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, VII, VIII, IX, IXa, X, XI, XII, XIV, XVI and XVII and novel processes for their preparation as well as processes for preparing atorvastatin Forms I, II, IV, V and amorphous atorvastatin.

1 . Solid crystalline atorvastatin hemi-calcium and solvates thereof characterized by a powder X-ray diffraction pattern generated using CuK α  radiation substantially as depicted in  FIG. 6 . 
   
   
       2 . Solid crystalline atorvastatin hemi-calcium and solvates thereof characterized by a reproducible physical or spectroscopic analysis result selected from the group consisting of:
 a) a powder X-ray diffraction pattern generated using CuK α  radiation with peaks at 19.1, 19.9, 21.4, 22.5, 23.5±0.2 degrees two-theta;   b) 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 Å;   c) a monoclinic unit cell with cell parameters: a=18.75-18.85 Å, b=5.525-5.54 Å, c=30.9-31.15 Å and β=96.5 to 97.5°;   d) a solid state cross-polarization/magic angle spinning  13 C nuclear magnetic resonance spectrum with 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; and   e) a solid state cross-polarization/magic angle spinning  13 C nuclear magnetic resonance spectrum wherein the chemical shift differences between the lowest resonance and other resonances are: 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.   
   
   
       3 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 2  wherein the result is the powder X-ray diffraction pattern having peaks at 19.1, 19.9, 21.4, 22.5, 23.5±0.2 degrees two-theta and the powder X-ray diffraction pattern further includes peaks at 6.9, 17.0, 17.4, 18.2, 18.6±0.2 degrees two-theta. 
   
   
       4 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 2  wherein the result is the d-spacings and Form IX is further characterized by 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 Å. 
   
   
       5 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 2  wherein the result is a solid state cross-polarization/magic angle spinning  13 C nuclear magnetic resonance spectrum with 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 and the spectrum further includes resonances at 18.0, 20.4, 40.4, 46.4, 71.0, 73.4, 114.3, 116.0, 159.9, 166.3, 178.4 and 186.6 parts per million. 
   
   
       6 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 2  wherein the result is a solid state cross-polarization/magic angle spinning  13 C nuclear magnetic resonance spectrum with 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 and the spectrum is substantially as depicted  FIG. 8 . 
   
   
       7 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 2  containing up to 7% water. 
   
   
       8 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 2  containing from about one to about four moles of water. 
   
   
       9 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 2  that is a butanolate. 
   
   
       10 . The solid crystalline atorvastatin hemi-calcium butanolate of  claim 9  containing up to about 5% butanol. 
   
   
       11 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 2  having a narrow particle size distribution. 
   
   
       12 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 11  wherein all of the particles are 100 microns or less in diameter. 
   
   
       13 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 12  wherein all of the particles are 50 microns or less in diameter. 
   
   
       14 . A process for preparing solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IX 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 solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IX from the suspension.   
   
   
       15 . The process of  claim 14  wherein the other form is selected from the group consisting of Form I, Form V and Form XII. 
   
   
       16 . The process of  claim 14  wherein the temperature of the suspension is elevated to the reflux temperature of 1-butanol before recovering solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form 1× from the suspension. 
   
   
       17 . The process of  claim 14  further comprising the step of adding an anti-solvent to the suspension before recovering solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IX. 
   
   
       18 . The process of  claim 17  wherein the anti-solvent is selected from the group consisting of n-hexane, isopropanol and water. 
   
   
       19 . A process for preparing solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IX comprising exposing atorvastatin hemi-calcium Form VIII to an atmosphere of from about 80% to about 100% relative humidity. 
   
   
       20 . The process of  claim 19  wherein the Form VIII is exposed to the humid atmosphere for about 9 days or less. 
   
   
       21 . The process of  claim 19  wherein the Form VIII is exposed to the humid atmosphere at room temperature. 
   
   
       22 . A process for preparing solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IX comprising the steps of:
 a) suspending Form VIII atorvastatin hemi-calcium in ethanol for a period of time sufficient to convert the Form VIII into the solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IX and   b) recovering the solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IX from the suspension.   
   
   
       23 . The process of  claim 22  wherein the ethanol contains about 0.5% or less water. 
   
   
       24 . The process of  claim 23  wherein the ethanol contains about 0.2% or less water. 
   
   
       25 . The process of  claim 22  wherein the temperature of the suspension is maintained at about room temperature over the time period in which the other form is converted into the solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IX. 
   
   
       26 . The process of  claim 22  wherein the time period sufficient to convert the other form into the solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IX is about 16 hours. 
   
   
       27 . Solid crystalline atorvastatin hemi-calcium and solvates thereof characterized by a powder X-ray diffraction pattern having peaks at 9.3 and 9.5±0.2 degrees two-theta. 
   
   
       28 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 27  further characterized by peaks in the powder X-ray diffraction pattern at 15.7, 20.5, 21.1, 22.8, 23.8, 24.0, 25.3, 26.4, 26.8, 27.2, 29.2 and 31.6 degrees two-theta. 
   
   
       29 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 27  further characterized by a powder X-ray diffraction pattern generated using CuK α  radiation substantially as depicted in  FIG. 9 . 
   
   
       30 . A process for preparing atorvastatin hemi-calcium having at least one characteristic of Form IXa comprising the steps of:
 a) suspending atorvastatin hemi-calcium Form V in a mixture selected from the group consisting of mixtures from about 85% to about 95% 1-butanol and from about 5% to about 15% water and mixtures of from about 5% to about 15% 1-butanol and from about 85% to about 95% water for a period of time sufficient to convert Form V to the atorvastatin hemi-calcium having at least one characteristic of Form IXa, and   b) recovering solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IXa from the suspension.   
   
   
       31 . The process of  claim 30  wherein the mixture is about 90% 1-butanol and about 10% water on a volume basis. 
   
   
       32 . The process of  claim 30  wherein the mixture is about 10% 1-butanol and about 90% water on a volume basis. 
   
   
       33 . The process of  claim 30  wherein the mixture is present in an amount of at least about 20 milliliters per gram of atorvastatin hemi-calcium Form V. 
   
   
       34 . The process of  claim 30  wherein the suspension is heated to an elevated temperature before recovering the solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IXa from the suspension. 
   
   
       35 . The process of  claim 34  wherein the elevated temperature is about the reflux temperature of the mixture. 
   
   
       36 . The process of  claim 35  wherein the reflux temperature is about 85° C. 
   
   
       37 . The process of  claim 30  wherein the time sufficient to convert Form V to the solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IXa is about 16 hours or less. 
   
   
       38 . The process of  claim 30  wherein the Form V is impure and the solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IXa is more pure than the Form V by about 50% or more. 
   
   
       39 . Solid crystalline atorvastatin hemi-calcium and solvates thereof having at least one characteristic of Form IXa prepared by a process comprising the steps of:
 a) suspending atorvastatin hemi-calcium Form V in a mixture selected from the group consisting of mixtures from about 85% to about 95% 1-butanol and from about 5% to about 15% water and mixtures of from about 5% to about 15% 1-butanol and from about 85% to about 95% water for a period of time sufficient to convert Form V to the atorvastatin hemi-calcium having at least one characteristic of Form IXa, and   b) recovering solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IXa from the suspension.   
   
   
       40 . Solid crystalline and highly pure atorvastatin hemi-calcium and solvates thereof having at least one characteristic of Form IX prepared by a process comprising the steps of:
 a) suspending atorvastatin hemi-calcium Form V in a mixture of 90% 1-butanol and 10% water on a volume basis for a period of time sufficient to convert Form V to the atorvastatin hemi-calcium having at least one characteristic of Form IXa, and   b) recovering solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form IXa from the suspension in 99.3% or greater chemical purity as determined by high performance liquid chromatographic separation of and quantitation by UV absorption at 254 nanometers.   
   
   
       41 . Solid crystalline atorvastatin hemi-calcium and solvates thereof characterized by a powder X-ray diffraction pattern having peaks at 7.6, 9.8, 16.5, 29.4±0.2 degrees two-theta. 
   
   
       42 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 41  further characterized by peaks at 18.1, 20.0, 20.4, 21.9, 22.4 and 23.6±0.2 degrees two-theta in its powder X-ray diffraction pattern. 
   
   
       43 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 41  further characterized by a powder X-ray diffraction pattern generated using CuK α  radiation substantially as depicted in  FIG. 15 . 
   
   
       44 . A process for preparing solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form XIV and solvates thereof comprising:
 a) suspending atorvastatin hemi-calcium in water, and   b) recovering the flakes from the suspension.   
   
   
       45 . The process of  claim 44  wherein the atorvastatin hemi-calcium that is suspended is Form V. 
   
   
       46 . The process of  claim 44  wherein the converting occurs over about 5 days. 
   
   
       47 . The process of  claim 44  wherein a fine suspended solid is formed about two to about 10 hours after the atorvastatin hemi-calcium is suspended in water. 
   
   
       48 . The process of  claim 44  wherein the fine suspended solid converts into flakes over from about one to about five days. 
   
   
       49 . The process of  claim 48  wherein conversion of the fine suspended solid into flakes occurs over about five days. 
   
   
       50 . Solid crystalline atorvastatin hemi-calcium and solvates thereof characterized by powder X-ray diffraction pattern having peaks at 16.5, 21.9, 29.5±0.2 degrees two-theta. 
   
   
       51 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 50  further characterized by additional peaks at 7.7, 9.9, 16.5, 17.7, 18.3, 20.0, 21.9, 29.5±0.2 degrees two-theta in the powder X-ray diffraction pattern. 
   
   
       52 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 50  further characterized by a powder X-ray diffraction pattern generated using CuK α  radiation substantially as depicted in  FIG. 16 . 
   
   
       53 . A process for preparing solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form XVI and solvates thereof comprising:
 a) maintaining atorvastatin hemi-calcium Form XIV crystals at from about 20° C. to about 50° C., and   b) recovering the crystals as solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form XVI.   
   
   
       54 . The process of  claim 53  wherein the atorvastatin hemi-calcium is maintained at about 22° C. 
   
   
       55 . The process of  claim 53  wherein the atorvastatin hemi-calcium is exposed to air while being maintained. 
   
   
       56 . Solid crystalline Atorvastatin hemi-calcium and solvates thereof characterized by a powder X-ray diffraction pattern having peaks at 19.1, 20.6, 21.4 and 23.6±0.2 degrees two-theta. 
   
   
       57 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 56  further characterized by additional peaks at 7.8, 9.5, 10.2, 18.2, 19.1, 25.3, 26.2, 30.1±0.2 degrees two-theta in the powder X-ray diffraction pattern. 
   
   
       58 . The solid crystalline atorvastatin hemi-calcium and solvates thereof of  claim 56  further characterized by a powder X-ray diffraction pattern generated using CuK α  radiation substantially as depicted in  FIG. 17 . 
   
   
       59 . A process for preparing solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form XVII and solvates thereof comprising:
 a) suspending atorvastatin hemi-calcium Form V in a mixture of about 96% ethanol and about 4% water,   b) heating the suspension,   c) cooling the suspension, and   d) recovering solid atorvastatin hemi-calcium from the suspension having at least one characteristic of Form XVII.   
   
   
       60 . The process of  claim 59  wherein the mixture is used in an amount of at least about 500 ml. 
   
   
       61 . The process of  claim 59  wherein the suspension is heated to about 78-80° C. 
   
   
       62 . A pharmaceutical composition comprising atorvastatin hemi-calcium selected from the group consisting of Forms IX, IXa, XIV, XVI, XVII and mixtures thereof and a pharmaceutically acceptable carrier. 
   
   
       63 . Use of atorvastatin hemi-calcium selected from the group consisting of Forms IX, IXa, XIV, XVI, XVII and mixtures thereof to prepare a pharmaceutical dosage form. 
   
   
       64 . A pharmaceutical dosage form comprising atorvastatin hemi-calcium selected from the group consisting of Forms IX, IXa, XIV, XVI, XVII and mixtures thereof. 
   
   
       65 . A method of reducing the plasma low density lipoprotein level of a patient suffering from or susceptible to hypercholesterolemia by administering to the patient the pharmaceutical dosage form of  claim 64 . 
   
   
       66 . Use of atorvastatin hemi-calcium selected from the group consisting of Forms IX, IXa, XIV, XVI, XVII and mixtures thereof to prepare a pharmaceutical dosage form. 
   
   
       67 . A process for preparing solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form I and solvates thereof comprising:
 a) heating crystals of atorvastatin hemi-calcium Form XIV to about 50° C. or above, and   b) recovering the crystals as solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form I.   
   
   
       68 . The process of  claim 67  wherein the atorvastatin hemi-calcium Form XIV is heated to about 65° C. 
   
   
       69 . A process for preparing solid crystalline atorvastatin hemi-calcium having at least one characteristic of Form VIII comprising:
 a) providing atorvastatin hemi-calcium Form XVII,   b) drying the Form XVII to transform it into atorvastatin hemi-calcium having at least one characteristic of Form VIII, and   c) recovering the atorvastatin having at least one characteristic of Form VIII.   
   
   
       70 . The process of  claim 69  wherein drying includes heating the Form XVII to an elevated temperature. 
   
   
       71 . The process of  claim 70  wherein the elevated temperature is from about 40° C. to about 70° C.