by slurrying atorvastatin magnesium salt in water, at a temperature of the boiling point of the suspension.
  • Atorvastatin hemi-magnesium salt Form IV may be prepared by dissolving atorvastatin Mg in methanol and precipitating by the addition of water (1-4 parts, v/v) at a temperature between 20 0 C and 40°C.
  • Atorvastatin hemi-magnesium salt Form V according to the invention may be prepared by slurrying atorvastatin magnesium salt under magnetical stirring in water, at an elevated temperature between 40°c and 70 0 C.
  • Atorvastatin hemi-magnesium salt Form Vl according to the invention is prepared by dissolving atorvastatin Mg in a solvent from the group comprised of ethyl acetate, ethanol, methanol, 1-butanol or 2-butanol, at a temperature between 20 0 C and the boiling point, and adding water in an amount between 0.5 to 30 ml/ 1g of atorvastatin Mg. Water may also be added before heating the solution to a temperature between 20 0 C to the reflux temperature of the solution.
  • Atorvastatin hemi-magnesium salt Form VII is prepared by dissolving atorvastatin Mg in a solvent from the group comprised of ethanol or 1- butanol and water in an amount between 10 to 20 ml/ 1g of atorvastatin Mg, at a temperature between 50 0 C and the reflux temperature of the solution, and cooling the solution to room temperature. Water may also be added before heating the solution to a temperature between 20 0 C to the reflux temperature of the solution.
  • Atorvastatin hemi-magnesium salt Form VIII according to the invention may be prepared by slurrying atorvastatin magnesium salt under mechanical stirring or magnetical stirring in water, in an amount of between 0.0005 and 0.07g of atorvastatin Mg/ml of water, and at an elevated temperature between 20°C and 70°C.
  • Atorvastatin hemi-magnesium salt Form IX is prepared by dissolving atorvastatin Mg in a mixture of an alcohol, such as ethanol, and water, and leaving to crystallize for prolonged periods of time, e.g. for 3-20 days at room temperature.
  • Amorphous form atorvastatin hemi-magnesium according to the invention is prepared by:
  • atorvastatin hemi-magnesium in 2-propanol or acetonitrile or precipitating atorvastatin hemi-magnesium from a solution in alcohol or ketone (ethylmethyl ketone) by addition of a hydrocarbon.
  • the x-ray powder diffraction patterns of the polymorphs and amorphous forms according to the invention were obtained by using a Phillips PW3040/60 X'Pert PRO diffractometer; and CuK 0 , radiation 1 ,541874 Angstrom wavelength.
  • Polymorphic form I of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 4.3, 5.9, 8.7, 11.3, 12.2, 14.2, 19.0, 22.9 ⁇ 0.2.
  • Polymorphic form Il of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 5.3, 8.3, 18.3 ⁇ 0.2.
  • Polymorphic form III of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 5.6, 8.4, 9.5, 14.4, 16.2, 22.7 ⁇ 0.2.
  • Polymorphic form IV of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 5.1 , 5.7, 6.6, 8.5, 10.3, 13.4 and 18.8 ⁇ 0.2.
  • Polymorphic form V of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 6.4, 8.1 , 9.7, 10.5, 11.6, 18.9, 20.0 ⁇ 0.2.
  • Polymorphic form I of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 4.8, 7.2, 8.8, 18.2, 18.9 ⁇ 0.2.
  • Polymorphic form Il of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 3.1 , 9.1 , 11.6, 12.4, 14.3, 18.5, 19.2 ⁇ 0.2.
  • Polymorphic form III of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 7.6, 9.1 , 9.6, 12.1 , 20.1 , 22.4 ⁇ 0.2.
  • polymorphic form III of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 7.6, 9.1 , 9.6, 12.1 , 13.4, 14.2, 14.8, 15.5, 16.7, 17.3, 18.0, 20.1 , 22.4, 23.9, 27.2 ⁇ 0.2.
  • Polymorphic form IV of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 3.2, 8.9, 11.6, 17.3, 18.5, 22.0, 28.1 ⁇ 0.2.
  • Polymorphic form V of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 7.6, 9.5, 11.7, 20.0, 21.9, 24.1 ⁇ 0.2.
  • polymorphic form V of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 6.2, 7.6, 9.5, 11.7, 12.5, 13.5, 15.6, 18.7, 20.0, 21.9, 24.1 ⁇ 0.2.
  • Polymorphic form Vl of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 8.5, 12.0, 14.3, 18.4, 19.2, 20.1 ⁇ 0.2.
  • polymorphic form Vl of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 4.5, 5.7, 8.5, 12.0, 14.3, 18.4, 19.2, 20.1 ⁇ 0.2.
  • Polymorphic form VII of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 5.7, 8.5, 9.1 , 11.8, 18.2 ⁇ 0.2.
  • Polymorphic form VIII of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 8.6, 10.0, 11.5, 16.5, 20.1 , 21.6, ⁇ 0.2.
  • polymorphic form VIII of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 5.7, 7.2, 8.6, 10.0, 10.7, 11.5, 12.3, 14.3, 16.5, 17.7, 20.1 , 21.6, 23.0 ⁇ 0.2.
  • Polymorphic form IX of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 3.3, 8.9, 9.2, 9.9, 18.2, 21.9, 23.3 ⁇ 0.2.
  • polymorphic form IX of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 3.3, 7.4, 8.9, 9.2, 9.9, 11.6, 11.9, 12.4, 14.8, 16.5, 17.4, 18.2, 18.8, 19.9, 21.9, 23.3, 24.0, 24.9, 28.3, 30.0 ⁇ 0.2.
  • the polymorph forms and the amorphous form of atorvastatin sodium and hemi- magnesium according to the invention can also be present as solvates thereof.
  • These solvates include for example water, to result in hydrates, or other solvents, in particular alcohols, ketone or ethers, and mixtures thereof.
  • the invention also relates to a pharmaceutical composition comprising at least one of the polymorph or amorphous forms according to the invention, and at least one pharmaceutically acceptable excipient.
  • compositions of the polymorphic or amorphous forms of the sodium or hemi- magnesium salt of atorvastatin according to the invention can be solid, semi-solid or liquid.
  • Solid compositions include powders, granules, tablets, capsules, sachets, suppositories, and dispersible granules.
  • the compositions according to the invention of the atorvastatin sodium or hemi-magnesium forms are tablets, most preferably film-coated tablets.
  • the solid dosage form compositions may be, for example, an immediate release dosage form, a fast melt dosage form, a controlled release dosage form, a lyophilized dosage form, a delayed release dosage form, en extended release dosage form, a pulsatile release dosage form, a mixed immediate release and a controlled release dosage form, or a combination thereof.
  • the solid dosage form composition according to this invention is preferably an immediate release dosage form offering advantages regarding the bioavailability and the stability of the active compound.
  • compositions of atorvastatin sodium or hemi-magnesium forms according to the invention may be prepared by well known technological processes 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 polymorphic and amorphous forms according to the invention can be processed to tablets with an acceptable content uniformity.
  • the relative standard deviation of the content uniformity of the tablets (and eventually of the film coated tablets) is less than 10 %, preferably less than 5 %, even more preferably less than 3 %.
  • compositions according to the invention also provide free flow of the compression mixtures, which are suitable for compression into tablets and preferably, further film coating.
  • Excipients useful in the compositions of the invention are selected from the group of diluents/fillers, disintegrants, binders, lubricants, glidants, stabilizers, solubilizers, sweetening agents, flavouring agents etc.
  • the excipients present in the compositions according to the invention can be diluents such as lactose in different 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, lactitol, xylitol, sorbitol, calcium hydrogen phosphate, calcium carbonate, calcium lactate or combinations of diluents.
  • Starches such as pregelatinized starch, can also be used as a diluent.
  • the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.
  • diluents selected from microcrystalline cellulose and lactose monohydrate.
  • composition according to the invention may also comprise binders, such as povidone, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose (comprising from 5 to 16% by weight of hydroxypropyl groups), hydroxypropylmethyl cellulose or other cellulose ethers, starch, pregelatinised starch or polymethacrylate or mixture of binders. It is preferred that the excipients include at least one binder selected from cellulose or its derivatives. If a wet granulation process is applied, hydroxypropyl cellulose is preferably used as binder.
  • binders such as povidone, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose (comprising from 5 to 16% by weight of hydroxypropyl groups), hydroxypropylmethyl cellulose or other cellulose ethers, starch, pregelatinised star
  • disintegrants and/or superdisintegrants may also be present such as starches (e.g. maize starch, potato starch), modified starches (sodium starch glycolate), modified cellulose (croscarmellose, i.e. cross-linked carboxymethyl- cellulose sodium), cross-linked polyvinylpyrrolidone (crospovidone), microcrystalline cellulose, carboxymethylcellulose sodium, Amberlite ® , alginic acid, sodium alginate, guar gum, gellan gum, Xanthan SM ® or calcium silicate. If used as a disintegrant, microcrystalline cellulose is preferably used in an amount of 5 to 15% by weight.
  • the excipients include at least one disintegrant or superdisintegrant selected from croscarmellose, crospovidone and microcrystalline cellulose. If necessary, a combination of two or more disintegrants can be used, for example, croscarmelose sodium, crospovidone and microcrystalline cellulose.
  • lubricants may also be present as excipients, such as stearic acid, magnesium stearate, calcium stearate, sodium laurylsulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, macrogols. It is preferred that the excipients include at least one lubricant selected from magnesium stearate, sodium stearyl fumarate or hydrogenated vegetable oil.
  • Excipents may also have multiple functions, i.e. one excipient may be diluent and additionally binder, binder and disintegrant etc.
  • surfactants can be included in a solid pharmaceutical composition.
  • Surfactants can be selected from the group of non-ionic or ionic surfactants or mixtures thereof.
  • Suitable non-ionic surfactants are selected from the group of alkylglucosides, alkylmaltosides, alkylthioglukosides, lauryl macrogolglycerides, polyoxyethylene alkylphenols, polyoxyethylene alkylethers, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, polyglyceryl fatty acid esters, polyoxyethylene glycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, sterols, and mixtures thereof.
  • Preferred non-ionic surfactants are polyoxyethylene sorbitan fatty acid esters, which are sold under the trade names Polysorbate or Tween.
  • Suitable ionic surfactants are selected from the group of fatty acid salts, bile salts, phospholipides, phosphoric acid esters, carboxylates, sulphates, sulphonates and mixture thereof.
  • a preferred ionic surfactant is sodium laurylsulphate.
  • the pharmaceutical composition according to the invention may comprise from 0.1 - 5 %, preferably 0.2 - 4 % by weight of a surfactant, most preferably 0.3 - 3 %.
  • the pharmaceutical composition according to the invention can also comprise a stabilizer.
  • Basifying agents or buffers can be used as stabilizers, for example, alkali metal compounds or earth alkali metal compounds.
  • alkali metal additives such as for example sodium hydroxide, sodium superoxide, sodium carbonate, sodium hydrogencarbonate, sodium phosphate, sodium hydrogenphosphate or sodium salts with organic acids (for example sodium citrate or sodium tartrate) potassium hydroxide, potassium superoxide, potassium carbonate, potassium hydrogencarbonate, potassium phosphate, potassium hydrogenphosphate or potassium salts with organic acids (for example potassium citrate or potassium tartrate) are used.
  • the composition usually comprises 0.01 % to 20 %, preferably 0.1 % to 15 % and most preferred 0.2 % to 10 % by weight of the alkali metal additive.
  • the composition according to the invention contains the polymorphic and amorphous forms of the sodium or magnesium salt of atorvastatin according to the invention as active ingredient, optionally an alkali metal additive selected from sodium and potassium compounds, and the composition is optionally exposed to an atmosphere comprising 1 to 16 % by volume of oxygen.
  • the composition contains the polymorph forms of atorvastatin sodium or hemi- magnesium as the active ingredient, sodium hydroxide or sodium carbonate as basifying agents and is optionally exposed to an atmosphere comprising 1 to 16 % by volume of oxygen.
  • the composition is present in a packaging, with a blister packaging or a bottle being preferred.
  • a packaged composition is formed.
  • the packaging can be provided with means for trapping and disposal of free oxygen.
  • the composition is preferably enclosed in a substantially gas exchange non-permeable material as packaging which has an atmosphere with the required reduced oxygen content.
  • the substantially gas exchange non-permeable packaging is preferably selected from the group consisting of an AI/AI blister package, an Al- polychloro-3-fluoroethylene homopolymer/PVC laminate blister or a bottle.
  • compositions may be applied, e.g. direct compression, wet or dry granulation etc, to obtain the composition according to the invention.
  • the composition is preferably in the form of coated tablets.
  • the coating can be made of conventional materials used for film coating.
  • Film coating formulations usually contain the following components: polymer(s), plasticizer(s), colourant(s)/opacifier(s), vehicle(s) and optionally, flavours, surfactants and waxes in minor quantities.
  • Cellulose derivatives such as the cellulose ethers (hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose) or acrylic polymers and co-polymers, high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials can be used as coating agents.
  • hydroxypropyl cellulose or polyvinyl alcohol are used as coating polymers.
  • the useful plasticizers may be categorized into three groups: polyols (glycerol, propylene glycol, macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, triacetin), and oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).
  • polyols glycerol, propylene glycol, macrogols
  • organic esters phthalate esters, dibutyl sebacetate, citrate esters, triacetin
  • oils/glycerides castor oil, acetylated monoglycerides, fractionated coconut oil.
  • Colourants/opacifiers can be selected from the groups of organic dyes or inorganic colours.
  • Film coating suspensions can be used as ready-to-make preparations that are available on the market.
  • commercially available ready to make mixtures such as different Opadry® (of Colorcon) mixtures are used.
  • Film coating dispersion can be prepared by using different solvents such as water, alcohols, ketones, esters, chlorinated hydrocarbons, preferably water.
  • composition according to the invention can also contain a coating with waxy materials such Gelucire.
  • Gelucire coatings are particularly effective when preventing environmental gases to ingress into tablet cores, either when applied alone or in combination with coatings based on carboxymethylcellulose sodium (NaCMC) or polyvinyl alcohol (PVA).
  • Gelucire compositions are inert semi-solid waxy materials which are amphiphilic in character and are available with varying physical characteristics. They are surface active in nature and disperse or solubilize in aqueous media forming micelles, microscopic globules or vesicles. They are identified by their melting point/HLB value.
  • the melting point is expressed in degrees Celsius and the HLB (Hydrophile-Lipophile Balance) is a numerical scale extending from 0 to approximately 20.
  • the large family of Gelucire compositions is characterized by a wide range of melting points of from about 33 0 C to about 64 0 C and most commonly from about 35 0 C to about 55 0 C, and by a variety of HLB values of from about 1 to about 14, most commonly from about 7 to about 14.
  • Gelucire 50/13 designates a melting point of approximately 5O 0 C and an HLB value of about 13.
  • Gelucire 50/13 has been found to be particularly effective when coating the composition according to the invention. It is composed of fatty acid (majority of Ci6 and Cis) esters of glycerol, PEG esters and free PEG (lauryl macrogol glycerides).
  • the coatings can be applied by the process of melt coating or solutions/dispersions in water or organic solvents can be used as coating suspensions.
  • composition according to the invention For preparing the composition according to the invention, different technological processes can be applied, such as direct compression, dry granulation, wet granulation (with water or organic solvents), spray drying, freeze drying etc.
  • active ingredient is mixed together with excipients and compressed.
  • Solid dosage forms of composition e.g. tablet cores
  • Excipients may optionally be processed before mixing with the active ingredient, for example by wet granulation, using either water or organic solvent or mixture thereof as granulating liquid.
  • Suitable mixing devices for the direct compression or optionally the wet granulation process as described above is conventional equipment used for mixing of active ingredients, excipients or combination of active ingredient(s) and excipients.
  • the equipment is chosen from standard equipment for example high shear granulator or fluid bed granulator.
  • Magnetical stirring was performed by: Magnetic stirrer IKAMAG RCT basic, Janke- Kunkel GmbH, IKA Labortechnik, stirring speed 200-600 rpm
  • the reaction mixture was heated at reflux temperature 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 te/t-butyl methyl ether (1 x 30 ml, 1 x 10 ml).
  • the lower aqueous phase was partially concentrated under reduced pressure in order to remove most of te/f-butyl methyl ether and methanol. Due to the initial foaming, pressure must be carefully controlled. Evaporation was interrupted when no more distillate was collecting in the receiver at 47 mbar and a temperature of a water bath of 38 0 C.
  • the residual gel was deep frozen using liquid nitrogen bath and lyophilized on a Lio 5 (Kambic) freeze dryer as necessary (about 1 day) to yield 4.59 g of sodium atorvastatin Form I as a powder containing 6.53% of water according to Karl Fischer analysis (91 % yield). The product was 99.4% pure by HPLC analysis.
  • the turbid mixture was heated at reflux temperature 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 te/t-butyl methyl ether (1 x 20 ml, 1 x 10 ml).
  • the lower aqueous phase was partially concentrated under reduced pressure in order to remove tert- butyl methyl ether.
  • the pressure was reduced gradually and the evaporation was interrupted at 70 mbar and a temperature of a water bath of 38 0 C.
  • the residual gel was deep frozen using liquid nitrogen bath and lyophilized on a Lio 5 (Kambic) freeze dryer as necessary (about 1 day) to yield 4.67 g of sodium atorvastatin Form I as a powder containing 8.40% of water according to Karl Fischer analysis (91% yield).
  • the product was more than 99.5% pure by HPLC analysis.
  • the reaction mixture was heated at reflux temperature 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 te/f-butyl methyl ether. The lower aqueous phase was partially concentrated under reduced pressure in order to remove te/t-butyl methyl ether. Due to the initial foaming, pressure must be carefully controlled. Evaporation was interrupted at 52 mbar and a temperature of a water bath of 35 0 C, when the distillation of 1 ,4-dioxane commenced.
  • the resulting solution was deep frozen using liquid nitrogen bath and lyophilized on a Lio 5 (Kambic) freeze dryer as necessary (about 1 day) to yield 4.79 g of sodium atorvastatin Form Il as a white powder containing 3.76% of water according to Karl Fischer analysis (97.7% yield).
  • the product was more than 99.5% pure by HPLC analysis.
  • the reaction flask was purged with argon flow for 10 min and the turbid mixture was heated at reflux temperature under inert atmosphere for 4 hours when the concentration of the starting compound was reduced to about 2 % as determined by HPLC.
  • the reaction mixture was cooled to room temperature and washed three times with te/t-butyl methyl ether (1 x 160 ml, 2 x 100 ml).
  • the lower aqueous phase was partially concentrated under reduced pressure in order to remove te/t-butyl methyl ether.
  • the pressure was reduced gradually and the evaporation was interrupted when no more distillate was collecting in the receiver at 400 mbar and a temperature of a water bath of 45 0 C.
  • the resulting solution was diluted with 150 ml of te/t-butanol, then deep frozen using liquid nitrogen bath and lyophilized as necessary (about 1 day) to yield the product as a white powder.
  • This material was further dried in vacuum, first at room temperature for about 4 hours, then at 50 0 C for 18 h to provide 34.70 g of sodium atorvastatin Form Il containing 3.83% of water according to Karl Fischer analysis (88.4% yield).
  • the product was more than 99.5% pure by HPLC analysis.
  • atorvastatin hemi-magnesium salt form Il 1.0 g was dissolved in 9 ml of acetone by heating to reflux. The solution was cooled to room temp, and 8.5 ml of water were added dropwise. The mixture was stirred for 1 h, filtered and dried, first air-dried overnight, then in vacuum at 50 0 C for 5 h. 0.8 g of atorvastatin hemi-magnesium salt form Il were obtained.
  • atorvastatin hemi-magnesium salt form Il 5.0 g of atorvastatin hemi-magnesium salt form Il were dissolved in 65 ml of 96% ethanol by heating to reflux. While stirred magnetically, the solution was cooled to room temp, and 60 ml of water were added dropwise. The mixture was stirred for additional 15 min and the precipitate was filtered and air-dried to give 3.94 g of atorvastatin hemi-magnesium salt form II.
  • atorvastatin hemi-magnesium salt form Il 5.0 g of atorvastatin hemi-magnesium salt form Il were dissolved in 50 ml of 96% ethanol by heating to reflux. While stirred mechanically, the solution was cooled to room temp, and 50 ml of water were added dropwise. The mixture was stirred for additional 15 min and the precipitate was filtered and air-dried to give 4.06 g of atorvastatin hemi-magnesium salt form II.
  • atorvastatin hemi-magnesium salt form Il 1.01 g of atorvastatin hemi-magnesium salt form Il were dissolved in 7 ml of acetone by stirring at room temp, for about 4 days. To the resulting solution were added sequentially hexane (20 ml) and water (20 ml). Solid precipitated upon addition of water, which was filtered and air-dried to give 0.91 g of atorvastatin hemi-magnesium salt form II.
  • atorvastatin hemi-magnesium salt form Il 1.01 g of atorvastatin hemi-magnesium salt form Il were dissolved in 30 ml of 90% aqueous ethanol by heating to reflux. The solution was cooled to room temp., then hexane (10 ml) and water (30 ml) were added seqentially. After stirring at room temp, for 10 min the gelatinuous suspension was filtered and air-dried to give 0.835 g of atorvastatin hemi-magnesium salt form II.
  • atorvastatin hemi-magnesium salt form Il 1.0 g
  • water (20 ml) was added dropwise at room temp.
  • the resulting suspension was stirred for further 10 min, then filtered and air-dried to give 0.93 g of atorvastatin hemi-magnesium salt form IV.
  • atorvastatin hemimagnesium salt form Il 0.206 g were dissolved in 1 ml of ethyl acetate by heating to reflux. The solution was cooled to room temp, and about 0.1 ml of water were added dropwise. Oily material separated, which was allowed to stay for 8 days at room temp. The resulting solid was filtered and air-dried overnight to give 0.20 g of atorvastatin hemi-magnesium salt form Vl.
  • atorvastatin hemi-magnesium salt form Il 0.206 g were dissolved in 0.4 ml of methanol by heating to reflux. The solution was cooled to room temp, and about 0.1 ml of water were added dropwise. The resulting solid was allowed to stay overnight, filtered and air-dried to give 0.187 g of atorvastatin hemi-magnesium salt form Vl mixed with an additional phase.
  • a suspension of atorvastatin hemi-magnesium salt form Il (1.01 g) in 20 ml of ethanol was placed into an ultrasonic bath for 2 min. 14 ml of water were added and the mixture placed into the ultrasonic bath for another 2 min. The resulting solution was kept at room temp, without stirring for 14 days during which time slow growth of crystals was observed. The crystals were filtered and air-dried to give 0.45 g of atorvastatin hemi-magnesium salt form IX.
  • atorvastatin hemi-magnesium salt form Il 1.0 g was dissolved in 40 ml of abs. ethanol by heating to reflux. The solution was cooled to room temp, and concentrated in vacuum to give 1.05 g of amorphous atorvastatin hemi-magnesium salt.
  • atorvastatin hemi-magnesium salt form Il were dissolved in 1 ml of acetonitrile by heating to reflux. The mixture was stirred at room temperature overnight. The resulting suspension was cooled in an ice bath for 20 min, then filtered and air-dried overnight to give 0.126 g of the amorphous atorvastatin hemi- magnesium salt.
  • atorvastatin hemi-magnesium salt form Il 0.211 g of atorvastatin hemi-magnesium salt form Il were dissolved in 0.9 ml of 2- propanol by heating to reflux. The mixture was stirred at room temp, overnight. The resulting suspension was cooled in an ice bath for 30 min, then filtered and air-dried to give 0.18 g of the amorphous atorvastatin hemi-magnesium salt.
  • atorvastatin hemi-magnesium salt form Il 1.025 g of atorvastatin hemi-magnesium salt form Il were dissolved in 20 ml of 1- butanol by heating to reflux. The solution was cooled to room temp, and 20 ml of pentane were added. After stirring at room temp, for 10 min, the solid was filtered and air-dried to give 0.33 g of the amorphous atorvastatin hemi-magnesium salt.
  • atorvastatin hemi-magnesium salt form Il 1.01 g of atorvastatin hemi-magnesium salt form Il were dissolved in 5 ml of ethylmethyl ketone by stirring at room temp, for 17 h followed by addition of pentane (14 ml). A semisolid precipitate formed which solidified completely in about half an hour. After stirring at room temp, for 30 min, the solid was filtered and air-dried to give 0.80 g of the amorphous atorvastatin hemi-magnesium salt.
  • atorvastatin hemi-magnesium salt form Il 1.0 g was dissolved in 7 ml of 2-propanol by heating to reflux for 1 h. The mixture was stirred at room temp, overnight. The resulting suspension was filtered and air-dried to give 0.88 g of the amorphous atorvastatin hemi-magnesium salt.
  • atorvastatin hemi-magnesium salt form Il 1.03 g of atorvastatin hemi-magnesium salt form Il were dissolved in a mixture of 1- butanol (10 ml) and abs. ethanol (10 ml) by heating to reflux. The solution was stirred at room temp, overnight, then hexane (25 ml) was added. After stirring at room temp, for 10 min the solid was filtered and air-dried to give 0.52 g of the amorphous atorvastatin hemi-magnesium salt.
  • the atorvastatin Na or Mg used in the following examples was either one of the polymorph or the amorphous forms according to the invention.
  • the sodium hydroxide was dissolved in methanol and atorvastatin sodium, sodium laurylsulfate as well as hydroxypropyl cellulose were added.
  • the obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 7 to 10 and pressed into tablet cores using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer.
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
  • the oxygen content in blisters was measured using a mass spectrometer.
  • a syringe needle was used for sampling of the blister atmosphere.
  • the method involved removing a single foil blister from a pharmaceutical package containing atorvastatin tablets. On to the top of the blister was applied a small amount of silicon sealant to form an airtight seal. Once dry, a syringe needle was inserted into the sealant being careful not to pierce the blister. The needle was then evacuated to remove any air/oyxgen contamination before being inserted directly into the blister cavity. Headspace analysis was then performed using a mass spectrometer and the oxygen concentration was calculated from the measured 02+/Ni 4 Ni 5 + ion abundance ratio.
  • the sodium hydroxide was dissolved in methanol and atorvastatin sodium, sodium laurylsulfate as well as hydroxypropyl cellulose were added.
  • the obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 7 to 10 and pressed into tablets cores using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer.
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
  • the sodium hydroxide was dissolved in methanol and atorvastatin sodium, sodium laurylsulfate as well as hydroxypropyl cellulose were added.
  • the obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 7 to 10 and pressed into tablets cores using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer.
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
  • the hydroxypropyl cellulose was dissolved in isopropyl alcohol and sodium phosphate tribasic, sodium atorvastatin and sodium laurylsulfate were added.
  • the obtained granulating mixture (in the form of a suspension) was sprayed onto the sucrose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 6 to 9 and pressed into tablet cores using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating).
  • Example 41 The tablets were packed in aluminium bags under reduced oxygen partial pressure and in air and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC.
  • Example 41 The tablets were packed in aluminium bags under reduced oxygen partial pressure and in air and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC.
  • Example 41 The degradation products were determined by HPLC.
  • a 0,6 kg batch was prepared.
  • Sodium atorvastatin and Gelucire were mixed in a double-wall high-shear mixer. During the granulation process the external space of the mixer was heated to 56°C. The obtained granulate was cooled to the room temperature, sieved and mixed with other ingredients, except magnesium stearate, in a biconic mixer. Magnesium stearate was admixed and the obtained mixture was pressed into tablet cores, using round, slightly biconvex punches to a target hardness of approx. 130 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w according to the core.
  • Opadry Il HP PVA based polymer
  • Example 42 The tablets were packed in aluminium bags under reduced oxygen partial pressure and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC.
  • Example 42 The tablets were packed in aluminium bags under reduced oxygen partial pressure and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC.
  • Example 42 The degradation products were determined by HPLC.
  • the sodium hydroxide was dissolved in methanol and atorvastatin hemimagnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added.
  • the obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer.
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
  • the oxygen content in blisters was measured using a mass spectrometer. A syringe needle was used for sampling of the blister atmosphere.
  • the method involved removing a single foil blister from a pharmaceutical package containing atorvastatin tablets. On to the top of the blister was applied a small amount of silicon sealant to form an airtight seal.
  • a syringe needle was inserted into the sealant being careful not to pierce the blister.
  • the needle was then evacuated to remove any air/oyxgen contamination before being inserted directly into the blister cavity. Headspace analysis was then performed using a mass spectrometer and the oxygen concentration was calculated from the measured 02+/Ni 4 Ni 5 + ion abundance ratio.
  • the sodium hydroxide was dissolved in methanol and atorvastatin magnesium sodium laurylsulfate as well as hydroxypropyl cellulose were added.
  • the obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer.
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
  • the sodium hydroxide was dissolved in methanol and atorvastatin magnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added.
  • the obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer.
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
  • the sodium hydroxide was dissolved in methanol and atorvastatin hemimagnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added.
  • the obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer.
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
  • the oxygen content in blisters was measured using a mass spectrometer. A syringe needle was used for sampling of the blister atmosphere.
  • the method involved removing a single foil blister from a pharmaceutical package containing atorvastatin tablets. On to the top of the blister was applied a small amount of silicon sealant to form an airtight seal.
  • a syringe needle was inserted into the sealant being careful not to pierce the blister.
  • the needle was then evacuated to remove any air/oyxgen contamination before being inserted directly into the blister cavity. Headspace analysis was then performed using a mass spectrometer and the oxygen concentration was calculated from the measured 02+/Ni 4 Ni 5 + ion abundance ratio.
  • the sodium hydroxide was dissolved in methanol and atorvastatin hemimagnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added.
  • the obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer.
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
  • the sodium hydroxide was dissolved in methanol and atorvastatin magnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added.
  • the obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer.
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
  • the hydroxypropyl cellulose was dissolved in isopropyl alcohol and sodium phosphate tribasic, atorvastatin hemimagnesium and sodium laurylsulfate were added.
  • the obtained granulating mixture (in the form of an suspension) was sprayed onto the sucrose in a fluid bed granulator.
  • the resulting granulate was dried and sieved and mixed with the components 6 to 9 and pressed into tablets using round, slightly biconvex punches.
  • the obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating).
  • Example 49 The tablets were packed in aluminium bags under reduced oxygen partial pressure and in air and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC.
  • Example 49 The tablets were packed in aluminium bags under reduced oxygen partial pressure and in air and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC.
  • Example 49 The degradation products were determined by HPLC.
  • a 0,6 kg batch was prepared. Atorvastatin hemimagnesium and Gelucire were mixed in a double-wall high-shear mixer. During the granulation process the external space of mixer were heated to 56°C. The obtained granulate was cooled to the room temperature, sieved and mixed with other ingredients, except magnesium stearate in a biconic mixer. Magnesium stearate was admixed and the obtained mixture was pressed into tablets, using round, slightly biconvex punches to a target hardness of approx. 130 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w according to the core.
  • Opadry Il HP PVA based polymer
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks.
  • the degradation products were determined by HPLC.
  • Atorvastatin Na was first mixed with Na 2 CO 3 and sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Na was first mixed with sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Na was first mixed with Na 2 CO 3 and sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
  • Example 53 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Example 53 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Na was first mixed with sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating). The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Na was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Na was first mixed with sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
  • Example 56 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Example 56 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • a 20.0 kg batch was prepared.
  • the components 1 to 6 were mixed in a high-shear mixer.
  • Magnesium stearate was admixed and the obtained mixture was pressed into tablet cores, using round, slightly biconvex punches to a target hardness of approx. 90 N.
  • the loss on drying of the above compression mixture was 2.4%.
  • the cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w according to the core.
  • a 1 kg batch was prepared. First atorvastatin sodium and dextrates were mixed. The obtained mixture was mixed with other ingredients, except sodium stearyl fumarate, in a biconic mixer. Sodium stearyl fumarate was admixed and the obtained mixture was pressed into tablet cores, using round, slightly biconvex punches to a target hardness of approx. 90 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w relative to the core.
  • Opadry Il HP PVA based polymer
  • a 1 kg batch was prepared.
  • the components 1 to 6 were mixed in a biconic mixer.
  • Sodium stearyl fumarate was admixed and the obtained mixture was pressed into tablet cores, using round, slightly biconvex punches to a target hardness of approx. 100 N.
  • the cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w relative to the core.
  • Atorvastatin Mg was first mixed with Na 2 CO 3 and sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with Na 2 CO 3 and sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
  • Example 64 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Example 64 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating). The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with Na 2 CO 3 and sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were mixed. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
  • Example 67 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with Na 2 CO 3 and sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except magnesium stearate, were mixed. In the end magnesium stearate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with Na 2 CO 3 and sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
  • Example 70 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Example 70 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating). The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with Na 2 CO 3 and sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
  • the tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
  • Example 73 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • Example 73 The tablets were packed in aluminium bags under reduced oxygen partial pressure.
  • a 20.0 kg batch was prepared.
  • the components 1 to 6 were mixed in a high-shear mixer.
  • Magnesium stearate was admixed and the obtained mixture was pressed into tablets, using round, slightly biconvex punches to a target hardness of approx. 90 N.
  • the loss on drying of the compression mixture was 2.4%.
  • the obtained cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w according to the core.
  • a 1 kg batch was prepared. First atorvastatin magnesium and dextrates were mixed. The obtained mixture was mixed with other ingredients, except sodium stearyl fumarate, in a biconic mixer. Sodium stearyl fumarate was admixed and the obtained mixture was pressed into table cores, using round, slightly biconvex punches to a target hardness of approx. 90 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w relative to the core.
  • Opadry Il HP PVA based polymer
  • a 1 kg batch was prepared.
  • the components 1 to 6 were mixed in a biconic mixer.
  • Sodium stearyl fumarate was admixed and the obtained mixture was pressed into tablets, using round, slightly biconvex punches to a target hardness of approx. 100 N.
  • the cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w relative to the core.

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Abstract

Polymorph and amorphous forms of atorvastatin sodium and hemi-magnesium, processes for their preparation and pharmaceutical compositions comprising them are described.

Description

Polymorphs of atorvastatin salts
Field of the invention
The invention relates to new polymorphs of atorvastatin sodium and magnesium salts and their inclusion into pharmaceutical compositions which have an improved stability and bioavailability, as well as processes for their preparation.
Background of the invention
Atorvastatin is a member of the class of drugs called statins. Statins suppress cholesterol biosynthesis by competitively inhibiting 3-hydroxy-3-methyl-glutaryl- coenzyme A reductase which catalyzes the conversion of HMG-CoA to mevalonate, which is the rate determining step in the biosynthesis of cholesterol. They are currently the most therapeutically effective drugs available for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease.
Atorvastatin, [R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3- phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid, its lactone form and its alkali and earth alkali salts are known in the art, and processes for the preparation of atorvastatin and its key intermediates are disclosed in, for example, the United States 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 discloses the mono sodium, mono-potassium, hemi-calcium, N- methylglucamine, hemi-magnesium, hemi-zinc, and the 1-deoxy-1-(methylamino)-D- glucitol (N-methylglucamine) salts of atorvastatin. Additionally, US patent 6,583,295 discloses a series of amine salts of HMG-CoA reductase inhibitors which are used in a process for isolation and/or purification of these HMG-CoA reductase inhibitors. The tertiary butylamine and cyclohexylamine salts of atorvastatin are disclosed.
WO 2005/105738 discloses atorvastatin salts with ammonium, benethamine, benzathine, dibenzylamine, diethylamine, L-lysine, morpholine, olamine, piperazine, and 2-amino-2-methylpropan-1-ol and novel crystalline forms of the erbumine and sodium salt of atorvastatin. The atorvastatin sodium salt polymorph was prepared from a mixture of acetonitrile and water, which process resulted in formation of gels. These gels, however, were difficult to handle from the industrial point of view as 6 days of stirring at ambient temperature were necessary in order to be able to isolate the product. Further, acetonitrile is not a very suitable solvent for the preparation of pharmaceutically active compounds as some of it remains in the pharmaceutically active compound as residual solvent. This is very disadvantageous as acetonitrile is a harmful solvent.
WO 2006/0210216 describes new polymorphs of atorvastatin potassium salt and their inclusion into solid oral dosage forms. WO 2006/117761 discloses an atorvastatin hemi-magnesium salt, prepared from an alkali metal salt by contacting it with an organic or inorganic magnesium salt in the presence of a hydroxylic solvent.
WO 2007/020413 describes the preparation of atorvastatin sodium crystalline forms prepared from a mixture of an alcohol and a ketone.
The object of the present invention is to provide novel polymorphs of the sodium and hemi-magnesium salts of atorvastatin and processes for their preparation which are very suitable for use on an industrial scale. A further object of the present invention is to provide pharmaceutical compositions including these polymorphs, in particular solid oral dosage forms .
Brief description of drawings
Fig. 1 shows photographs and the X-ray powder diffraction pattern of Form I atorvastatin sodium according to the invention.
Fig. 2 shows photographs and the X-ray powder diffraction pattern of Form Il atorvastatin sodium according to the invention.
Fig. 3 shows photographs and the X-ray powder diffraction pattern of Form III atorvastatin sodium according to the invention.
Fig. 4 shows photographs and the X-ray powder diffraction pattern of Form IV atorvastatin sodium according to the invention.
Fig. 5 shows photographs and the X-ray powder diffraction pattern of Form V atorvastatin sodium according to the invention.
Fig. 6 shows photographs and the X-ray powder diffraction pattern of amorphous atorvastatin sodium according to the invention. Fig. 7 shows the X-ray powder diffraction pattern of Form I atorvastatin hemi- magnesium according to the invention.
Fig. 8 shows the X-ray powder diffraction pattern of Form Il atorvastatin hemi- magnesium according to the invention.
Fig. 9 shows the X-ray powder diffraction pattern of Form III atorvastatin hemi- magnesium according to the invention.
Fig. 10 shows the X-ray powder diffraction pattern of Form IV atorvastatin hemi- magnesium according to the invention .
Fig. 11 shows the X-ray powder diffraction pattern of Form V atorvastatin hemi- magnesium according to the invention.
Fig. 12 shows the X-ray powder diffraction pattern of Form Vl atorvastatin hemi- magnesium according to the invention.
Fig. 13 shows the X-ray powder diffraction pattern of Form VII atorvastatin hemi- magnesium according to the invention.
Fig. 14 shows the X-ray powder diffraction pattern of Form VIII atorvastatin hemi- magnesium according to the invention.
Fig. 15 shows the X-ray powder diffraction pattern of Form IX atorvastatin hemi- magnesium according to the invention.
Fig. 16 shows the X-ray powder diffraction pattern of amorphous atorvastatin hemi- magnesium according to the invention. Summary of the invention
According to the present invention new polymorphs and amorphous forms of the sodium and hemi-magnesium salt of atorvastatin are provided, which have improved solubility and other beneficial characteristics, and processes for their preparation.
Another aspect of the present invention is a pharmaceutical composition including them and in particular solid oral pharmaceutical dosage forms comprising also conventional pharmaceutically acceptable excipients, such as diluents, carriers, and/or other additives.
Detailed description of the invention
The novel polymorphs of atorvastatin sodium salt are prepared by crystallization and/or precipitation or by complete removal of the solvent from purified solutions of atorvastatin sodium by means of freeze-drying or spray-drying.
Purified solutions of atorvastatin sodium are available through hydrolysis of either [R- (R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)phenyl-4-[(phenylamino)- carbonyl]-1H-pyrrole-1-heptanoic acid tertiary butyl ester (atorvastatin te/t-butyl ester) or atorvastatin lactone with aqueous sodium hydroxide, or neutralization of atorvastatin free acid with aqueous sodium hydroxide in a water miscible solvent, followed by washing the mixture with a suitable water-immiscible solvent.
Aqueous solutions of sodium atorvastatin suitable for the freeze drying procedure are those containing water miscible co-solvents of reasonable volatility at low temperatures and a relatively high melting point, e.g. 1 ,4-dioxane or te/t-butanol. Aqueous suspensions of atorvastatin sodium containing no or small amount of co- solvents are also applicable.
Aqueous solutions of sodium atorvastatin suitable for the spray-drying procedure are those containing water miscible co-solvents, e.g. aliphatic alcohols, such as methanol, ethanol, isopropanol, te/t-butanol; ketones such as acetone; ethers such as tetrahydrofuran or 1 ,4-dioxane; or the mixtures of water, water miscible and water immiscible solvents, such as the combination of water, alcohols, ketones, ethers, etc. Non-aqueous solutions of atorvastatin sodium are also suitable for spray drying. The gas carrier for the spray drying may be selected from air, nitrogen, or argon.
Atorvastatin sodium Form I according to the invention may be prepared by partial evaporation of an aqueous solution of atorvastatin sodium containing a water miscible co-solvent, such as methanol, 1 ,4-dioxane or te/t-butanol, optionally being saturated with a water immiscible solvent, such as te/t-butyl methyl ether, to such a degree that volatile, low melting co-solvents are completely removed, and also that gelatinous precipitate is formed. The residual solvents are then removed completely, preferably by freezing the suspension, followed by freeze drying under high vacuum.
Atorvastatin sodium Form Il according to the invention may be prepared by partial evaporation of an aqueous solution of atorvastatin sodium containing a water miscible co-solvent, such as te/t-butanol or 1 ,4-dioxane, optionally being saturated with water immiscible solvent, such as te/t-butyl methyl ether, to such a degree that volatile, low melting co-solvents are completely removed, while precipitation should not take place. The residual solvents from the resulting solution are then removed completely, preferably by freezing the solution, followed by freeze drying under high vacuum.
Atorvastatin sodium Form III according to the invention may be prepared by contacting Form Il with humid air at temperatures from about 20 0C to about 80 0C.
Atorvastatin sodium Form IV according to the invention may be prepared by a process which comprises hydrolysis of atorvastatin tert-butyl ester with sodium hydroxide, in 20% to 50% (v/v) aqueous methanol, preferably in about 35% (v/v) aqueous methanol, at elevated temperatures, preferably at the reflux temperature of the mixture. After the hydrolysis procedure is complete, the reaction solution is allowed to cool, preferably to room temperature, in order to effect precipitation and/or crystallization. Atorvastatin sodium Form V according to the invention may be prepared by a process which comprises concentrating a solution of atorvastatin sodium in 50% to 90% (v/v) aqueous methanol, preferably in about 85% (v/v) aqueous methanol, to about one third of the original volume under reduced pressure, and cooling of the resulting solution to about 0 0C in order to effect precipitation and/or crystallization.
Amorphous form atorvastatin sodium according to the invention may be prepared by spray-drying of solutions of atorvastatin sodium.
The novel polymorphs of atorvastatin hemi-magnesium salts are prepared by crystallization and/or precipitation. Atorvastatin hemi-magnasium salt may be prepared from a solution of atorvastatin sodium salt by addition of a magnesium organic or inorganic salt, e.g. as is disclosed in Example 9. Primarily Form I or Form Il of atorvastatin hemi-magnesium is formed which upon drying transforms into other polymorphic forms, in particular into Form II.
Atorvastatin hemi-magnesium salt Form Il according to the invention may be prepared by dissolving atorvastatin Mg in a solvent from the group comprised of acetone, ethanol, methanol, 1-butanol or 2-butanol, at an elevated temperature between 300C to the reflux temperature, cooling to room temperature and adding water in an amount between 5 to 50 ml/ 1g of atorvastatin Mg, and/or hydrocarbon solvent, such as e.g. pentane, hexane, heptane or cyclohexane.
Atorvastatin hemi-magnesium salt Form III according to the invention may be prepared by slurrying atorvastatin magnesium salt in water, at a temperature of the boiling point of the suspension.
Atorvastatin hemi-magnesium salt Form IV according to the invention may be prepared by dissolving atorvastatin Mg in methanol and precipitating by the addition of water (1-4 parts, v/v) at a temperature between 200C and 40°C.
Atorvastatin hemi-magnesium salt Form V according to the invention may be prepared by slurrying atorvastatin magnesium salt under magnetical stirring in water, at an elevated temperature between 40°c and 700C. Atorvastatin hemi-magnesium salt Form Vl according to the invention is prepared by dissolving atorvastatin Mg in a solvent from the group comprised of ethyl acetate, ethanol, methanol, 1-butanol or 2-butanol, at a temperature between 200C and the boiling point, and adding water in an amount between 0.5 to 30 ml/ 1g of atorvastatin Mg. Water may also be added before heating the solution to a temperature between 200C to the reflux temperature of the solution.
Atorvastatin hemi-magnesium salt Form VII according to the invention is prepared by dissolving atorvastatin Mg in a solvent from the group comprised of ethanol or 1- butanol and water in an amount between 10 to 20 ml/ 1g of atorvastatin Mg, at a temperature between 500C and the reflux temperature of the solution, and cooling the solution to room temperature. Water may also be added before heating the solution to a temperature between 200C to the reflux temperature of the solution.
Atorvastatin hemi-magnesium salt Form VIII according to the invention may be prepared by slurrying atorvastatin magnesium salt under mechanical stirring or magnetical stirring in water, in an amount of between 0.0005 and 0.07g of atorvastatin Mg/ml of water, and at an elevated temperature between 20°C and 70°C.
Atorvastatin hemi-magnesium salt Form IX according to the invention is prepared by dissolving atorvastatin Mg in a mixture of an alcohol, such as ethanol, and water, and leaving to crystallize for prolonged periods of time, e.g. for 3-20 days at room temperature.
Amorphous form atorvastatin hemi-magnesium according to the invention is prepared by:
- evaporation of a solution of atorvastatin hemi-magnesium in alcohols in vacuum,
- cooling hot solutions of atorvastatin hemi-magnesium in 2-propanol or acetonitrile, or precipitating atorvastatin hemi-magnesium from a solution in alcohol or ketone (ethylmethyl ketone) by addition of a hydrocarbon. The x-ray powder diffraction patterns of the polymorphs and amorphous forms according to the invention were obtained by using a Phillips PW3040/60 X'Pert PRO diffractometer; and CuK0, radiation 1 ,541874 Angstrom wavelength.
Polymorphic form I of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 4.3, 5.9, 8.7, 11.3, 12.2, 14.2, 19.0, 22.9 ±0.2.
Polymorphic form Il of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 5.3, 8.3, 18.3 ±0.2.
Polymorphic form III of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 5.6, 8.4, 9.5, 14.4, 16.2, 22.7 ±0.2.
Polymorphic form IV of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 5.1 , 5.7, 6.6, 8.5, 10.3, 13.4 and 18.8 ±0.2.
Polymorphic form V of atorvastatin sodium salt is showing characteristic peaks at the following 2-theta degrees: 6.4, 8.1 , 9.7, 10.5, 11.6, 18.9, 20.0 ±0.2.
Polymorphic form I of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 4.8, 7.2, 8.8, 18.2, 18.9 ±0.2.
Polymorphic form Il of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 3.1 , 9.1 , 11.6, 12.4, 14.3, 18.5, 19.2 ±0.2.
Polymorphic form III of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 7.6, 9.1 , 9.6, 12.1 , 20.1 , 22.4 ±0.2. Preferably, polymorphic form III of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 7.6, 9.1 , 9.6, 12.1 , 13.4, 14.2, 14.8, 15.5, 16.7, 17.3, 18.0, 20.1 , 22.4, 23.9, 27.2 ±0.2.
Polymorphic form IV of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 3.2, 8.9, 11.6, 17.3, 18.5, 22.0, 28.1 ±0.2. Polymorphic form V of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 7.6, 9.5, 11.7, 20.0, 21.9, 24.1 ±0.2. Preferably, polymorphic form V of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 6.2, 7.6, 9.5, 11.7, 12.5, 13.5, 15.6, 18.7, 20.0, 21.9, 24.1 ±0.2.
Polymorphic form Vl of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 8.5, 12.0, 14.3, 18.4, 19.2, 20.1 ±0.2. Preferably, polymorphic form Vl of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 4.5, 5.7, 8.5, 12.0, 14.3, 18.4, 19.2, 20.1 ±0.2.
Polymorphic form VII of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 5.7, 8.5, 9.1 , 11.8, 18.2 ±0.2.
Polymorphic form VIII of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 8.6, 10.0, 11.5, 16.5, 20.1 , 21.6, ±0.2. Preferably, polymorphic form VIII of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 5.7, 7.2, 8.6, 10.0, 10.7, 11.5, 12.3, 14.3, 16.5, 17.7, 20.1 , 21.6, 23.0 ±0.2.
Polymorphic form IX of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 3.3, 8.9, 9.2, 9.9, 18.2, 21.9, 23.3 ±0.2. Preferably, polymorphic form IX of atorvastatin hemi-magnesium salt is showing characteristic peaks at the following 2-theta degrees: 3.3, 7.4, 8.9, 9.2, 9.9, 11.6, 11.9, 12.4, 14.8, 16.5, 17.4, 18.2, 18.8, 19.9, 21.9, 23.3, 24.0, 24.9, 28.3, 30.0 ±0.2.
The polymorph forms and the amorphous form of atorvastatin sodium and hemi- magnesium according to the invention can also be present as solvates thereof. These solvates include for example water, to result in hydrates, or other solvents, in particular alcohols, ketone or ethers, and mixtures thereof. The invention also relates to a pharmaceutical composition comprising at least one of the polymorph or amorphous forms according to the invention, and at least one pharmaceutically acceptable excipient.
Compositions of the polymorphic or amorphous forms of the sodium or hemi- magnesium salt of atorvastatin according to the invention can be solid, semi-solid or liquid. Solid compositions include powders, granules, tablets, capsules, sachets, suppositories, and dispersible granules. Preferably, the compositions according to the invention of the atorvastatin sodium or hemi-magnesium forms are tablets, most preferably film-coated tablets.
The solid dosage form compositions may be, for example, an immediate release dosage form, a fast melt dosage form, a controlled release dosage form, a lyophilized dosage form, a delayed release dosage form, en extended release dosage form, a pulsatile release dosage form, a mixed immediate release and a controlled release dosage form, or a combination thereof. The solid dosage form composition according to this invention is preferably an immediate release dosage form offering advantages regarding the bioavailability and the stability of the active compound.
The compositions of atorvastatin sodium or hemi-magnesium forms according to the invention may be prepared by well known technological processes 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 polymorphic and amorphous forms according to the invention can be processed to tablets with an acceptable content uniformity. For example, the relative standard deviation of the content uniformity of the tablets (and eventually of the film coated tablets) is less than 10 %, preferably less than 5 %, even more preferably less than 3 %.
The compositions according to the invention also provide free flow of the compression mixtures, which are suitable for compression into tablets and preferably, further film coating. Excipients useful in the compositions of the invention are selected from the group of diluents/fillers, disintegrants, binders, lubricants, glidants, stabilizers, solubilizers, sweetening agents, flavouring agents etc.
The excipients present in the compositions according to the invention can be diluents such as lactose in different 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, lactitol, xylitol, sorbitol, calcium hydrogen phosphate, calcium carbonate, calcium lactate or combinations of diluents. Starches 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. For a direct compression process, Cellactose in combination with other diluents such as starches or microcrystalline cellulose, is preferred.
The composition according to the invention may also comprise binders, such as povidone, microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose (comprising from 5 to 16% by weight of hydroxypropyl groups), hydroxypropylmethyl cellulose or other cellulose ethers, starch, pregelatinised starch or polymethacrylate or mixture of binders. It is preferred that the excipients include at least one binder selected from cellulose or its derivatives. If a wet granulation process is applied, hydroxypropyl cellulose is preferably used as binder.
Further, disintegrants and/or superdisintegrants may also be present such as starches (e.g. maize starch, potato starch), modified starches (sodium starch glycolate), modified cellulose (croscarmellose, i.e. cross-linked carboxymethyl- cellulose sodium), cross-linked polyvinylpyrrolidone (crospovidone), microcrystalline cellulose, carboxymethylcellulose sodium, Amberlite®, alginic acid, sodium alginate, guar gum, gellan gum, Xanthan SM® or calcium silicate. If used as a disintegrant, microcrystalline cellulose is preferably used in an amount of 5 to 15% by weight. It is preferred that the excipients include at least one disintegrant or superdisintegrant selected from croscarmellose, crospovidone and microcrystalline cellulose. If necessary, a combination of two or more disintegrants can be used, for example, croscarmelose sodium, crospovidone and microcrystalline cellulose.
Further, lubricants may also be present as excipients, such as stearic acid, magnesium stearate, calcium stearate, sodium laurylsulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, macrogols. It is preferred that the excipients include at least one lubricant selected from magnesium stearate, sodium stearyl fumarate or hydrogenated vegetable oil.
Excipents may also have multiple functions, i.e. one excipient may be diluent and additionally binder, binder and disintegrant etc.
Optionally, surfactants can be included in a solid pharmaceutical composition. Surfactants can be selected from the group of non-ionic or ionic surfactants or mixtures thereof. Suitable non-ionic surfactants are selected from the group of alkylglucosides, alkylmaltosides, alkylthioglukosides, lauryl macrogolglycerides, polyoxyethylene alkylphenols, polyoxyethylene alkylethers, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, polyglyceryl fatty acid esters, polyoxyethylene glycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, sterols, and mixtures thereof. Preferred non-ionic surfactants are polyoxyethylene sorbitan fatty acid esters, which are sold under the trade names Polysorbate or Tween.
Suitable ionic surfactants are selected from the group of fatty acid salts, bile salts, phospholipides, phosphoric acid esters, carboxylates, sulphates, sulphonates and mixture thereof. A preferred ionic surfactant is sodium laurylsulphate.
The pharmaceutical composition according to the invention may comprise from 0.1 - 5 %, preferably 0.2 - 4 % by weight of a surfactant, most preferably 0.3 - 3 %.
The pharmaceutical composition according to the invention can also comprise a stabilizer. Basifying agents or buffers can be used as stabilizers, for example, alkali metal compounds or earth alkali metal compounds. Preferably, alkali metal additives, such as for example sodium hydroxide, sodium superoxide, sodium carbonate, sodium hydrogencarbonate, sodium phosphate, sodium hydrogenphosphate or sodium salts with organic acids (for example sodium citrate or sodium tartrate) potassium hydroxide, potassium superoxide, potassium carbonate, potassium hydrogencarbonate, potassium phosphate, potassium hydrogenphosphate or potassium salts with organic acids (for example potassium citrate or potassium tartrate) are used.
The composition usually comprises 0.01 % to 20 %, preferably 0.1 % to 15 % and most preferred 0.2 % to 10 % by weight of the alkali metal additive.
Preferably, the composition according to the invention contains the polymorphic and amorphous forms of the sodium or magnesium salt of atorvastatin according to the invention as active ingredient, optionally an alkali metal additive selected from sodium and potassium compounds, and the composition is optionally exposed to an atmosphere comprising 1 to 16 % by volume of oxygen. Most preferably, the composition contains the polymorph forms of atorvastatin sodium or hemi- magnesium as the active ingredient, sodium hydroxide or sodium carbonate as basifying agents and is optionally exposed to an atmosphere comprising 1 to 16 % by volume of oxygen.
It is further preferred that the composition is present in a packaging, with a blister packaging or a bottle being preferred. Thus a packaged composition is formed. The packaging can be provided with means for trapping and disposal of free oxygen. Moreover, the composition is preferably enclosed in a substantially gas exchange non-permeable material as packaging which has an atmosphere with the required reduced oxygen content. The substantially gas exchange non-permeable packaging is preferably selected from the group consisting of an AI/AI blister package, an Al- polychloro-3-fluoroethylene homopolymer/PVC laminate blister or a bottle.
Any suitable process for the preparation of pharmaceutical compositions may be applied, e.g. direct compression, wet or dry granulation etc, to obtain the composition according to the invention. The composition is preferably in the form of coated tablets. The coating can be made of conventional materials used for film coating. Film coating formulations usually contain the following components: polymer(s), plasticizer(s), colourant(s)/opacifier(s), vehicle(s) and optionally, flavours, surfactants and waxes in minor quantities. Cellulose derivatives, such as the cellulose ethers (hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose) or acrylic polymers and co-polymers, high molecular weight polyethylene glycols, polyvinyl pyrrolidone, polyvinyl alcohol and waxy materials can be used as coating agents.
Preferably hydroxypropyl cellulose or polyvinyl alcohol are used as coating polymers.
The useful plasticizers may be categorized into three groups: polyols (glycerol, propylene glycol, macrogols), organic esters (phthalate esters, dibutyl sebacetate, citrate esters, triacetin), and oils/glycerides (castor oil, acetylated monoglycerides, fractionated coconut oil).
Colourants/opacifiers can be selected from the groups of organic dyes or inorganic colours.
Combination of different materials from each group can be made in a defined ratio. Film coating suspensions can be used as ready-to-make preparations that are available on the market. Preferably, commercially available ready to make mixtures, such as different Opadry® (of Colorcon) mixtures are used.
Film coating dispersion can be prepared by using different solvents such as water, alcohols, ketones, esters, chlorinated hydrocarbons, preferably water.
Further, the composition according to the invention can also contain a coating with waxy materials such Gelucire. Gelucire coatings are particularly effective when preventing environmental gases to ingress into tablet cores, either when applied alone or in combination with coatings based on carboxymethylcellulose sodium (NaCMC) or polyvinyl alcohol (PVA). Gelucire compositions are inert semi-solid waxy materials which are amphiphilic in character and are available with varying physical characteristics. They are surface active in nature and disperse or solubilize in aqueous media forming micelles, microscopic globules or vesicles. They are identified by their melting point/HLB value. The melting point is expressed in degrees Celsius and the HLB (Hydrophile-Lipophile Balance) is a numerical scale extending from 0 to approximately 20. The large family of Gelucire compositions is characterized by a wide range of melting points of from about 330C to about 640C and most commonly from about 350C to about 550C, and by a variety of HLB values of from about 1 to about 14, most commonly from about 7 to about 14. For example, Gelucire 50/13 designates a melting point of approximately 5O0C and an HLB value of about 13. Gelucire 50/13 has been found to be particularly effective when coating the composition according to the invention. It is composed of fatty acid (majority of Ci6 and Cis) esters of glycerol, PEG esters and free PEG (lauryl macrogol glycerides).
The coatings can be applied by the process of melt coating or solutions/dispersions in water or organic solvents can be used as coating suspensions.
For preparing the composition according to the invention, different technological processes can be applied, such as direct compression, dry granulation, wet granulation (with water or organic solvents), spray drying, freeze drying etc.
If the direct compression process is used, it may be performed in the way that
(a) active ingredient is added to the mixture of excipients and compressed, or
(b) active ingredient is mixed together with excipients and compressed.
Solid dosage forms of composition (e.g. tablet cores) can be optionally coated.
Excipients may optionally be processed before mixing with the active ingredient, for example by wet granulation, using either water or organic solvent or mixture thereof as granulating liquid.
Suitable mixing devices for the direct compression or optionally the wet granulation process as described above, is conventional equipment used for mixing of active ingredients, excipients or combination of active ingredient(s) and excipients. In the case of wet granulation as described above, the equipment is chosen from standard equipment for example high shear granulator or fluid bed granulator.
The present invention is further illustrated, but in no way limited by the following examples:
Examples
In the following examples
Magnetical stirring was performed by: Magnetic stirrer IKAMAG RCT basic, Janke- Kunkel GmbH, IKA Labortechnik, stirring speed 200-600 rpm
Mechanical stirring was performed by: Overhead stirrer EURO-ST P CV, IKA-Werke, stirring speed 200-600 rpm
A.) SODIUM ATORVASTATIN
Preparation of sodium atorvastatin Form I
Example 1
To the solution of 5.00 g [R-(R*, R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1- methylethyl)phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid tertiary butyl ester (8.13 mmol) in 17 ml_ of methanol and 15 ml_ of te/t-butyl methyl ether was added a solution of 0.33 g of NaOH (8.25 mmol, 1 ,01 equivalent) in 30 ml_ of water. The reaction mixture was heated at reflux temperature 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 te/t-butyl methyl ether (1 x 30 ml, 1 x 10 ml). The lower aqueous phase was partially concentrated under reduced pressure in order to remove most of te/f-butyl methyl ether and methanol. Due to the initial foaming, pressure must be carefully controlled. Evaporation was interrupted when no more distillate was collecting in the receiver at 47 mbar and a temperature of a water bath of 38 0C. The residual gel was deep frozen using liquid nitrogen bath and lyophilized on a Lio 5 (Kambic) freeze dryer as necessary (about 1 day) to yield 4.59 g of sodium atorvastatin Form I as a powder containing 6.53% of water according to Karl Fischer analysis (91 % yield). The product was 99.4% pure by HPLC analysis.
Example 2
To the solution of 5.00 g of [R-(R*, R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1- methylethyl)phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid tertiary butyl ester (8.13 mmol) in 17 ml_ of te/t-butanol and 15 ml_ of te/t-butyl methyl ether was added a solution of 0.33 g of NaOH (8.25 mmol, 1.01 equivalent) in 30 ml_ of water. The turbid mixture was heated at reflux temperature 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 te/t-butyl methyl ether (1 x 20 ml, 1 x 10 ml). The lower aqueous phase was partially concentrated under reduced pressure in order to remove tert- butyl methyl ether. The pressure was reduced gradually and the evaporation was interrupted at 70 mbar and a temperature of a water bath of 38 0C. The residual gel was deep frozen using liquid nitrogen bath and lyophilized on a Lio 5 (Kambic) freeze dryer as necessary (about 1 day) to yield 4.67 g of sodium atorvastatin Form I as a powder containing 8.40% of water according to Karl Fischer analysis (91% yield). The product was more than 99.5% pure by HPLC analysis.
Preparation of sodium atorvastatin Form Il
Example 3
To the solution of 5.00 g [R-(R*, R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1- methylethyl)phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid tertiary butyl ester (8.13 mmol) in 17 mL of 1 ,4-dioxane and 15 mL of te/t-butyl methyl ether was added a solution of 0.33 g of NaOH (8.25 mmol, 1 ,01 equivalent) in 30 mL of water. The reaction mixture was heated at reflux temperature 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 te/f-butyl methyl ether. The lower aqueous phase was partially concentrated under reduced pressure in order to remove te/t-butyl methyl ether. Due to the initial foaming, pressure must be carefully controlled. Evaporation was interrupted at 52 mbar and a temperature of a water bath of 35 0C, when the distillation of 1 ,4-dioxane commenced. The resulting solution was deep frozen using liquid nitrogen bath and lyophilized on a Lio 5 (Kambic) freeze dryer as necessary (about 1 day) to yield 4.79 g of sodium atorvastatin Form Il as a white powder containing 3.76% of water according to Karl Fischer analysis (97.7% yield). The product was more than 99.5% pure by HPLC analysis.
Example 4
To the solution of 40.0 g [R-(R*, R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1- methylethyl)phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid tertiary butyl ester (65 mmol) in 136 ml_ of te/t-butanol and 120 ml_ of te/t-butyl methyl ether was added a solution of 2.6 g of NaOH (65 mmol, 1 equivalent) in 240 ml_ of water. The reaction flask was purged with argon flow for 10 min and the turbid mixture was heated at reflux temperature under inert atmosphere for 4 hours when the concentration of the starting compound was reduced to about 2 % as determined by HPLC. The reaction mixture was cooled to room temperature and washed three times with te/t-butyl methyl ether (1 x 160 ml, 2 x 100 ml). The lower aqueous phase was partially concentrated under reduced pressure in order to remove te/t-butyl methyl ether. The pressure was reduced gradually and the evaporation was interrupted when no more distillate was collecting in the receiver at 400 mbar and a temperature of a water bath of 45 0C. The resulting solution was diluted with 150 ml of te/t-butanol, then deep frozen using liquid nitrogen bath and lyophilized as necessary (about 1 day) to yield the product as a white powder. This material was further dried in vacuum, first at room temperature for about 4 hours, then at 50 0C for 18 h to provide 34.70 g of sodium atorvastatin Form Il containing 3.83% of water according to Karl Fischer analysis (88.4% yield). The product was more than 99.5% pure by HPLC analysis.
Preparation of sodium atorvastatin Form III
Example 5
A sample of sodium atorvastatin Form Il (1 g) was kept at 40 0C and 75% relative humidity in an open vessel for 14 days. Form III of sodium atorvastatin was obtained according to XRPD analysis. Preparation of sodium atorvastatin Form IV
Example 6
To the mixture of 10.00 g of [R-(R*, R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1- methylethyl)phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid tertiary butyl ester (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 temperature for few hours until all solid material dissolved. The resulting solution was allowed to cool to room temperature and kept at this temperature overnight. The solid was then filtered and dried in air to give 5.60 g (about 59%) of sodium atorvastatin Form IV. The product was more than 99% pure by HPLC analysis.
Preparation of sodium atorvastatin Form V
Example 7
A mixture of 80.0 g of atorvastatin hemicalcium 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 sulphate and concentrated. The oily residue (about 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 temperature for few hours. After cooling to room temperature the resulting solution was partially concentrated and cooled in an ice- bath. The solid was then filtered and dried in air to give sodium atorvastatin Form V.
Preparation of amorphous atorvastatin sodium
Example 8
525 ml of the te/t-butyl methyl ether washed solution of atorvastatin sodium (0.138 M, 72.5 mmol), prepared according to Example 1 , was spray-dried on a Bϋchi 190 mini spray drier using nitrogen as a drying gas under the following conditions: inlet temperature of 130-135 0C, outlet temperature of 58-62 0C, nitrogen flow of about 750 ml/min. The solid was collected and further dried in a vacuum drier for 3 days at room temperature and for 6 hours at 50 0C. 29.87 g of amorphous atorvastatin sodium were obtained as a white powder, which contained 1.97% of water according to Karl Fischer analysis (70% yield). The product was more than 99.5% pure by HPLC analysis.
B.) MAGNESIUM ATORVASTATIN
Preparation of atorvastatin hemi-magnesium salt Forms I and Il
Example 9
A solution of MgCI26H2O (10.4 g, 0.0512 mol) in 180 ml of purified water was added to 800 ml of the te/f-butyl methyl ether washed solution of atorvastatin sodium (0.1024 mol, 59.4 g; prepared according to Example 1 (= atorvastatin sodium form I). The addition took 15 min under nitrogen atmosphere. The resulting suspension was stirred for 10 min and diluted with 780 ml of purified water within 30 min. The mixture was stirred for further 30 min, then the solid was collected by filtration and washed twice with 120 ml of purified water to obtain 126.3 g of wet product (Form I of atorvastatin hemi-magnesium salt). Drying of Form I in a vacuum drier at 50 0C overnight afforded atorvastatin hemi-magnesium salt Form Il (55.2 g, 94.7%), which contained 1.7% of water according to Karl-Fisher analysis.
Preparation of atorvastatin hemi-magnesium salt Form Il
Example 10
1.0 g of atorvastatin hemi-magnesium salt form Il was dissolved in 9 ml of acetone by heating to reflux. The solution was cooled to room temp, and 8.5 ml of water were added dropwise. The mixture was stirred for 1 h, filtered and dried, first air-dried overnight, then in vacuum at 50 0C for 5 h. 0.8 g of atorvastatin hemi-magnesium salt form Il were obtained. Example 11
5.0 g of atorvastatin hemi-magnesium salt form Il were dissolved in 65 ml of 96% ethanol by heating to reflux. While stirred magnetically, the solution was cooled to room temp, and 60 ml of water were added dropwise. The mixture was stirred for additional 15 min and the precipitate was filtered and air-dried to give 3.94 g of atorvastatin hemi-magnesium salt form II.
Example 12
5.0 g of atorvastatin hemi-magnesium salt form Il were dissolved in 50 ml of 96% ethanol by heating to reflux. While stirred mechanically, the solution was cooled to room temp, and 50 ml of water were added dropwise. The mixture was stirred for additional 15 min and the precipitate was filtered and air-dried to give 4.06 g of atorvastatin hemi-magnesium salt form II.
Example 13
A stirred mixture of 1.0 g of atorvastatin hemi-magnesium salt form Il in 1-butanol (10 ml) and water (10 ml) was heated to reflux for 1 h, followed by cooling to room temp. After the stirring was stopped, two clear layers were formed. To the upper layer pentane (9 ml) was added dropwise. The resulting solid was filtered and air-dried to give 0.44 g of atorvastatin hemi-magnesium salt form II.
Example 14
1.01 g of atorvastatin hemi-magnesium salt form Il were dissolved in 7 ml of acetone by stirring at room temp, for about 4 days. To the resulting solution were added sequentially hexane (20 ml) and water (20 ml). Solid precipitated upon addition of water, which was filtered and air-dried to give 0.91 g of atorvastatin hemi-magnesium salt form II. Example 15
1.01 g of atorvastatin hemi-magnesium salt form Il were dissolved in 30 ml of 90% aqueous ethanol by heating to reflux. The solution was cooled to room temp., then hexane (10 ml) and water (30 ml) were added seqentially. After stirring at room temp, for 10 min the gelatinuous suspension was filtered and air-dried to give 0.835 g of atorvastatin hemi-magnesium salt form II.
Preparation of atorvastatin hemi-magnesium salt Form III
Example 16
A suspension of 1.0 g of atorvastatin hemi-magnesium salt form Il in 10 ml of water was refluxed for 1.5 h, followed by magnetic stirring at room temp, for 18 h. The resulting suspension was filtered and air-dried to give 0.98 g of atorvastatin hemi- magnesium salt form III.
Preparation of atorvastatin hemi-magnesium salt Form IV
Example 17
To a solution of atorvastatin hemi-magnesium salt form Il (1.0 g) in methanol (10 ml), water (20 ml) was added dropwise at room temp. The resulting suspension was stirred for further 10 min, then filtered and air-dried to give 0.93 g of atorvastatin hemi-magnesium salt form IV.
Preparation of atorvastatin hemi-magnesium salt Form V
Example 18
A suspension of 2.01 g of atorvastatin hemi-magnesium salt form Il in 30 ml of water was stirred magnetically at 60 0C for 4 h. The resulting slurry was filtered and dried in vacuum. 1.07 g of atorvastatin hemi-magnesium salt form V were obtained according to XRPD analysis. Preparation of atorvastatin hemi-magnesium salt Form Vl
Example 19
0.206 g of atorvastatin hemimagnesium salt form Il were dissolved in 1 ml of ethyl acetate by heating to reflux. The solution was cooled to room temp, and about 0.1 ml of water were added dropwise. Oily material separated, which was allowed to stay for 8 days at room temp. The resulting solid was filtered and air-dried overnight to give 0.20 g of atorvastatin hemi-magnesium salt form Vl.
Example 20
0.206 g of atorvastatin hemi-magnesium salt form Il were dissolved in 0.4 ml of methanol by heating to reflux. The solution was cooled to room temp, and about 0.1 ml of water were added dropwise. The resulting solid was allowed to stay overnight, filtered and air-dried to give 0.187 g of atorvastatin hemi-magnesium salt form Vl mixed with an additional phase.
Example 21
To a magnetically stirred solution of atorvastatin hemi-magnesium salt form Il (1.01 g) in ethanol (13.5 ml) and water (2.4 ml), water (20 ml) was added dropwise at room temp. The resulting slurry was stirred for further 10 min, then filtered and air-dried to give 0.91 g of atorvastatin hemi-magnesium salt form Vl.
Preparation of atorvastatin hemi-magnesium salt Form VII
Example 22
A suspension of 1.0 g of atorvastatin hemi-magnesium salt form Il in 1-butanol (4 ml) and water (16 ml) was heated to reflux for 1 h. The mixture was cooled and stirred magnetically at room temp .for additional 16 h. The solid was filtered and air-dried to give 0.44 g of atorvastatin hemi-magnesium salt form VII.
Example 23
A suspension of 1.0 g of atorvastatin hemi-magnesium salt form Il in 1-butanol (4 ml) and water (16 ml) was heated to reflux for 1 h. The mixture was cooled and stirred mechanically at room temp, for additional 16 h. The solid was filtered and air-dried to give 0.98 g of atorvastatin hemimagnesium salt form VII.
Example 24
A mixture of atorvastatin hemi-magnesium salt form Il (1.01 g) in ethanol (9 ml) and water (1.6 ml) was heated at 50 0C for 1 h with magnetic stirring. The resulting solution was stirred at room temp, for about 2.5 days. A suspension was formed, which was filtered and air-dried to give 0.45 g of atorvastatin hemi-magnesium salt form VII.
Preparation of atorvastatin hemi-magnesium salt Form VIII
Example 25
A suspension of 2.00 g of atorvastatin hemi-magnesium salt form Il in 30 ml of water was stirred mechanically at 60 0C for 4 h. The resulting slurry was filtered and dried in vacuum to give 1.97 g of atorvastatin hemi-magnesium salt form VIII.
Example 26
A suspension of 1.0 g of atorvastatin hemi-magnesium salt form Il in 400 ml of water was stirred magnetically at room temp, for 18 h. The resulting suspension was filtered and air-dried to give 0.61 g of atorvastatin hemi-magnesium salt form VIII.
Example 27
A suspension of 1.0 g of atorvastatin hemi-magnesium salt form Il in 400 ml of water was stirred mechanically at room temp, for 18 h. The resulting suspension was filtered and air-dried to give 0.77 g of atorvastatin hemi-magnesium salt form VIII.
Preparation of atorvastatin hemi-magnesium salt Form IX
Example 28
A suspension of atorvastatin hemi-magnesium salt form Il (1.01 g) in 20 ml of ethanol was placed into an ultrasonic bath for 2 min. 14 ml of water were added and the mixture placed into the ultrasonic bath for another 2 min. The resulting solution was kept at room temp, without stirring for 14 days during which time slow growth of crystals was observed. The crystals were filtered and air-dried to give 0.45 g of atorvastatin hemi-magnesium salt form IX.
Preparation of amorphous atorvastatin hemi-magnesium salt
Example 29
1.0 g of atorvastatin hemi-magnesium salt form Il was dissolved in 40 ml of abs. ethanol by heating to reflux. The solution was cooled to room temp, and concentrated in vacuum to give 1.05 g of amorphous atorvastatin hemi-magnesium salt.
Example 30
0.234 g of atorvastatin hemi-magnesium salt form Il were dissolved in 1 ml of acetonitrile by heating to reflux. The mixture was stirred at room temperature overnight. The resulting suspension was cooled in an ice bath for 20 min, then filtered and air-dried overnight to give 0.126 g of the amorphous atorvastatin hemi- magnesium salt.
Example 31
0.211 g of atorvastatin hemi-magnesium salt form Il were dissolved in 0.9 ml of 2- propanol by heating to reflux. The mixture was stirred at room temp, overnight. The resulting suspension was cooled in an ice bath for 30 min, then filtered and air-dried to give 0.18 g of the amorphous atorvastatin hemi-magnesium salt.
Example 32
1.04 g of atorvastatin hemi-magnesium salt form Il were dissolved in 7 ml of abs. ethanol by heating to reflux. The solution was cooled to room temp, and 30 ml of pentane was added. A semisolid precipitate formed which solidified completely upon scratching. After stirring at room temp, for 1 h, the solid was filtered and air-dried to give 0.87 g of the amorphous atorvastatin hemi-magnesium salt.
Example 33
1.025 g of atorvastatin hemi-magnesium salt form Il were dissolved in 20 ml of 1- butanol by heating to reflux. The solution was cooled to room temp, and 20 ml of pentane were added. After stirring at room temp, for 10 min, the solid was filtered and air-dried to give 0.33 g of the amorphous atorvastatin hemi-magnesium salt.
Example 34
1.01 g of atorvastatin hemi-magnesium salt form Il were dissolved in 5 ml of ethylmethyl ketone by stirring at room temp, for 17 h followed by addition of pentane (14 ml). A semisolid precipitate formed which solidified completely in about half an hour. After stirring at room temp, for 30 min, the solid was filtered and air-dried to give 0.80 g of the amorphous atorvastatin hemi-magnesium salt.
Example 35
1.0 g of atorvastatin hemi-magnesium salt form Il was dissolved in 7 ml of 2-propanol by heating to reflux for 1 h. The mixture was stirred at room temp, overnight. The resulting suspension was filtered and air-dried to give 0.88 g of the amorphous atorvastatin hemi-magnesium salt.
Example 36
1.03 g of atorvastatin hemi-magnesium salt form Il were dissolved in a mixture of 1- butanol (10 ml) and abs. ethanol (10 ml) by heating to reflux. The solution was stirred at room temp, overnight, then hexane (25 ml) was added. After stirring at room temp, for 10 min the solid was filtered and air-dried to give 0.52 g of the amorphous atorvastatin hemi-magnesium salt.
C.) PREPARATION OF FILM COATED TABLETS (FLUID BED GRANULATION WITH ORGANIC SOLVENT)
The atorvastatin Na or Mg used in the following examples was either one of the polymorph or the amorphous forms according to the invention. Example 37:
* corresponds to 40 mg of atorvastatin
The sodium hydroxide was dissolved in methanol and atorvastatin sodium, sodium laurylsulfate as well as hydroxypropyl cellulose were added. The obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 7 to 10 and pressed into tablet cores using round, slightly biconvex punches.
The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer. The tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
The oxygen content in blisters was measured using a mass spectrometer. A syringe needle was used for sampling of the blister atmosphere. The method involved removing a single foil blister from a pharmaceutical package containing atorvastatin tablets. On to the top of the blister was applied a small amount of silicon sealant to form an airtight seal. Once dry, a syringe needle was inserted into the sealant being careful not to pierce the blister. The needle was then evacuated to remove any air/oyxgen contamination before being inserted directly into the blister cavity. Headspace analysis was then performed using a mass spectrometer and the oxygen concentration was calculated from the measured 02+/Ni4Ni5+ ion abundance ratio.
Example 38:
corresponds to 40 mg of atorvastatin
The sodium hydroxide was dissolved in methanol and atorvastatin sodium, sodium laurylsulfate as well as hydroxypropyl cellulose were added. The obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 7 to 10 and pressed into tablets cores using round, slightly biconvex punches. The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer. The tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
Example 39:
* corresponds to 40 mg of atorvastatin
The sodium hydroxide was dissolved in methanol and atorvastatin sodium, sodium laurylsulfate as well as hydroxypropyl cellulose were added. The obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 7 to 10 and pressed into tablets cores using round, slightly biconvex punches.
The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer. The tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
Example 40:
* corresponds to 40 mg of atorvastatin
The hydroxypropyl cellulose was dissolved in isopropyl alcohol and sodium phosphate tribasic, sodium atorvastatin and sodium laurylsulfate were added. The obtained granulating mixture (in the form of a suspension) was sprayed onto the sucrose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 6 to 9 and pressed into tablet cores using round, slightly biconvex punches.
The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure and in air and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC. Example 41 :
* corresponds to 40 mg of atorvastatin
A 0,6 kg batch was prepared. Sodium atorvastatin and Gelucire were mixed in a double-wall high-shear mixer. During the granulation process the external space of the mixer was heated to 56°C. The obtained granulate was cooled to the room temperature, sieved and mixed with other ingredients, except magnesium stearate, in a biconic mixer. Magnesium stearate was admixed and the obtained mixture was pressed into tablet cores, using round, slightly biconvex punches to a target hardness of approx. 130 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w according to the core.
The tablets were packed in aluminium bags under reduced oxygen partial pressure and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC. Example 42:
* corresponds to 40 mg of atorvastatin
The sodium hydroxide was dissolved in methanol and atorvastatin hemimagnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added. The obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer. The tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen). The oxygen content in blisters was measured using a mass spectrometer. A syringe needle was used for sampling of the blister atmosphere. The method involved removing a single foil blister from a pharmaceutical package containing atorvastatin tablets. On to the top of the blister was applied a small amount of silicon sealant to form an airtight seal. Once dry, a syringe needle was inserted into the sealant being careful not to pierce the blister. The needle was then evacuated to remove any air/oyxgen contamination before being inserted directly into the blister cavity. Headspace analysis was then performed using a mass spectrometer and the oxygen concentration was calculated from the measured 02+/Ni4Ni5+ ion abundance ratio.
Example 43:
corresponds to 40 mg of atorvastatin
The sodium hydroxide was dissolved in methanol and atorvastatin magnesium sodium laurylsulfate as well as hydroxypropyl cellulose were added. The obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches. The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer. The tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
Example 44:
* corresponds to 40 mg of atorvastatin
The sodium hydroxide was dissolved in methanol and atorvastatin magnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added. The obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer. The tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
Example 45:
* corresponds to 40 mg of atorvastatin
The sodium hydroxide was dissolved in methanol and atorvastatin hemimagnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added. The obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer. The tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen). The oxygen content in blisters was measured using a mass spectrometer. A syringe needle was used for sampling of the blister atmosphere. The method involved removing a single foil blister from a pharmaceutical package containing atorvastatin tablets. On to the top of the blister was applied a small amount of silicon sealant to form an airtight seal. Once dry, a syringe needle was inserted into the sealant being careful not to pierce the blister. The needle was then evacuated to remove any air/oyxgen contamination before being inserted directly into the blister cavity. Headspace analysis was then performed using a mass spectrometer and the oxygen concentration was calculated from the measured 02+/Ni4Ni5+ ion abundance ratio.
Example 46:
corresponds to 40 mg of atorvastatin
The sodium hydroxide was dissolved in methanol and atorvastatin hemimagnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added. The obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches. The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer. The tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
Example 47:
* corresponds to 40 mg of atorvastatin
The sodium hydroxide was dissolved in methanol and atorvastatin magnesium, sodium laurylsulfate as well as hydroxypropyl cellulose were added. The obtained granulating mixture (in the form of an opalescent solution) was sprayed onto the lactose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 7 to 11 and pressed into tablets using round, slightly biconvex punches.
The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating) and optionally Gelucire 50/13 (2%, lauryl macrogol glycerides) as a second layer. The tablets were packed in aluminium bags under reduced oxygen partial pressure (3-4 % v/v oxygen, 10 % v/v oxygen, 15 % v/v oxygen).
Example 48:
* corresponds to 40 mg of atorvastatin
The hydroxypropyl cellulose was dissolved in isopropyl alcohol and sodium phosphate tribasic, atorvastatin hemimagnesium and sodium laurylsulfate were added. The obtained granulating mixture (in the form of an suspension) was sprayed onto the sucrose in a fluid bed granulator. The resulting granulate was dried and sieved and mixed with the components 6 to 9 and pressed into tablets using round, slightly biconvex punches.
The obtained tablet cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure and in air and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC. Example 49:
* corresponds to 40 mg of atorvastatin
A 0,6 kg batch was prepared. Atorvastatin hemimagnesium and Gelucire were mixed in a double-wall high-shear mixer. During the granulation process the external space of mixer were heated to 56°C. The obtained granulate was cooled to the room temperature, sieved and mixed with other ingredients, except magnesium stearate in a biconic mixer. Magnesium stearate was admixed and the obtained mixture was pressed into tablets, using round, slightly biconvex punches to a target hardness of approx. 130 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w according to the core.
The tablets were packed in aluminium bags under reduced oxygen partial pressure and stored at 40°C/75% relative humidity for 2, 4 and 8 weeks. The degradation products were determined by HPLC.
D.) DIRECT COMPRESSION Example 50:
* corresponds to 40 mg of atorvastatin
Atorvastatin Na was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 51 :
corresponds to 40 mg of atorvastatin Atorvastatin Na was first mixed with sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 52:
* corresponds to 40 mg of atorvastatin
Atorvastatin Na was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure. Example 53:
* corresponds to 40 mg of atorvastatin
Atorvastatin Na was first mixed with sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 54:
* corresponds to 40 mg of atorvastatin
Atorvastatin Na was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 55:
* corresponds to 40 mg of atorvastatin
Atorvastatin Na was first mixed with sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure. Example 56:
* corresponds to 40 mg of atorvastatin
A 20.0 kg batch was prepared. The components 1 to 6 were mixed in a high-shear mixer. Magnesium stearate was admixed and the obtained mixture was pressed into tablet cores, using round, slightly biconvex punches to a target hardness of approx. 90 N. The loss on drying of the above compression mixture was 2.4%. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w according to the core.
Examples 57-59:
* corresponds to 40 mg of atorvastatin
A 1 kg batch was prepared. First atorvastatin sodium and dextrates were mixed. The obtained mixture was mixed with other ingredients, except sodium stearyl fumarate, in a biconic mixer. Sodium stearyl fumarate was admixed and the obtained mixture was pressed into tablet cores, using round, slightly biconvex punches to a target hardness of approx. 90 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w relative to the core.
Example 60:
corresponds to 40 mg of atorvastatin
A 1 kg batch was prepared. The components 1 to 6 were mixed in a biconic mixer. Sodium stearyl fumarate was admixed and the obtained mixture was pressed into tablet cores, using round, slightly biconvex punches to a target hardness of approx. 100 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w relative to the core.
Example 61 :
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 62:
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 63:
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure. Example 64:
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating). The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 65:
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were mixed. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 66:
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure. Example 67:
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except magnesium stearate, were added. In the end magnesium stearate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 68:
corresponds to 40 mg of atorvastatin Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except magnesium stearate, were mixed. In the end magnesium stearate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 69:
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure. Example 70:
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except stearyl fumarate, were added. In the end stearyl fumarate was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating). The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 71 :
* corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with Na2CO3 and sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and the compression mixture was compressed into cores. The cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure.
Example 72:
corresponds to 40 mg of atorvastatin
Atorvastatin Mg was first mixed with sodium laurylsulfate; other excipients, except hydrogenated vegetable oil, were added. In the end hydrogenated vegetable oil was added and compression mixture was compressed into cores. These cores were further coated with Opadry Il HP (3 % w/w of coating).
The tablets were packed in aluminium bags under reduced oxygen partial pressure. Example 73:
* corresponds to 40 mg of atorvastatin
A 20.0 kg batch was prepared. The components 1 to 6 were mixed in a high-shear mixer. Magnesium stearate was admixed and the obtained mixture was pressed into tablets, using round, slightly biconvex punches to a target hardness of approx. 90 N. The loss on drying of the compression mixture was 2.4%. The obtained cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w according to the core.
Examples 74-76:
* corresponds to 40 mg of atorvastatin
A 1 kg batch was prepared. First atorvastatin magnesium and dextrates were mixed. The obtained mixture was mixed with other ingredients, except sodium stearyl fumarate, in a biconic mixer. Sodium stearyl fumarate was admixed and the obtained mixture was pressed into table cores, using round, slightly biconvex punches to a target hardness of approx. 90 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w relative to the core.
Example 77:
corresponds to 40 mg of atorvastatin
A 1 kg batch was prepared. The components 1 to 6 were mixed in a biconic mixer. Sodium stearyl fumarate was admixed and the obtained mixture was pressed into tablets, using round, slightly biconvex punches to a target hardness of approx. 100 N. The cores were coated in a coating pan with Opadry Il HP (PVA based polymer) - 3% w/w relative to the core.

Claims

CLAIMS:
1. Polymorph Form I of the sodium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 4.3, 5.9, 8.7, 11.3, 12.2, 14.2, 19.0, 22.9 ±0.2.
2. Polymorph Form Il of the sodium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 5.3, 8.3, 18.3 ±0.2.
3. Polymorph Form III of the sodium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 5.6, 8.4, 9.5, 14.4, 16.2, 22.7 ±0.2.
4. Polymorph Form IV of the sodium salt of atorvastatin having an X-ray powder diffraction pattern, showing peaks at the following 2-theta values measured by using CuKα-radiation: 5.1 , 5.7, 6.6, 8.5, 10.3, 13.4 and 18.8 ±0.2.
5. Polymorph Form V of the sodium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks of the following 2-theta values measured by using CuKα-radiation: 6.4, 8.1 , 9.7, 10.5, 11.6, 18.9, 20.0 ±0.2.
6. Amorphous form of the sodium salt of atorvastatin.
7. Polymorph form or amorphous form according to any of claims 1 to 6 which is in the form of a solvate in particular a hydrate thereof.
8. Polymorph form or amorphous form according to claim 7, wherein the solvate includes water, alcohols, ketones, and /or ethers.
9. Method of preparing atorvastatin sodium Form I according to claim 1 comprising: i.) partial evaporation of an aqueous solution of atorvastatin sodium containing a water miscible co-solvent, optionally being saturated with a water immiscible solvent, to such a degree that volatile, low melting co- solvents are completely removed, and also that gelatinous precipitate is formed, and ii.) complete removal of residual solvents.
10. Method according to claim 9, wherein the water miscible co-solvent is methanol, 1 ,4-dioxane or te/t-butanol, and the optional water immiscible solvent is te/t-butyl methyl ether.
11. Method according to claim 9 or 10, wherein the complete removal of residual solvents is achieved by freezing the suspension, followed by freeze drying under high vacuum.
12. Method of preparing atorvastatin sodium Form Il according to claim 2, comprising: i.) partial evaporation of an aqueous solution of atorvastatin sodium containing a water miscible co-solvent, optionally being saturated with a water immiscible solvent, to such a degree that volatile, low melting co- solvents are completely removed, while precipitation should not take place, and ii.) complete removal of residual solvents.
13. Method according to claim 12, wherein the water miscible co-solvent is 1 ,4- dioxane or te/t-butanol, and the optional water immiscible solvent is te/t-butyl methyl ether.
14. Method according to claim 12 or 13, wherein the complete removal of residual solvents is achieved by freezing the suspension, followed by freeze drying under high vacuum.
15. Method of preparing atorvastatin sodium Form III according to claim 3, comprising contacting Form Il of atorvastatin sodium with humid air at temperatures from about 200C to about 800C.
16. Method of preparing atorvastatin sodium Form IV according to claim 4, comprising: i.) hydrolysis of atorvastatin tert-butyl ester with sodium hydroxide in 20% to 50% (v/v) aqueous methanol, preferably in 35% (v/v) 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 effect precipitation and/or crystallization.
17. Method of preparing atorvastatin sodium Form V according to claim 5, comprising: i.) concentrating a solution of atorvastatin sodium in 50% to 90% (v/v) aqueous methanol, preferably in about 85% (v/v) aqueous methanol, to about one third of the original volume under reduced pressure, and ii.) cooling the resulting solution to about 0 0C in order to effect precipitation and/or crystallization.
18. Method of preparing amorphous atorvastatin sodium according to claim 6, comprising spray-drying a solution of atorvastatin sodium.
19. Polymorph form I of the hemi-magnesium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 4.8, 7.2, 8.8, 18.2, 18.9 ±0.2.
20. Polymorph form Il of the hemi-magnesium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 3.1 , 9.1 , 11.6, 12.4, 14.3, 18.5, 19.2 ±0.2.
21. Polymorph form III of the hemi-magnesium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 7.6, 9.1 , 9.6, 12.1 , 20.1 , 22.4 ±0.2.
22. Polymorph form IV of the hemi-magnesium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 3.2, 8.9, 11.6, 17.3, 18.5, 22.0, 28.1 ±0.2.
23. Polymorph form V of the hemi-magnesium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 7.6, 9.5, 11.7, 20.0, 21.9, 24.1 ±0.2.
24. Polymorph form Vl of the hemi-magnesium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 8.5, 12.0, 14.3, 18.4, 19.2, 20.1 ±0.2.
25. Polymorph form VII of the hemi-magnesium salt of atorvastatin having an X- ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 5.7, 8.5, 9.1 , 11.8, 18.2 ±0.2.
26. Polymorph form VIII of the hemi-magnesium salt of atorvastatin having an X- ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 8.6, 10.0, 11.5, 16.5, 20.1 , 21.6, ±0.2.
27. Polymorph form IX of the hemi-magnesium salt of atorvastatin having an X-ray powder diffraction pattern showing peaks at the following 2-theta values measured by using CuKα-radiation: 3.3, 8.9, 9.2, 9.9, 18.2, 21.9, 23.3 ±0.2.
28. Amorphous form of hemi-magnesium salt of atorvastatin.
29. Polymorph form or amorphous form according to any one of claims 19 to 28, which is in the form of a solvate, in particular a hydrate, thereof.
30. Method of preparing atorvastatin hemi-magnesium Form I according to claim 19, comprising:
(i) adding to a solution of form I atorvastatin sodium salt according to claim
1 an organic or inorganic magnesium salt, and (ii) precipitating or crystallizing the product.
31. Method of preparing atorvastatin hemi-magnesium Form Il according to claim
20, comprising:
(i) dissolving atorvastatin Mg in a solvent from the group comprised of acetone, ethanol, methanol, 1-butanol or 2-butanol, at an elevated temperature between 300C to the reflux temperature,
(ii) cooling to room temperature, and
(iii) adding water in an amount between 5 to 50 ml/ 1g of atorvastatin Mg, and/or a hydrocarbon solvent, such as e.g. pentane, hexane, heptane or cyclohexane.
32. Method of preparing atorvastatin hemi-magnesium Form III according to claim
21 , comprising:
(i) slurrying atorvastatin magnesium salt in water, at a temperature of the boiling point of the suspension.
33. Method of preparing atorvastatin hemi-magnesium Form IV according to claim
22, comprising:
(i) dissolving atorvastatin Mg in methanol, and
(ii) precipitating the product by the addition of 1-4 parts of water (v/v) water at a temperature between 200C and 40°C.
34. Method of preparing atorvastatin hemi-magnesium Form V according to claim
23, comprising:
(i) slurrying atorvastatin magnesium salt under magnetical stirring in water, at an elevated temperature between 400C and 70°C.
35. Method of preparing atorvastatin hemi-magnesium Form Vl according to claim
24, comprising:
(i) dissolving atorvastatin Mg in a solvent from the group comprised of ethyl acetate, ethanol, methanol, 1-butanol or 2-butanol, at a temperature between 200C and the boiling point, and
(ii) adding water to the solution in an amount between 0.5 to 30 ml/ 1g of atorvastatin Mg.
36. Method of preparing atorvastatin hemi-magnesium Form VII according to claim 25, comprising:
(i) dissolving atorvastatin Mg in a solvent from the group comprised of ethanol or 1-butanol, and water in an amount between 10 to 20 ml/ 1g of atorvastatin Mg, at a temperature between 500C and the reflux temperature of the solution, and
(ii) cooling the solution to room temperature.
37. Method of preparing atorvastatin hemi-magnesium salt Form VIII according to claim 26, comprising:
(i) slurrying atorvastatin magnesium salt under mechanical stirring or magnetical stirring in water, in an amount of between 0.0005 and 0.07 g of atorvastatin Mg/ml of water, and at an elevated temperature between 200C and 70°C.
38. Method of peparing atorvastatin hemi-magnesium salt Form IX according to claim 27, comprising:
(i) dissolving atorvastatin Mg in a mixture of an alcohol, such as ethanol, and water, and (ii) leaving the solution to crystallize for prolonged periods of time, e.g. for
3-20 days, at room temperature.
39. Method for preparing amorphous form atorvastatin hemi-magnesium according to claim 28, comprising
(i) evaporating a solution of atorvastatin hemi-magnesium in alcohols in vacuum, (ii) cooling hot solutions of atorvastatin hemi-magnesium in 2-propanol or acetonitrile, or (iii) precipitating from a solution of atorvastatin hemi-magnesium in alcohol or ketone, preferably ethylmethyl ketone, by addition of a hydrocarbon.
40. Pharmaceutical composition comprising a polymorph form or an amorphous form according to any one of claims 1 to 8 or 19 to 29, together with at least one pharmaceutically acceptable excipient.
41. Composition according to claim 40, which is in the form of tablets, pills, dispersible granules, capsules, powders, lozenges, or suppositories.
42. Use of the polymorph form or amorphous form according to any one of claims 1 to 8 or 19 to 29 for the preparation of a medicament, and in particular for treating hypercholesteremia or hyperlipidemia.
EP07728152A 2006-04-14 2007-04-16 Polymorphs of atorvastatin sodium and magnesium salts Withdrawn EP2049479A2 (en)

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