Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms

Abstract

The present invention provides novel forms of atorvastatin designated Forms VI, VIII, IX, X, XI and XII and novel processes for their preparation as well as processes for preparing atorvastatin Forms I, II, IV, V and amorphous atorvastatin.

We claim:  
     
         1 . Atorvastatin hemi-calcium Form VI and solvates thereof having a powder X-ray diffraction pattern substantially as depicted in FIG. 1.  
     
     
         2 . The atorvastatin hemi-calcium Form VI and solvates thereof of  claim 1  characterized by a powder X-ray diffraction pattern having peaks at 8.7, 10.0, 12.5, 17.9, 19.5, 20.9, 22.4±0.2 degrees 2θ.  
     
     
         3 . The atorvastatin hemi-calcium Form VI and solvates thereof of  claim 2  further characterized by having peaks at 7.7, 8.2, 13.8, 20.4, 21.7, 23.2, 25.5±0.2 degrees 2 in its powder X-ray diffraction pattern.  
     
     
         4 . The atorvastatin hemi-calcium Form VI and solvates thereof of  claim 2  having a narrow particle size distribution.  
     
     
         5 . The atorvastatin hemi-calcium Form VI and solvates thereof of  claim 4  wherein all of the particles are 100 microns or less in diameter.  
     
     
         6 . The atorvastatin hemi-calcium Form VI and solvates thereof of  claim 5  wherein all of the particles are 50 microns or less in diameter.  
     
     
         7 . A process for preparing atorvastatin hemi-calcium Form VI comprising the steps of: 
 a) solubilizing any other crystalline or amorphous form of atorvastatin hemi-calcium in acetone,    b) precipitating atorvastatin hemi-calcium Form VI by addition of an anti-solvent, and    c) separating the solid crystalline Form VI.    
     
     
         8 . Atorvastatin hemi-calcium Form VIII and hydrates thereof having a powder X-ray diffraction pattern substantially as depicted in FIG. 3.  
     
     
         9 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 8  characterized by a powder X-ray diffraction pattern having peaks at 9.3, 9.6, 16.3, 19.2, 20.0, 21.6, 22.4, 23.9±0.2 degrees two-theta.  
     
     
         10 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 9  further characterized by having peaks at 17.1 (broad), 24.7, 25.6, 26.5±0.2 degrees two-theta in its powder X-ray diffraction pattern.  
     
     
         11 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 8  having a narrow particle size distribution.  
     
     
         12 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 11  wherein all of the particles are 100 microns or less in diameter.  
     
     
         13 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 12  wherein all of the particles are 50 microns or less in diameter.  
     
     
         14 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 8  having a water content of up to 7%.  
     
     
         15 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 8  that is a trihydrate.  
     
     
         16 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 8  containing up to about four moles of water.  
     
     
         17 . The atorvastatin hemi-calcium Form VIII of  claim 8  containing up to about 3% ethanol.  
     
     
         18 . Atorvastatin hemi-calcium Form VIII and hydrates thereof with d-spacings of about 30.81, 18.46, 16.96, 15.39, 14.90, 12.78, 11.05, 9.58, 9.22, 7.42, 6.15, 5.43, 4.62, 4.44, and 3.98 angstroms.  
     
     
         19 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 18  that produce a high resolution X-ray powder diffraction pattern substantially as shown in FIG. 4 when irradiated with X-rays with a wavelength of about 1.15 angstroms.  
     
     
         20 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 18  having monoclinic unit cell with the following unit cell parameters: a=18.55-18.7 Å, b=5.52-5.53 Å, c=31.0-31.2 Å and β=97.5-99.5.  
     
     
         21 . Atorvastatin hemi-calcium Form VIII and hydrates thereof having a solid-state  13 C nuclear magnetic resonance spectrum substantially as depicted in FIG. 5.  
     
     
         22 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 21  further characterized by solid-state  13 C nuclear magnetic resonances at 24.8, 25.2, 26.1, 119.5, 120.1, 121.8, 122.8, 126.6, 128.8, 129.2, 134.2, 135.1, 137.0, 138.3 and 139.8 parts per million.  
     
     
         23 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 22  characterized by solid-state  13 C nuclear magnetic resonances at 17.8, 20.0, 24.8, 25.2, 26.1, 40.3, 40.8, 41.5, 43.4, 44.1, 46.1, 70.8, 73.3, 114.1, 116.0, 119.5, 120.1, 121.8, 122.8, 126.6, 128.8, 129.2, 134.2, 135.1, 137.0, 138.3, 139.8, 159.8, 166.4, 178.8 and 186.5 parts per million.  
     
     
         24 . The atorvastatin hemi-calcium Form VIII and hydrates thereof of  claim 21  having the following chemical shift differences between the lowest resonance and other resonances: 2.2, 7.0, 7.4, 8.3, 22.5, 23.0, 23.7, 25.6, 26.3, 28.3, 53.0, 55.5, 96.3, 98.2, 101.7, 102.3, 104.0, 105.0, 108.8, 111.0, 111.4, 116.4, 117.3, 119.2, 120.5, 122.0, 142.0, 148.6, 161.0 and 168.7 parts per million.  
     
     
         25 . Atorvastatin hemi-calcium Form VIII ethanolate.  
     
     
         26 . The atorvastatin hemi-calcium ethanolate of  claim 25  containing up to about 3% ethanol.  
     
     
         27 . A process for preparing atorvastatin hemi-calcium Form VIII comprising the steps of: 
 a) suspending atorvastatin hemi-calcium in a mixture of ethanol and water for a period of time sufficient to convert Form V into Form VIII and    b) recovering Form VIII from the suspension.    
     
     
         28 . The process of  claim 27  wherein the mixture is a mixture of at least about 19 volumes of ethanol to about 1 volume of water.  
     
     
         29 . The process of  claim 27  wherein the temperature of the suspension is raised to 78-80° C. before Form VIII is recovered from the suspension.  
     
     
         30 . A process for preparing atorvastatin hemi-calcium Form VIII from atorvastatin comprising the steps of: 
 a) converting the atorvastatin into atorvastatin hemi-calcium by contacting the atorvastatin with a source of calcium ion,    b) suspending the atorvastatin hemi-calcium in a mixture of ethanol and water for a period of time sufficient to convert the atorvastatin hemi-calcium into Form VIII, and    c) recovering Form VIII from the suspension.    
     
     
         31 . The process of  claim 30  wherein the mixture is a mixture of ethanol and water in a volume ratio of about 5:1.  
     
     
         32 . The process of  claim 30  wherein additional water is added to the suspension of atorvastatin hemi-calcium before recovering Form VIII in order to increase the recovery of Form VIII from the suspension.  
     
     
         33 . The process of  claim 30  wherein the temperature of the suspension is elevated before recovering Form VIII from the suspension.  
     
     
         34 . The process of  claim 33  wherein the elevated temperature is about 78-80° C.  
     
     
         35 . A process for preparing atorvastatin hemi-calcium containing less than 0.1% des-fluoro atorvastatin hemi-calcium comprising suspending atorvastatin hemi-calcium that contains greater than 0.1% des-fluoro atorvastatin hemi-calcium in a mixture of about 96% ethanol and about 4% water and recovering atorvastatin hemi-calcium containing less than 0.1% des-fluoro atorvastatin hemi-calcium.  
     
     
         36 . The process for preparing atorvastatin hemi-calcium of  claim 35  wherein the atorvastatin is recovered containing less than 0.07% des-fluoro atorvastatin  
     
     
         37 . A process for preparing atorvastatin hemi-calcium containing less than 1% trans atorvastatin hemi-calcium comprising suspending atorvastatin hemi-calcium that contains greater than 1% trans atorvastatin hemi-calcium in a mixture of about 96% ethanol and about 4% water and recovering atorvastatin hemi-calcium containing less than 1% trans atorvastatin hemi-calcium  
     
     
         38 . The process for preparing atorvastatin hemi-calcium of  claim 37  wherein the atorvastatin hemi-calcium is recovered containing less than 0.6% trans atorvastatin hemi-calcium.  
     
     
         39 . A process for preparing atorvastatin hemi-calcium Form VIII comprising the steps of: 
 a) suspending atorvastatin hemi-calcium Form V in a mixture of water and a lower alcohol selected from the group consisting of 1-butanol and ethanol for a period of time to cause the conversion of Form V to Form VIII, and    b) recovering atorvastatin hemi-calcium Form VIII from the mixture.    
     
     
         40 . The process of  claim 39  wherein the mixture contains about 20% 1-butanol by volume.  
     
     
         41 . The process of  claim 39  wherein the lower alcohol is ethanol and the mixture contains about 4% water.  
     
     
         42 . A process for preparing atorvastatin hemi-calcium Form VIII comprising the steps of: 
 a) suspending atorvastatin hemi-calcium in ethanol for a period of time sufficient to convert it into Form VIII and    b) recovering Form VIII from the suspension.    
     
     
         43 . The process of  claim 42  wherein the atorvastatin hemi-calcium is Form V.  
     
     
         44 . The process of  claim 42  wherein the atorvastatin hemi-calcium is Form XII.  
     
     
         45 . The process of  claim 42  wherein the atorvastatin hemi-calcium is Form I.  
     
     
         46 . The process of  claim 42  wherein the ethanol contains about 0.5% or less water.  
     
     
         47 . The process of  claim 46  wherein the ethanol contains about 0.2% or less water.  
     
     
         48 . The process of  claim 42  wherein the temperature of the suspension is elevated to about 78° C. before Form VIII is recovered from the suspension.  
     
     
         49 . The process of  claim 48  further comprising adding methanol to the suspension before recovering Form VIII to improve the chemical purity of Form VIII recovered from the suspension.  
     
     
         50 . Atorvastatin hemi-calcium Form IX and hydrates thereof having a powder X-ray diffraction pattern substantially as depicted in FIG. 6.  
     
     
         51 . The atorvastatin hemi-calcium Form IX of  claim 50  and hydrates thereof characterized by its powder X-ray diffraction pattern having peaks at 19.1, 19.9, 21.4, 22.5, 23.5±0.2 degrees 2θ.  
     
     
         52 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 51  further characterized by its powder X-ray diffraction pattern having peaks at 6.9, 17.0, 17.4, 18.2, 18.6±0.2 degrees two-theta.  
     
     
         53 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 51  containing up to 7% water.  
     
     
         54 . An atorvastatin hemi-calcium Form IX hydrate of  claim 51  containing from about one to about four moles of water.  
     
     
         55 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 51  having a narrow particle size distribution.  
     
     
         56 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 55  wherein all of the particles are 100 microns or less in diameter.  
     
     
         57 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 56  wherein all of the particles are 50 microns or less in diameter.  
     
     
         58 . Atorvastatin hemi-calcium Form IX and hydrates thereof with d-spacings of about 30.86, 18.67, 16.91, 15.17, 12.66, 11.20, 9.50, 9.28, 8.63, 7.69, 7.38, 6.51, 5.45, 5.26, 5.20, 5.12, 4.87, 4.76, 4.63, 4.47, 4.14, 4.08, 3.78, 3.73, 3.62, and 3.58 angstroms.  
     
     
         59 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 58  that produce a high resolution X-ray powder diffraction pattern substantially as shown in FIG. 7 when irradiated with X-rays with a wavelength of about 1.15 angstroms.  
     
     
         60 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 58  having monoclinic unit cell with the following unit cell parameters: a18.75-18.85 Å, b=5.525-5.54 Å, c=30.9-31.15 Å and β=96.5 to 97.5°.  
     
     
         61 . Atorvastatin hemi-calcium Form IX and hydrates thereof having a solid state  13 C nuclear magnetic resonance spectrum substantially as depicted in FIG. 8.  
     
     
         62 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 61  further characterized by solid-state  13 C nuclear magnetic resonances at 24.9, 26.1, 119.5, 120.2, 121.7, 122.8, 126.7, 128.6, 129.4, 134.3, 135.1, 136.8, 138.3 and 139.4 parts per million.  
     
     
         63 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 62  characterized by solid-state  13 C nuclear magnetic resonances at 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 and 186.6 parts per million.  
     
     
         64 . The atorvastatin hemi-calcium Form IX and hydrates thereof of  claim 61  having the following chemical shift differences between the lowest 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 and 168.6 parts per million.  
     
     
         65 . Atorvastatin hemi-calcium Form IX butanolate.  
     
     
         66 . Atorvastatin hemi-calcium Form IX containing up to about 5% butanol.  
     
     
         67 . A process for preparing atorvastatin hemi-calcium Form IX and solvates thereof comprising the steps of: 
 a) suspending any other crystalline or amorphous form of atorvastatin hemi-calcium in 1-butanol for a period of time sufficient to convert the other form to Form IX and    b) recovering Form IX from the suspension.    
     
     
         68 . The process of  claim 67  wherein the other form is Form I.  
     
     
         69 . The process of  claim 67  wherein the other form is Form V.  
     
     
         70 . The process of  claim 42  wherein the other form is Form XII.  
     
     
         71 . The process of  claim 67  wherein the temperature of the suspension is elevated to the reflux temperature of 1-butanol before recovering Form IX from the suspension.  
     
     
         72 . The process of  claim 67  wherein the time sufficient to convert the other form to Form IX is about half an hour or less.  
     
     
         73 . The process of  claim 67  further comprising the step of adding an anti-solvent to the suspension before recovering Form IX in order to increase the amount of Form IX recovered from the suspension.  
     
     
         74 . The process of  claim 73  wherein the anti-solvent is selected from the group consisting of n-hexane, isopropanol and water.  
     
     
         75 . A process for preparing atorvastatin hemi-calcium Form IX from Form VIII by exposing atorvastatin hemi-calcium Form VIII to an atmosphere of from about 80% to about 100% relative humidity.  
     
     
         76 . The process of  claim 75  wherein the Form VIII is exposed to the humid atmosphere for about 9 days or less.  
     
     
         77 . The process of  claim 75  wherein the Form VIII is exposed to the humid atmosphere at room temperature.  
     
     
         78 . A process for preparing atorvastatin hemi-calcium Form IX comprising the steps of: 
 a) suspending Form VIII atorvastatin hemi-calcium in ethanol for a period of time sufficient to convert the other form into Form IX and    b) recovering Form IX from the suspension.    
     
     
         79 . The process of  claim 78  wherein the ethanol contains about 0.5% or less water.  
     
     
         80 . The process of  claim 79  wherein the ethanol contains about 0.2% or less water.  
     
     
         81 . The process of  claim 78  wherein the temperature of the suspension is maintained at about room temperature over the time period in which the other form is converted into Form IX.  
     
     
         82 . The process of  claim 78  wherein the time period sufficient to convert the other form into Form IX is about 16 hours.  
     
     
         83 . Atorvastatin hem-calcium Form X and solvates thereof having a powder X-ray diffraction pattern substantially as depicted in FIG. 9.  
     
     
         84 . Atorvastatin hemi-calcium Form X and solvates thereof of  claim 83  characterized by a powder X-ray diffraction pattern having sharp peaks at 19.1 and 19.4±0.2 degrees 2 and other peaks at 20.0 and 20.8±0.2 degrees 2θ.  
     
     
         85 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 84  further characterized by having peaks at 222.8, 23.6 and 25.0±0.2 degrees 2 in its powder X-ray diffraction pattern.  
     
     
         86 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 83  containing up to about 5% water.  
     
     
         87 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 83  containing one to three moles of water.  
     
     
         88 . Atorvastatin hemi-calcium Form X and solvates thereof containing up to about 2% ethanol.  
     
     
         89 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 83  having a narrow particle size distribution.  
     
     
         90 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 89  wherein all of the particles are 100 microns or less in diameter.  
     
     
         91 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 90  wherein all of the particles are 50 microns or less in diameter.  
     
     
         92 . Atorvastatin hemi-calcium Form X and solvates thereof with d-spacings of about 30.63, 18.49, 16.66, 15.12, 12.49, 11.19, 10.20, 9.38, 9.24, 9.13, 8.58, 7.64, 7.36, 7.26, 6.81, 6.50, 6.16, 5.91, 5.24, 5.19, 5.06, 4.86, 4.74, 4.65, 4.61, 4.56, 4.12, 4.05, 3.93, 3.90, and 3.77 angstroms.  
     
     
         93 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 92  that produce a high resolution X-ray powder diffraction pattern substantially as shown in FIG. 10 when irradiated with X-rays with a wavelength of about 1.15 angstroms.  
     
     
         94 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 92  having a monoclinic unit cell with the following unit cell parameters: a=18.55-18.65 Å, b=5.52-5.53 Å, c=30.7-30.85 Å and β=95.7 to 96.7°.  
     
     
         95 . Atorvastatin hemi-calcium Form X and solvates thereof having a solid state  13 C nuclear magnetic resonance spectrum substantially as depicted in FIG. 11.  
     
     
         96 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 95  further characterized by solid-state  13 C nuclear magnetic resonances at 24.9, 119.5, 122.4, 126.7, 128.9, 134.5, 138.0, 159.4 and 166.2 parts per million.  
     
     
         97 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 96  characterized by solid-state  13 C nuclear magnetic resonances at 17.7, 18.7, 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 and 186.1 parts per million.  
     
     
         98 . The atorvastatin hemi-calcium Form X and solvates thereof of  claim 95  having the following chemical shift differences between the lowest 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 and 168.4 parts per million.  
     
     
         99 . A process for preparing atorvastatin hemi-calcium Form X comprising the steps of: 
 a) suspending any other crystalline or amorphous form of atorvastatin hemi-calcium in a mixture of ethanol and water for a period of time sufficient to convert the other form into Form X and    b) recovering Form X from the suspension.    
     
     
         100 . The process of  claim 99  wherein the suspension is heated to the reflux temperature of the ethanol-water mixture before recovery of Form X from the suspension.  
     
     
         101 . The process of  claim 99  wherein the time sufficient to convert the other form into Form X is about an hour.  
     
     
         102 . The process of  claim 99  wherein the mixture contains about six parts ethanol to one part water.  
     
     
         103 . The process of  claim 99  wherein the mixture contains about five parts ethanol to one part water.  
     
     
         104 . Atorvastatin hemi-calcium Form XI and solvates thereof having a powder X-ray diffraction pattern substantially as depicted in FIG. 12.  
     
     
         105 . The atorvastatin hemi-calcium Form XI and solvates thereof of  claim 104  characterized by PXRD 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, 24.0±0.2 degrees two-theta.  
     
     
         106 . The atorvastatin hemi-calcium Form XI and solvates thereof of  claim 104  having a narrow particle size distribution.  
     
     
         107 . The atorvastatin hemi-calcium Form XI and solvates thereof of  claim 106  wherein all of the particles are 100 microns or less in diameter.  
     
     
         108 . The atorvastatin hemi-calcium Form XI and solvates thereof of  claim 107  wherein all of the particles are 50 microns or less in diameter.  
     
     
         109 . A process for preparing atorvastatin hemi-calcium Form XI comprising the steps of: 
 a) suspending atorvastatin hemi-calcium in methyl ethyl ketone at room temperature for a period of time sufficient to cause the conversion into atorvastatin hemi-calcium Form XI, and    b) recovering atorvastatin hemi-calcium Form XI from the suspension.    
     
     
         110 . The process for preparing atorvastatin hemi-calcium Form XI of  claim 109  wherein the atorvastatin hemi-calcium is Form V.  
     
     
         111 . A process for preparing atorvastatin hemi-calcium Form XI comprising the steps of dissolving atorvastatin hemi-calcium in isopropyl alcohol at elevated temperature to form a solution of atorvastatin hemi-calcium, cooling the solution until it gels and then drying the gel to obtain atorvastatin hemi-calcium Form XI.  
     
     
         112 . Atorvastatin hemi-calcium Form XII and solvates thereof characterized by a powder X-ray diffraction pattern having peaks at 8.0, 8.4, 11.8, 18.2, 19.0±0.2 degrees 2θ.  
     
     
         113 . The atorvastatin hemi-calcium Form XII and solvates thereof of  claim 112  having a narrow particle size distribution.  
     
     
         114 . The atorvastatin hemi-calcium Form XII and solvates thereof of  claim 113  wherein all of the particles are 100 microns or less in diameter.  
     
     
         115 . The atorvastatin hemi-calcium Form XII and solvates thereof of  claim 114  wherein all of the particles are 50 microns or less in diameter.  
     
     
         116 . A process for preparing atorvastatin hemi-calcium Form XII comprising the steps of: 
 a) suspending [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester in ethanol,    b) deprotecting the [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester by adding hydrochloric acid to the suspension, thereby forming a solution of atorvastatin ester derivatives in ethanol,    c) adding calcium hydroxide to the solution, thereby forming a solution of atorvastatin hemi-calcium in ethanol,    d) optionally removing any excess calcium hydroxide, and    e) precipitating atorvastatin hemi-calcium from the solution as Form XII.    
     
     
         117 . A process for preparing atorvastatin hemi-calcium Form I comprising the steps of: 
 a) suspending any other form of atorvastatin hemi-calcium in water for a period of time sufficient to convert the other form into Form I and    b) recovering Form I from the suspension.    
     
     
         118 . A process for preparing atorvastatin hemi-calcium Form II comprising the steps of: 
 a) suspending [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester in methanol,    b) deprotecting the [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester by adding hydrochloric acid to the suspension, thereby forming a solution of atorvastatin ester derivatives in methanol,    c) adding calcium hydroxide to the solution, thereby forming a solution of atorvastatin hemi-calcium in methanol,    d) optionally removing any excess calcium hydroxide, and    e) precipitating atorvastatin hemi-calcium from the solution as Form II.    
     
     
         119 . A process for preparing amorphous hemi-calcium comprising the steps of: 
 a) suspending a crystalline form of atorvastatin hemi-calcium in acetonitrile,    b) sonicating the suspension for a period of time sufficient to convert the crystalline form to amorphous atorvastatin hemi-calcium, and    c) recovering amorphous atorvastatin hemi-calcium from the suspension.    
     
     
         120 . The process of  claim 119  wherein the crystalline form of atorvastatin hemi-calcium is Form VII.  
     
     
         121 . The process of  claim 119  wherein the crystalline form of atorvastatin hemi-calcium is Form I.  
     
     
         122 . The process of  claim 119  wherein the suspension is sonicated for a period of from about 1 to about 3 minutes.  
     
     
         123 . The process of  claim 119  wherein the suspension is sonicated at room temperature.  
     
     
         124 . A process for preparing atorvastatin hemi-calcium Form IV comprising the steps of: 
 a) suspending atorvastatin hemi-calcium Form I in 1-butanol for a period of time sufficient to convert Form I into Form IV and    b) recovering Form IV from the suspension.    
     
     
         125 . The process of  claim 124  wherein the suspension is maintained at room temperature for the period time in which Form I is converted into Form IV.  
     
     
         126 . The process of  claim 124  wherein the time sufficient to convert Form I into Form IV is about 24 h.  
     
     
         127 . A process for preparing atorvastatin hemi-calcium Form IV comprising the steps of: 
 a) suspending atorvastatin hemi-calcium Form V in a mixture of ethanol and water for a period of time sufficient to convert Form V into Form IV and    b) recovering Form IV from the suspension.    
     
     
         128 . The process of  claim 127  wherein the temperature of the suspension is elevated to about 50° C. before recovering Form IV from the suspension.  
     
     
         129 . The process of  claim 127  wherein the period of time sufficient to convert Form V into Form IV is about one hour.  
     
     
         130 . The process of  claim 127  wherein the mixture contains about 15% water.  
     
     
         131 . A process of preparing atorvastatin hemi-calcium Form IV comprising the steps of: 
 a) suspending atorvastatin hemi-calcium Form V in methanol for a period of time sufficient to convert Form V into Form IV, and    b) recovering Form IV from the suspension.    
     
     
         132 . The process of  claim 131  wherein the suspension is maintained at a temperature of from about room temperature to the reflux temperature of methanol for the period of time in which Form Vis converted into Form IV.  
     
     
         133 . The process of  claim 131  wherein the period of time sufficient to convert the other form into Form IV is from about 1 hour to about 20 hours.  
     
     
         134 . A process for preparing atorvastatin hemi-calcium Form V comprising the steps of: 
 a) suspending [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic acid ester in ethanol,    b) deprotecting the [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dioxane-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester by adding hydrochloric acid to the suspension, thereby forming a solution of atorvastatin lactone and [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic acid ester in ethanol,    c) adding calcium hydroxide to the solution, thereby forming a solution of atorvastatin hemi-calcium in ethanol,    d) precipitating atorvastatin hemi-calcium from the solution, and    e) drying the precipitated atorvastatin hemi-calcium to obtain atorvastatin hemi-calcium as Form V.    
     
     
         135 . A process for purifying atorvastatin hemi-calcium Form V comprising suspending the atorvastatin hemi-calcium Form V in a mixture of ethanol and water and recovering Form V from the mixture in greater purity.  
     
     
         136 . The process of  claim 135  wherein the mixture comprises from about 10% water and about 90% ethanol by volume.  
     
     
         137 . A process for preparing amorphous atorvastatin hemi-calcium comprising the steps of: 
 a) contacting any crystalline form of atorvastatin hemi-calcium with acetone for a period of time sufficient to convert the crystalline form into amorphous atorvastatin hemi-calcium and    b) separating solid amorphous atorvastatin hemi-calcium from the acetone.    
     
     
         138 . The process for preparing amorphous atorvastatin hemi-calcium of  claim 137  wherein the crystalline form of atorvastatin hemi-calcium dissolves in the acetone to yield a substantially clear solution and further wherein solid amorphous atorvastatin hemi-calcium is precipitated from the substantially clear solution.  
     
     
         139 . A process of  claim 137  wherein the crystalline form of atorvastatin hemi-calcium is Form V.  
     
     
         140 . The process of  claim 137  wherein the crystalline form of atorvastatin hemi-calcium and acetone are contacted at room temperature.  
     
     
         141 . The process of  claim 137  wherein the period of time sufficient to convert the crystalline form into amorphous atorvastatin hemi-calcium is about 16 hours.  
     
     
         142 . A process for preparing amorphous atorvastatin hemi-calcium by ball milling any crystalline form of atorvastatin hemi-calcium.  
     
     
         143 . The process of  claim 142  wherein the crystalline form of atorvastatin hemi-calcium is selected from the group consisting of Form I, Form V and Form VIII.  
     
     
         144 . A pharmaceutical composition comprising atorvastatin hemi-calcium Form VI, VIII, IX, X, XI, XII or a mixture thereof.  
     
     
         145 . Use of atorvastatin Form VI, VIII, IX, X, XI, XII or mixtures thereof, to prepare a pharmaceutical dosage form.  
     
     
         146 . A pharmaceutical dosage form comprising atorvastatin hemi-calcium Form VI, VIII, IX, X, XI, XII or mixtures thereof.