Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/282—Organic compounds, e.g. fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds

Definitions

• the present invention relates to crystalline polymorphic forms of atorvastatin hemi-calcium, novel processes for preparing crystalline forms of atorvastatin hemi- calcium and crystalline atorvastatin hemi-calcium with a small particle size distribution
• Atorvastatin ([R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(l-methylethyl)-3- pl ⁇ enyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid), depicted in lactone form in formula (I) and its calcium salt trihydrate of formula (II) are well known in the art, and described, inter alia, in U.S. Patents Nos. 4,681,893, 5,273,995, and in copending USSN 60/166,153, filed November 17, 2000, all of which are herein incorporated by reference.
• Atorvastatin is a member of the class of drugs called statins.
• Statin drugs are currently the most therapeutically effective drugs available for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease.
• LDL low density lipoprotein
• a high level of LDL in the bloodstream has been linked to the formation of coronary lesions which obstruct the flow of blood and can rupture and promote thrombosis.
• the Pharmacological Basis of Therapeutics 879 (9th ed. 1996). Reducing plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and patients who are free of cardiovascular disease but who have hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.
• statin drags The mechanism of action of statin drags has been elucidated in some detail. They interfere with the synthesis of cholesterol and other sterols in the liver by competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme ("HMG-CoA reductase"). HMG-CoA reductase catalyzes the conversion HMG to mevalonate, which is the rate determining step in the biosynthesis of cholesterol, and so, its inhibition leads to a reduction in the concentration of cholesterol in the liver. Very low density lipoprotein (NLDL) is the biological vehicle for transporting cholesterol and triglycerides from the liver to peripheral cells.
• NLDL Very low density lipoprotein
• NLDL is catabolized in the peripheral cells which releases fatty acids which may be stored in adopcytes or oxidized by muscle.
• the NLDL is converted to intermediate density lipoprotein (IDL), which is either removed by an LDL receptor, or is converted to LDL.
• IDL intermediate density lipoprotein
• Decreased production of cholesterol leads to an increase in the number of LDL receptors and corresponding reduction in the production of LDL particles by metabolism of IDL.
• Atorvastatin hemi-calcium salt trihydrate is marketed under the name LIPITOR by Warner-Lambert Co. Atorvastatin was first disclosed to the public and claimed in U.S.
• Patent No. 4,681,893 The hemi-calcium salt depicted in formula (II) is disclosed in U.S. Patent No. 5,273,995.
• the '995 patent teaches that the hemi-calcium salt is obtained by crystallization from a brine solution resulting from the transposition of the sodium salt with CaCl 2 and further purified by recrystaUization from a 5:3 mixture of ethyl acetate and hexane.
• the present invention provides new crystal forms of atorvastatin hemi-calcium in both solvated and hydrated states.
• the occurrence of different crystal forms (polymorphism) is a property of some molecules and molecular complexes.
• a single molecule like the atorvastatin in formula (I) or the salt complex of formula (II), may give rise to a variety of solids having distinct physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and NMR spectrum.
• the differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid.
• polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family.
• One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment.
• Crystalline Forms I, II, III and IN of atorvastatin hemi-calcium are the subjects of
• Fig. 1 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form VI obtained using a conventional X-ray generator with a copper anode.
• Fig. 2 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form Nil obtained using a conventional X-ray generator with a copper anode.
• Fig. 3 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form NIII obtained using a conventional X-ray generator with a copper anode.
• Fig. 4 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form NIII obtained using a synchrotron X-ray source.
• Fig. 5 is a characteristic solid state 13 C ⁇ MR spectrum of atorvastatin Form NIII.
• Fig. 6 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form IX obtained using a conventional X-ray generator with a copper anode.
• Fig. 7 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form IX obtained using a synchrotron X-ray source.
• Fig. 8 is a characteristic solid state 13 C ⁇ MR spectrum of atorvastatin Form IX.
• Fig. 9 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form X obtained using a conventional X-ray generator with a copper anode.
• Fig. 10 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form X obtained using a synchrotron X-ray source.
• Fig. 11 is a characteristic solid state 13 C ⁇ MR spectrum of atorvastatin hemi- calcium Form X.
• Fig. 12 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi- calcium Form XI obtained using a conventional X-ray generator with a copper anode.
• Fig. 13 is an overlay of typical powder X-ray diffraction patterns of atorvastatin hemi-calcium Form XII obtained using a conventional X-ray generator with a copper anode.
• the present invention provides new atorvastatin hemi-calcium solvates and hydrates.
• the present invention provides a novel crystalline form of atorvastatin hemi- calcium denominated Form VI and novel processes for its preparation.
• the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form NIII and novel processes for its preparation.
• the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form IX and novel processes for its preparation. In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form X and novel processes for its preparation.
• the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form XI and novel processes for its preparation.
• the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form XII and novel processes for its preparation.
• the present invention provides novel processes for preparing atorvastatin hemi-calcium Form I.
• the present invention provides novel processes for preparing atorvastatin hemi-calcium Form II. In another aspect, the present invention provides novel processes for preparing atorvastatin hemi-calcium Form IN.
• the present invention provides novel processes for preparing atorvastatin hemi-calcium Form N.
• the present invention provides novel processes for preparing amorphous atorvastatin hemi-calcium
• compositions and dosage forms comprising atorvastatin hemi-calcium Forms VI, Nil, NIII, IX, X, XI and their mixtures.
• Synchrotron Light Source of the Brookhaven National Laboratory (diffractometer station X3B1). Samples were loosely packed into thin-walled glass capillaries. X-ray radiation was approximately 1J5 A. Since the wavelength of incident light does correspond to the wavelength most commonly used in conventional PXRD analysis, X-ray peak positions in the diffraction patterns obtained from the synchrotron source are expressed in terms of d spacings, which are invariant with changes in wavelength of the X-radiation used to produce the pattern. The scan width was from 1 to 20 degrees 2 ⁇ . The resolution of the spectra is in the range of 0.01 to 0.03 degrees full width at half maximum. The positions of well resolved peaks are accurate to within 0.003 to 0.01 degrees.
• Atorvastatin hemi-calcium Form VI is characterized by a powder X-ray diffraction pattern (Fig. 1) with peaks at 3.5, 5.1, 7.7, 8.2, 8.7, 10.0, 12.5, 13.8, 16.2, 17.2, 17.9 18.3,
• Atorvastatin hemi-calcium Form VI may be obtained by dissolving any other form of atorvastatin hemi-calcium, preferably Form I, in acetone and then precipitating Form VI by addition of an anti-solvent, preferably water.
• Atorvastatin hemi-calcium Form VII is characterized by a powder X-ray diffraction pattern (Fig. 2) having two broad peaks, one in the range 18.5-21.8 and the other in the range of 21.8-25.0 degrees 2 ⁇ , and other additional broad peaks at 4.7, 7.8, 9.3, 12.0, 17.1, 18.2 ⁇ 0.2 degrees 2 ⁇ .
• Samples of Form Nil may contain up to 12% water.
• Form Nil is readily distinguished from known forms of atorvastatin hemi-calcium by the broad peaks at 7.8 and 9.3 ⁇ 0.2 degrees 2 ⁇ . For instance, Form I has peaks at 9.2, 9.5, 10.3, 10.6, 11.0 and 12.2 degrees 2 ⁇ according to the information provided in U.S.
• Atorvastatin hemi-calcium Form Nil may be prepared by treating atorvastatin calcium Forms I or N with ethanol, preferably absolute ethanol, at room temperature to reflux temperature for a period of from about 1 h to about 24 h, preferably 2.5-16 h. If the process is carried out in refluxing EtOH, the conversion is complete in about 2.5 h. If the process is carried out at room temperature a longer period is required.
• Atorvastatin hemi-calcium Form NIII is characterized by a powder X-ray diffraction pattern (Fig. 3) obtained using conventional CuK,, radiation having peaks at 4.8, 5.2, 5.9, 7.0, 8.0, 9.3, 9.6, 10.4, 11.9, 16.3, 17.1(hroa ), 17.9, 18.6, 19.2, 20.0, 20.8, 21.1, 21.6, 22.4, 22.8, 23.9, 24.7, 25.6, 26.5, 29.0 ⁇ 0.2 degrees two-theta. The most characteristic peaks are at 6.9, 9.3, 9.6, 16.3, 17.1, 19.2, 20.0, 21.6, 22.4, 23,9, 24.7, 25.6, and 26.5 ⁇ 0.2 degrees 2 ⁇ . Samples of atorvastatin hemi-calcium Form NIII were found to contain up to 7% water by Karl Fisher. Form NIII is readily distinguished from
• Forms I-IN by its characteristic sharp peaks at 9.3 and 9.6 degrees 2 ⁇ . According to the information provided in U.S. Patent No. 5,969,156, Form I has one medium peak at 6.9 and sharp peaks at 9.2, 9.5, 10.3, 10.6, 11.0 and 12.2 ⁇ 0.2 degrees 2 ⁇ . Form IN is said to have two peaks at 8.0 and 9.7 degrees 2 ⁇ . Form II is said to have in this region two sharp peaks at 8.5 and 9.0 degrees 2 ⁇ . Form III has in this region one strong sharp peak at 8.7 degrees 2 ⁇ according to the information provided in U.S. Patent No. 6,121 ,461. The features are not observed in the Form VIII PXRD pattern.
• peaks in the Form NIII pattern that are unique to this form are the two strong and sharp peaks at 19.2 and 20.0 degrees 2 ⁇ .
• Form I has sharp peaks at 21.6, 22.7, 23.3 and 23.7 degrees 2 ⁇ according to the information provided in the '156 patent.
• Form IN is said to have peaks at 18.4 and 19.6 degrees 2 ⁇ , while Form II has two main peaks at 17.0 and 20.5 and Form III has peaks at 17.7, 18.2, 18.9, 20.0 and 20.3 ⁇ 0.2 degrees 2 ⁇ .
• Form NIII Synchrotron X-ray powder diffraction analysis was performed on Form NIII to determine its crystal system and unit cell dimensions.
• the unit cell parameters were determined using the Le Bail method.
• the diffractogram of Fig. 4 obtained using a synchrotron X-ray source has many sharp well resolved peaks.
• the -/-spacings of some of the more prominent peaks are listed in Table 1, along with the positions in units of two-theta that the peaks would have using CuK,. radiation of 1.5418A.
• Form NIII produced the solid-state 13 C ⁇ MR spectrum shown in Fig. 5.
• Form NIII is characterized by the following solid-state 13 C nuclear magnetic resonance chemical shifts inppm: 17.8, 20.0, 24.8, 25.2, 26J, 40.3, 40.8, 41.5,
• Form NIII is characterized by a solid-state 13 C nuclear magnetic resonance having the following chemical shifts differences between the lowest ppm resonance and other resonances: 2.2, 7.0, 7.4, 8.3,
• Atorvastatin hemi-calcium Form NIII can exist as an ethanol solvate containing up to about 3 % ethanol by weight.
• Form NIII The following methods have been found suitable for generating Form NIII. This form may, however, also be accessible by empirical development and by routine modification of these procedures.
• Atorvastatin hemi-calcium Form NIII may be obtained by slurrying atorvastatin hemi-calcium in a mixture of ethanol and water at elevated temperature, preferably about
• the slurrying procedure may be incorporated into the last step of a process for preparing atorvastatin hemi-calcium, which typically is generation of the hemi-calcium salt from the atorvastatin free acid or lactone by treatment with a source of calcium ion.
• the salt is generated in a solvent system comprising ethanol and water.
• the salt may be slurried in the reaction mixture for a period of several hours, preferably from about 6 to about 16 hours to obtain atorvastatin hemi- calcium Form NIII.
• Form NIII also may be obtained starting from Form N by treating Form N with a mixture of EtOH:H 2 O, preferably in the ratio of about 5 : 1 at an elevated temperature below reflux, preferably 78-80 °C.
• An especially preferred EtOH:H 2 O mixture contains about 4 % by volume water in ethanol.
• atorvastatin Form N gradually dissolves and at the point of 78-80°C turbidity, with or without seeding, is observed. At this point the suspension is immediately cooled to room temperature.
• Form NIII may be obtained by treating atorvastatin hemi-calcium in EtOH, preferably absolute EtOH, at elevated temperature, preferably boiling EtOH. Under these conditions, the atorvastatin dissolves and reprecipitates.
• MeOH may be added at reflux. Added MeOH may adversely affect the yield, but may improve the chemical purity of the product.
• Starting materials for preparing Form NIII by this process can be crystalline forms of atorvastatin hemi-calcium, preferably Forms I and N and mixtures thereof or amorphous atorvastatin hemi-calcium.
• the quantity of EtOH or mixture thereof with water is preferably in the range of from about 10 to about 100 ml g "1 , more preferably about 20 to about 80 ml g "1 .
• atorvastatin hemi-calcium that contains greater than 0.1% des-fluoro atorvastatin hemi-calcium and/or greater than 1 % trans atorvastatin hemi- calcium may be purified by suspending in a solution of about 96% ethanol and about 4% water at elevated temperature, preferably at reflux temperature.
• atorvastatin hemi-calcium is recovered with less than 0.07% contamination with des-fluoro atorvastatin hemi-calcium and less than 0.6% contamination with trans atorvastatin hemi- calcium.
• Form NIII also may be prepared by suspending atorvastatin hemi-calcium in certain 1-butanol/water and ethanol/water mixtures for a period of time sufficient to cause the conversion of the atorvastatin hemi-calcium to Form NIII.
• 1-Butanol/water mixtures should contain about 20% 1-butanol by volume at elevated temperature, preferably at reflux temperature.
• Atorvastatin hemi-calcium Form IX is characterized by a powder X-ray diffraction pattern (Fig.
• Form IX may contain up to 7% water.
• Form IX also can exist as a butanol solvate containing up to about 5 % butanol.
• Form IX is readily distinguished by its characteristic sharp peaks at 18.6, 19J, 19.9, 21.4, 22.5, 23.5 degrees 29.
• Form I has sharp peaks at 21.6, 22.7, 23.3 and 23.7 degrees 29
• Form IN has in this region sharp peaks at 18.4 and 19.6 degrees 29
• Form II has two main peaks at 17.0 and 20.5 degrees 29, according to information in the '156 patent.
• Form III has in this region peaks at 17.7, 18.3, 18.9, 20.0 and 20.3 degrees 29.
• there is in the PXRD pattern of Form IX as there is in the pattern of Form NIII, a sharp, well distinguished medium intensity peak at 7.0 degrees 29.
• Atorvastatin hemi-calcium Form IX produced the solid-state 13 C NMR spectrum shown in Fig. 8.
• Form IX is characterized by the following solid-state 13 C nuclear resonance chemical shifts in ppm: 18.0, 20.4, 24.9, 26.1, 40.4, 46.4, 71.0, 73.4, 114.3, 116.0, 119.5, 120.2, 121.7, 122.8, 126.7, 128.6, 129.4, 134.3, 135.1, 136.8, 138.3, 139.4, 159.9, 166.3, 178.4, 186.6.
• Form IX is characterized by a solid-state 13 C nuclear resonance having the following chemical shifts differences between the lowest ppm resonance and other resonances: 2.4, 6.9, 8.1, 22.4, 28.4, 53.0, 55.4, 96.3, 98.0, 101.5, 102.2, 103.7, 104.8, 108.7, 110.6, 111.4, 116.3, 117.1, 118.8, 120.3, 121.4, 141.9, 148.3, 160.4, 168.6. Characteristic parts of the pattern are found at 24-26 ppm (aliphatic range), 119-140 ppm (aromatic range) and other regions.
• the chemical shifts of Form IX are an average taken from spectra on two samples of Form IX. The shift values are accurate to within ⁇ OJ ppm.
• Form IX may be prepared by the following processes though this form may be accessed by empirical development and by routine modification of these procedures.
• Atorvastatin hemi-calcium Form IX may be prepared by slurrying atorvastatin hemi-calcium in butanol and isolating Form IX by, for example, filtration or decantation of the butanol, preferably by filtration. Preferred temperature ranges for the slurrying are from 78°C to the reflux temperature of the solvent.
• Recovery of atorvastatin hemi- calcium salt from the slurry can be enhanced by addition of an anti-solvent to the slurry before isolating Form IX.
• Preferred anti-solvents include isopropanol and «-hexane.
• Starting materials for preparing Form IX by this process can be crystalline or amorphous atorvastatin hemi-calcium, preferably Forms I and N and mixtures thereof.
• Form IX may be prepared by suspending Form NIII in ethanol, preferably absolute ethanol, at room temperature for a period of time sufficient to convert form NIII to Form IX, which may range from a few hours to 24 hours and typically requires about 16 hours. Thereafter Form IX is recovered from the suspension. Form IX also may be prepared by maintaining Form NIII under a humid atmosphere.
• Form IX also may be prepared by suspending atorvastatin hemi-calcium Form N in mixtures of 1 -butanol and either ethanol or water at reflux temperature for a period of time sufficient to convert Form N into Form IX and recovering Form IX from the suspension.
• the mixtures Preferably contain about 50 volume percent of each component.
• Atorvastatin hemi-calcium Form X is characterized by a powder X-ray diffraction pattern (Fig. 7) having peaks at 4.8, 5.3, 5.9, 9.6, 10.3, 11.5, 12.0, a double peak at 16.1 and 16.3, 16.9, 17.4, 18.2, 19.2, 19.4, 20.0, 20.8, 21.6, 22.0, 22.8, 23.6, 24.6, 25.0, 25.5, 26.2, 26.8, 27.4, 28.0, 30.3 ⁇ 0.2 degrees 29.
• the most characteristic peaks are two peaks at 20.0 and 20.8 ⁇ 0.2 degrees 20 and other peaks at 19J, 19.4, 22.8, 23.6, 25.0, 28.0, 30.3 ⁇ 0.2 degrees 29.
• Form X contains up to 2% ethanol and may contain up to 4% water.
• Form X is distinguished from that of Form IN by having characteristic peaks at 7.0, 19.9, 20.7, 24.1, 25.0, 28.0 and 30.3 ⁇ 0.2 degrees 29. These features are clearly distinguished from those appearing the corresponding regions of the PXRD patterns of
• the peak positions may deviate from the reported positions by as much as 0.5%. There may be larger shifts if the material undergoes size reduction as micronization.
• Form X produced the solid-state 13 C NMR spectrum shown in Fig. 11.
• Form X is characterized by the following solid-state I3 C nuclear resonance chemical shifts in ppm: 17.7, 18J, 19.6, 20.6, 24.9, 43.4, 63.1, 66.2, 67.5, 71.1, 115.9, 119.5, 122.4, 126.7, 128.9, 134.5, 138.0, 159.4, 166.2, 179.3, 181.1, 184.3, 186.
• Form X is characterized by a solid-state 13 C nuclear magnetic resonance having the following chemical shifts differences between the lowest ppm resonance and other resonances: 1.0, 1.9, 2.9, 7.2, 25.7, 45.4, 48.5, 49.8, 53.4, 98.2, 101.8, 104.7, 109.0, 111.2, 116.8, 120.3, 141.7, 148.5, 161.6, 163.4, 166.6, 168.4.
• Characteristic parts of the pattern are found at 24-26 ppm (aliphatic range), 119-140 ppm (aromatic range) and other regions.
• the chemical shifts of Form X are averaged from three spectra taken of three samples of Form X. The values reported are within ⁇ 0.1 ppm, except for the carbonyl . peak at 179. 3 ppm that is accurate within ⁇ 0.4 ppm.
• Atorvastatin hemi-calcium Form X may be prepared by treating crystalline atorvastatin hemi-calcium, preferably Form N or Form I or mixtures thereof, or amorphous atorvastatin hemi-calcium with a mixture of ethanol and water, preferably in a ratio of about 5:1, at elevated temperature, preferably at reflux temperature, for a period of from about half an hour to a few hours, preferably about 1 h.
• the starting material may be added to the EtOH:water mixture at room temperature, followed by gradual heating of the suspension to reflux.
• the starting form of atorvastatin hemi-calcium may be added to the refluxing solvent mixture.
• the atorvastatin hemi- calcium should be observed to dissolve in the mixture and then reprecipitate in Form X.
• the ratio of atorvastatin hemi-calcium to the EtOH: water mixture preferably ranges from about 1:16 to about 1:25 (g:ml), more preferably from about 1:16 to about 1:21 (g:ml) and most preferably about 1:16 (g:ml).
• Form X may be collected by filtration shortly after cooling to room temperature or the suspension may be stirred for an addition period of from about 1 to about 20 hours, more preferably from about 3 to about 16 hours, before collecting the Form X.
• Atorvastatin hemi-calcium Form XI is characterized by a powder X-ray diffraction pattern (Fig. 9) having peaks at 3.2, 3.7, 5.1, 6.3, 7.8, 8.6, 9.8, 11.2, 11.8, 12.4, 15.4, 18.7, 19.9, 20.5, 24.0 ⁇ 0.2 degrees two-theta.
• Form XI may be obtained by suspending atorvastatin hemi-calcium Form N in methyl ethyl ketone ("MEK”) at room temperature for a period of time sufficient to cause the conversion of Form N into Form XI.
• Form XI also may be obtained by preparing a gel containing atorvastatin hemi- calcium in isopropyl alcohol and then drying the gel. The gel is best prepared by saturating isopropyl alcohol with atorvastatin hemi-calcium at reflux temperature and then cooling to room temperature. Extensive stirring at room temperature, as long as or more than 20 h, may be required in order for the gel to form. In the gel state, the solution is detectably more resistant to stirring and does not pour smoothly. The gel remains flowable in the sense that it can be stirred if sufficient force is applied and would not tear under such force.
• MEK methyl ethyl ketone
• Atorvastatin hemi-calcium Form XII is characterized by a powder X-ray diffraction pattern having peaks at 2.1, 8.0, 8.4, 11.8, 18.2, 19.0, 19.8, 20.7 ⁇ 0,2 degrees two-theta, and a halo that indicates the presence of amorphous material.
• Typical X-ray powder diffraction patterns of atorvastatin hemi-calcium Form XII are shown in Fig. 10.
• Form XII may be prepared directly from the following compound
• Form XII is prepared by first subjecting PAE to conditions that cleave the acetonide and tert-butyl ester group. Prefered conditions employ aqueous hydrochloric acid, more preferably about 1.5% aqueous hydrochloric acid.
• the solution of atorvastatin, in either free acid or lactone form, or mixture thereof, is then treated with calcium hydroxide, preferably a modest excess thereof, more preferably about 1.5 equivalents with respect to the PAE.
• any excess calcium hydroxide may be separated by filtration.
• One important feature of this process is the subsequent manipulation of the filtrate. Water is slowly added to the reaction mixture at mildly elevated temperature, preferably about 65 °C, until atorvastatin hemi-calcium precipitates. At that point the temperature is increased until a clear solution is once again attained. The mixture is then allowed to cool resulting in the precipitation of atorvastatin hemi-calcium.
• the isolated precipitate is atorvastatin hemi-calcium Form XII.
• the present invention also provides novel processes for preparing known forms of atorvastatin hemi-calcium.
• Form I may be obtained by treating any form of atorvastatin hemi-calcium with water at room temperature to 100°C for a period between a few to about 25 hours, preferably about 16 hours.
• Preferred starting materials are Forms N, Nil, NIII, IX and X of atorvastatin hemi-calcium.
• Form I also may be prepared by sonicating a suspension of atorvastatin hemi- calcium in ethanol, preferably absolute ethanol or in water, at between room temperature and the reflux temperature of the solvent for a period of a few minutes. Preferably between 1 and 3 minutes. Atorvastatin hemi-calcium Form Nil is a preferred starting material though other forms may be used as well.
• Form II may be prepared directly from [R-(R*,R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ - dioxane-5 -( 1 -methylethy l)-3 -phenyl-4- [(phenylamino)carbonyl] - 1 H-pyrrole- 1 -tert- butylheptanoic ester (PAE) according to Example 31.
• Atorvastatin hemi-calcium Form IN may be prepared by suspending Form I or Form N in 1 -butanol for a period of time sufficient to complete the conversion of
• Form I or Form N to Form IN and then isolating Form IN from the mixture.
• the conversion may require a prolonged period depending on temperature and other conditions.
• the conversion typically takes about 24-72 hours at room temperature.
• Form IN also may be obtained by suspending Form N in EtOH/H 2 O at 50 °C for a period of time sufficient to cause the conversion of Form N to Form IN and then recovering Form IN from the suspensions.
• Prefered EtOH/H 2 O mixtures contain about 15% H 2 O.
• Form IN also may be obtained by suspending atorvastatin hemi-calcium Form N in methanol for a period of time sufficient to cause the conversion of Form N to Form IN.
• the rate of conversion is sensitive to temperature and may take from about 1 to about 25 hours under typical laboratory conditions. The conversion requires about 16 hours, at room temperature. The conversion may be conducted at elevated temperature up to the reflux temperature of the solvent.
• Form N may be prepared from PAE according to the process described with reference to the preparation of atorvastatin hemi-calcium Form XII.
• Form N may be obtained by drying Form XII at about 65 °C for about 24 hours.
• the atorvastatin hemi-calcium Form N obtained in this manner is of high purity. However, it may be further purified by suspending in a mixture of about 10% water and about 90% ethanol and re
• Amorphous atorvastatin hemi-calcium may be prepared by treating any other form of atorvastatin hemi-calcium with acetone at room temperature to reflux temperature for between a few hours and 25 hours, preferably about 16 hours.
• a preferred starting material is Form N.
• Amorphous atorvastatin hemi-calcium also may be prepared by sonicating any form of atorvastatin hemi-calcium in acetonitrile at any temperature between room temperature and the reflux temperature of acetonitrile. Sonicating for a few minutes, preferably from 1 to 3 minutes, is sufficient to transform the starting material into amorphous atorvastatin hemi-calcium.
• Preferred starting forms of atorvastatin hemi- calcium are Fonns Nil and I.
• Amorphous atorvastatin hemi-calcium also may be prepared by ball milling of any crystalline form of atorvastatin hemi-calcium.
• a further aspect of the present invention is a pharmaceutical composition and dosage form containing the novel forms of atorvastatin hemi-calcium.
• compositions of the invention include powders, granulates, aggregates and other solid compositions comprising novel Forms NI, Nil, NIII, IX, X, XI and XII of atorvastatin hemi-calcium.
• Forms VI, Nil, NIII, IX, X, XI and XII solid compositions that are contemplated by the present invention may further include diluents, such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents like calcium carbonate and calcium diphosphate and other diluents known to the pharmaceutical industry.
• suitable diluents include waxes, sugars,
• excipients that are within the contemplation of the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes.
• Excipients that also may be present in a solid composition of Forms NI, VII, NIII, IX, X, XI and XII atorvastatin hemi-calcium further include disintegrants like sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others.
• excipients may include tableting lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
• the dosages include dosages suitable for oral, buccal, rectal, parenteral
• inhalant including subcutaneous, intramuscular, and intravenous
• inhalant including subcutaneous, intramuscular, and intravenous
• ophthalmic administration although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
• the Dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
• Dosage forms include solid dosage forms, like tablets, powders, capsules, suppositories, sachets, troches and losenges as well as liquid suspensions and elixirs. While the description is not intended to be limiting, the invention is also not intended to pertain to true solutions of atorvastatin hemi-calcium whereupon the properties that distinguish the solid forms of atorvastatin hemi-calcium are lost. However, the use of the novel forms to prepare such solutions (e.g. so as to deliver, in addition to atorvastatin, a solvate to said solution in a certain ratio with a solvate) is considered to be within the contemplation of the invention.
• Capsule dosages will contain the solid composition within a capsule which may be made of gelatin or other conventional encapsulating material.
• Tablets and powders may be coated. Tablets and powders may be coated with an enteric coating.
• the enteric coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl-cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents.
• a coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric-coating.
• Preferred unit dosages of the pharmaceutical compositions of this invention typically contain from 0.5 to 100 mg of the novel atorvastatin hemi-calcium Forms
• the combined weight of the atorvastatin hemi-calcium forms of a unit dosage are from 2.5 mg. to 80 mg.
• Biolab ® Other reagents were reagent grade and were used as received.
• Ball milling was performed using a Retsch centrifugal ball-mill S-100 equipped with a 250 ml stainless steal milling chamber and twenty seven 10 mm diameter stainless steal balls as milling media.
• Example 1 Atorvastatin hemi-calcium Form I (1 g) was dissolved in acetone (9 ml) at room temperature and stirred for 2.5 hours. Then, water (8.5 ml) was added to get a precipitation and the mixture was then stirred for another 2.5 hours. The white solid was then filtered and dried at 50°C for 5 hrs to obtain atorvastatin hemi-calcium Form VI (0.88 g, 88%).
• Atorvastatin hemi-calcium Form V (1.00 g) was stirred in absolute EtOH (400 ml) at room temperature for 16 h. The solid was collected by filtration and dried at 65 °C for 24 h to give atorvastatin hemi-calcium Form VII (40 mg, 40%).
• Atorvastatin hemi-calcium Form I (75 mg) was stirred in absolute EtOH (30 ml) at room temperature for 16 h. The solid was collected by filtration and dried at 65 °C for 24 h to give atorvastatin hemi-calcium Form VII (0.60 g, 80%).
• Example 5 Atorvastatin hemi-calcium Form I (1 g) was slurried in absolute EtOH (80 ml), under reflux, for 24 hrs. The white solid was then filtered and dried at 65°C for 20 hrs to obtain atorvastatin hemi-calcium Form VIII (0.85 g, 85%).
• Atorvastatin hemi-calcium salt Form V 5.0g of Atorvastatin hemi-calcium salt Form V were added to a boiled solution of Ethanol 96% (150ml). The mixture was refluxed for 2.5 hrs. Then it was cooled to 20 °C during 1.5 hrs, and stirred at this temperature for additional 16 hrs. The solid was filtered, washed with Ethanol 96% (2x25ml) and dried at 65 °C for 20 hrs to give 4.4g (88%o) of Atorvastatin hemi-calcium salt Form VIII. During this process chemical purification occurs, so this process is good also for purification.
• Atorvastatin hemi calcium salt Form V 5.0 g of Atorvastatin hemi calcium salt Form V, with a level of 0.12% of Des- fluoro Atorvastatin, were added to a boiled solution of Ethanol 96% (150ml). The mixture was refluxed for 2.5 hrs. Then it was cooled to 20°C during 1.5 hrs and stirred at this temperature for additional 16 hrs. The solid was filtered, washed with
• Atorvastatin Ethanol 96% (2x25ml) and dried at 65 °C for 20 hrs to give 4.4g (88%) of Atorvastatin hemi calcium salt with a level of 0.06% of Des-fluoro Atorvastatin. Atorvastatin is obtained in Form VIII by this procedure.
• Atorvastatin hemi-calcium Form V (5 g) in absolute EtOH (35 ml) was refluxed for 2.5 h. The reaction mixture was then cooled to room temperature and stirred for an additional 16 h. Absolute ethanol (15 ml) was then added and the suspension was filtered and the collected solids were dried at 65 °C for 20 h to yield atorvastatin hemi-calcium Form VIII (4.7 g, 94%).
• Example 12 Atorvastatin hemi-calcium Form I (1 g) was slurried in 1 -butanol (20 ml) under reflux for 30 minute. Then 7.-hexane (40 ml) was added for further precipitation and the reaction mixture was stirred at room temperature for 2 hours. The white solid was then filtered and dried at 50°C in a vacuum oven for 20 hrs to yield atorvastatin Form IX (0.96 g, 96%).
• Atorvastatin hemi-calcium Form I (1 g) was slurried in 1 -butanol (20 ml) under reflux for 30 minute. Then, IPA (40 ml) was added for further precipitation and the reaction mixture was stirred at room temperature for 2 hours. The white solid was then filtered and dried at 50°C for 20 hrs in a vacuum oven to yield atorvastatin hemi- calcium Form IX (0.94 g, 94%) containing 0.9% water by Karl Fisher analysis.
• Atorvastatin hemi-calcium Form VIII (800 mg) was stirred in absolute EtOH (320 ml) at room temperature for 16 h. The solid was collected by filtration and dried at 65 °C for 24 hours to give atorvastatin hemi-calcium Form IX (630 mg, 79%).
• Example 16 Atorvastatin hemi-calcium Form VIII was stored under 100% relative humidity at room temperature for nine days. The resulting solid was identified as Form IX by powder X-ray diffraction analysis.
• Atorvastatin hemi-calcium salt form IX Example 18 lg of Atorvastatin hemi-calcium salt form V in 1-BuOH (10ml) and EtOH (10ml) was heated to reflux for 1 h. The mixture was then cooled to room temperature and stirred at this temperature for additional 16 hrs. Filtration and drying at 65 °C for 24 hrs gave 0.98g (98%) of Atorvastatin. hemi-calcium salt form IX.
• Atorvastatin hemi-calcium Form V (10.00 g) was suspended in a mixture of EtOH (135 ml) and water (24 ml) and heated to reflux for 1 h. The mixture was then cooled to room temperature and stirred for an addition 16 h. The solid was collected by filtration and dried at 65 °C for 24 h to give atorvastatin hemi-calcium Form X (8.26 g, 83%).
• Atorvastatin hemi-calcium Form V (1.00 g) in a mixture of EtOH (9 ml) and water (1.6 ml) was refluxed for 1 h. The mixture was cooled to room temperature and then stirred an additional 3 h. The solid was collected by filtration and dried at 65 °C for 24 h to give atorvastatin hemi-calcium Form X (0.80 g, 80%).
• Example 21 (Preparation of Atorvastatin Hemi-Calcium Form XI)
• MEK Methylethyl ketone
• the reaction mixture was heated to 40 °C for 9-11 hrs, while a continuous distillation of a mixture of Ethanol, Acetone and water, under reduced pressure (500-600mbar), was performed. Make-up of absolute Ethanol was done every hour (35-40ml.). After 9-11 hours there was a reduction in the level of PAE to below 0.1% (according to HPLC). Without any further treatment, Ca(OH) 2 (1.5eq., 3.4g) were added. The reaction mixture was heated to 70°C for 4-5 hrs. Then the excess of Ca(OH) 2 was collected by filtration. To the hot filtrate (65 °C), 350ml of water were added slowly (using a dosing pump) during 3 /-l hour at 65 °C.
• Atorvastatin hemi-calcium salt precipitated. After the addition of water the reaction mixture was heated to reflux (84 °C) till a clear solution was obtained. Then the mixture was cooled to 20 °C during 3 hrs and was stirred at this temperature for an additional 12-16 hrs. The solid was then filtered to give 45. Og of wet cake of Atorvastatin hemi- calcium salt crystal form XII. (Preparation of Known Atorvastatin Hemi-Calcium Form I)
• Atorvastatin hemi-calcium Form N (1.00 g) was stirred in water (400 ml) at room temperature for 16 h. The solid was collected by filtration and dried at 65 °C for
• Example 25 A mixture of atorvastatin hemi-calcium Form Nil (10.00 g) in water (100 ml) was refluxed for 2 h. The mixture was cooled to room temperature and stirred for an additional hour. The solid was collected by filtration and dried at 65 °C for 24 h to yield atorvastatin hemi-calcium Form I (9.64 g, 96%).
• Example 26 Atorvastatin hemi-calcium Form VIII (800 mg) was stirred in water (320 ml) at room temperature for 16 h. The solid was collected by filtration and dried at 65 °C for 24 h to yield atorvastatin hemi-calcium Form I (350 mg, 44%).
• Example 27 Atorvastatin hemi-calcium Form X (1.0 g) was stirred in water (400 ml) at room temperature for 24 h. The solid was collected by filtration and dried at 65 °C for 24 h to yield atorvastatin hemi-calcium Form I (720 mg, 72%).
• Example 28 Atorvastatin hemi-calcium Form IX (750 mg) was stirred in water (300 ml) at room temperature for 24 h. The solid was collected and dried at 65 °C for 20 h to give atorvastatin calcium Form I (420 mg, 56%).
• Example 29 Atorvastatin hemi-calcium Form IX (750 mg) was stirred in water (300 ml) at room temperature for 24 h. The solid was collected and dried at 65 °C for 20 h to give atorvastatin calcium Form I (420 mg, 56%).
• Atorvastatin hemi-calcium salt Form I (1.0 g) was stirred in 9ml of 1 -butanol at room temperature for 24 hours. The white solid was then filtered and dried at 50°C in a vacuum oven for 16 hours to obtain 0.83 g (83%) of atorvastatin hemi-calcium salt Form IV.
• Example 33 Atorvastatin hemi-calcium salt Form V (1.0 g) was stirred in 20 ml of 1 -butanol at room temperature for 72 hours. The white solid was then filtered and dried at 65°C in an oven for 20 hours to obtain 0.82 g (82%) of atorvastatin hemi- calcium salt Form IV.
• Example 34 Atorvastatin hemi-calcium salt form V (2.0 g) was stirred in a mixture of EtOH (18 ml) and water (3.2 ml) at 50°C for 1 hour. The precipitate was then filtered and dried at 65°C for 20 hours to obtain 1.60 g (80%) of atorvastatin hemi-calcium salt form IV.
• Example 35 A mixture of atorvastatin hemi-calcium Form V (2.00 g) and methanol (20 ml) was refluxed for 1 hour. The mixture was cooled to room temperature and stirred for an additional 16 hours. The solid was collected by filtration and dried at 65 °C for 24 to give atorvastatin calcium Form IV (1.37 g, 56%).
• Example 36 A mixture of atorvastatin hemi-calcium Form V (2.00 g) and methanol (20 ml) was refluxed for 1 hour. The mixture was cooled to room temperature and stirred for an additional 16 hours. The solid was collected by filtration and dried at 65 °C for 24 to give atorvastatin calcium Form IV (1.37 g, 56%).
• Example 36 A mixture of atorvastatin hemi-calcium Form V (2.00 g) and methanol (20 ml) was refluxed for 1 hour. The mixture was cooled to room temperature and stirred for an additional 16 hours. The solid was collected by filtration and dried
• Atorvastatin hemi-calcium salt Form V 5.0g were added to a boiled aqueous solution of Ethanol 90% (150ml). The mixture was refluxed for 2.5 hrs. Then it was cooled to 20 °C during 1.5 hrs and stirred at this temperature for additional 16 hrs. The solid was then filtered, washed with Ethanol 90% (2x25ml) and dried at 65 °C for 20 hrs to give 3.4g (68%) of Atorvastatin hemi-calcium salt Form V.
• Atorvastatin hemi-calcium Form V (2.00 g) was stirred in acetone (14 ml) at room temperature in a closed flask for 16 h. After 2 hours, the mixture clarified. While continuing to stir at room temperature, a solid precipitated. The acetone was decanted and the solid was collected with a spatula and transferred to a drying oven and dried at 65°C for 20 h to give amorphous atorvastatin hemi-calcium (1.85 g,
• Atorvastatin hemi-calcium Form I (1.00 g) was stirred in acetonitrile (20 ml) at room temperature. The slurry was then placed into a sonicator for 2 min. (energy
• Atorvastatin hemi-calcium (108 g) and twenty seven 10 mm diameter stainless steel milling balls were loaded into the milling chamber of the ball mill.
• the chamber was weighed and the mill was balanced according to the weight.
• the mill was operated at 500 rpm with the mill's reversing system on for 0.5 hr.
• the build-up material was scraped from the chamber walls into the bulk, and the mill was again operated for 4 hr, with cleaning of build-up every 15 min. finally, the material was separated from the balls by sieving with 300 m screen.
• the resulting material was analyzed by PXRD and found to be amorphous. The process was repeated using atorvastatin Forms I, V and VIII and in each instance amorphous atorvastatin hemi- calcium was obtained.

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