Title of Invention

"A PROCESS FOR PREPARING AMORPHOUS ATORVASTATIN HEMI-CALCIUM SALT"

Abstract The present invention relates to a process for preparing amorphous atorvastatin hemi-calcium salt comprising: a) suspending crystalline atorvastatin Form V in a mixture of 30% 1-butanol and 70% water at a temperature of about 91°C. b) cooling the suspension of step a) to room temperature and then to 0°C; and c) separating amorphous atorvastatin from the suspension of step b).
Full Text The present invention relates to a process for preparing amorphous atorvastatin hemi-calcium salt.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a contriuation in part application of U.S. application Serial Number 09/997126, filed on November 29,2001 and claims the benefit of provisional applications Serial Numbers 60/250,072, filed November 30,2000; 60/267,897, filed February 9,2001; 60/281,872, filed April 5; 2001; 60/312,144, filed August 13,2001; 60/326,529, filed October 1,2001; 60/357181, filed February 15,2002 and 60/425,325, filed November 12,2002, all of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to crystalline polymorphic forms of atorvastatin hemi-calcium and novel processes for preparing crystalline forms of atorvastatin hemi-calcium.
BACKGROUND OF THE INVENTION
Atormtatm,([R-(R*,R*)]-2-{4-miorophenyl)-ß-δ-dihydroxy-5-(1-methylethyl)-3-phenyl-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid), depicted in lactone form in (Formula Removed)
formula (I) and its calcium salt 6f 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.
Processes for preparing atorvastatin and its hemi-calcium salt are also disclosed in U.S.
Patent Application Publication No. 2002/0099224; U.S. Patents Nos. 5,273,995; 5,298,627; 5,003,080; 5,097,045; 5,124,482; 5,149,837; 5,216,174; 5,245,047,5,280,126; Baumann,

K.L, ct al. TeL Lett 1992,33,2283-2284, which are hereby incorporated by reference in their entirety and in particular for their teachings related to the preparation of atorvastatin and atorvastatin ham-calcium.
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. 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, Goodman and Gilman, 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 tree of cardiovascular disease but who have hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; lipid Research Climes program, 19&4a, 19S4b.
The mechanism of action of statin drugs 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-metbyl-glutaryl-coenzyme A reductase enzyme ("HMG~CoA reductase"). HMG-CoA reductase catalyzes the conversion HMG to mevalonale, 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 (VLDL) is the biological vehicle for transporting cholesterol and triglycerides from the liver to peripheral cells. VLDL is catabolized in the peripheral cells which releases fetty acids which may be stored in adopcytes or oxidized by muscle. The VLDL is converted to intermediate density lipoprotein (TDL), which is cither removed by an LDL receptor, or is converted to LDL. 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 Wamer-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 CaCl2 and further purified by rccrystallization from a 53 mixture of ethyl acetate and hexane.
The present invention provides new crystal forms of atorvastatin hena-calcium in both solvated and bydrated 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 (1) 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 intermolecnlar interactions of adjacent molecules (complexes) in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous and/or disadvantageous physical properties compared to other forms m the polymorph, family. One of the most importarrt 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 On the other hand, where the effectiveness of a drug correlates with peak bloodstream levels of the drug, a property shared by statin drags, and provided the drug is rapidly absorbed by the GI system, then a more rapidly dissolving form is likely to exhibit increased effectiveness over a comparable amount of a more slowly dissolving form.
Crystalline Forms I, II, III and IV of atorvastatin hejni-calcium are the subjects of U.S. Patents Nos. 5,959,156 and 6,121,461 assigned to Warner-Lambert and crystalline atorvastatin hemi-calcium Form V is disclosed in commonly-owned International Publication No. WO 01/36384 (PCT Application No. PCT/US00/31555). There is an assertion in the '156 patent that Form I possesses more favorable filtration and drying characteristics than the known amorphous form of atorvastatin hemi-calcium. According to the ' 156 patent, Form I is characterized by powder X-ray diffraction pattern having peaks at 9.150, 9.470,10.266, 10.560,11.853,12.195,17.075,19.485,21.626,21.960, 22.748,23.335,23.734,24.438, 28.915 and 29.234 degrees two~theta.
Commonly owned, co-pending U.S. Patent Application No. 2002/0115709 discloses atorvastatin henri-calcium Form VII, processes for preparing it and pharmaceutical compositions containing it The *709 patent is hereby incorporated by reference in its entirety.
Although Fonn I remedies some of the deficiencies of the amorphous material m terms of manufacturabity, mere remains a need for yet further improvement in these properties as well as improvernents m other properties such as flowabihty, vapor impermeability and solubility. Further, the discovery of new crystalline polymorphic forms of a drug enlarges the repertoire of materials that a formulation scientist has with which to design a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
BRIEF DESCRIPITON OF THE FIGURES
Fig. 1 is a characteristic powder X-ray diffiaction 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 VII 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 VIII obtained using a conventional X-ray generator with a copper anode.
Fig. 4 is a characteristic powder X-ray diffiaction pattern of atorvastatin hemi-calcium Form VIII obtained using a synchrotron X-ray source.
Fig. 5 is a characteristic solid state ,3C NMR spectrum of atorvastatin Form VIII. 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 sobd state 13C NMR spectrum of atorvastatin Form IX. Fig. 9 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi-calcium Form IXa obtained using a conventional X-ray generator with a copper anode.
Fig. 10 is a characteristic powder X-ray diffiaction pattern of atorvastatin hemi-calcium Form X obtained using a conventional X-ray generator with a copper anode.
Fig. 11 is a characteristic powder X-ray diffraction pattern of atorvastatm ham-calcium Form X obtained using a synchrotron X-ray source.
Kg. 12 is a characteristic solid state 13C MMR spectrum of atorvastatin hemi-calcium Form X.
Fig. 13 is a characteristic powder X-ray diffraction pattern of atorvastatin herai-calcium Form XI obtained using a conventional X-ray generator with a copper anode.
Fig. 14 is an overlay of typical powder X-ray diffraction patterns of atorvastatin hemi-calcinro Form XII obtained using a conventional X-ray generator with a copper anode.
Fig. 15 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi-calcium Form XIV obtained using a conventional X-ray generator with a copper anode.
Fig. 16 is a characteristic powder X~ray diffraction pattern of atorvastatin hemi-calcium Form XVI obtained using a conventional X-ray generator with a copper anode.
Fig. 17 is a characteristic powder X-ray difiraction pattern of atorvastatm hemi-calcium Form XVIL
SUMMARY OF THE INVENTION
The present invention provides new atorvastatin hemi-calcium solvates and hydrates.
The present invention provides a novel crystalline form of atorvastatin hemi-calcium dermninated Form VI and novel processes for its preparation.
In another aspect, the present invention provides a novel crystalline form of atorvastatm hemi-calcium denominated Form VIII and novel processes for its preparation.
la another aspect, the present invention provides a novel crystalline form of atorvastatin hcmi-calcium denominated Form IX and novel processes for its preparation.
In another aspect, the present invention provides a novel crystalline form of atorvastatm hemi-calcium denominated Form IXa and novel processes for its preparation,
In another aspect, the present invention provides a novel crystalline form of atorvastatm hemi-calcrum denominated Form X and novel processes for its preparation.
In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denorrrinated Form XI and novel processes for its preparation.
In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form XII and novel processes for its preparation-
In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form XIV and novel processes for its preparation.
In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form XV and novel processes for its preparation.
In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form XVI and novel processes for its preparation.
in another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form XVIIand novel processes for its preparation another aspect, the present invention provides novel processes for preparing atorvastatin hemi-calcium Form L
In another aspect, 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-calchim Form IV.
In another aspect, the present invention provides novel processes for preparing atorvastatin hemi-calcium Form V,
In another aspect, the present invention provides novel processes for preparing amorphous atorvastatin hemi-calcium
In another aspect, the invention provides compositions and dosage forms comprising atorvastatin hermi-alchtm Forms VI, VII, VII, IX, X, XI, Xla, XIV, XVI, XVII and their mixtures.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Some crystalline forms of atorvastatin hemi-calcium of the present invention exist in a solvated state and hydrated state. Hydrates have been analyzed by Karl-Fisher and thennogravirnetric analysis.

Powder X-ray diffraction PXRD**) analysis employing conventional CuKj, radiation was performed by methods known in the an using a SCINTAG powder X-ray diffractometer model X'TRA equipped with a solid-state detector. Copper radiation of  *= 1.5418 A was used. Measurement range: 2-40 degrees 20. The sample was introduced using a round standard ahirnirram sample holder with round zero background quartz plate in the bottom. Powdered samples were gently ground and filled in the round cavity of the sample; holder by pressing with a glass plate.
PXRD analysis using a synchrotron X-ray source was performed at the National 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 M5 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 20. 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.
The CP/MAS ,5C NMR measurements were made at 125.76 MHz and were performed on a Broker DMX-500 digital Fi NMR spectrometer equipped with a EL-4 CP/MAS probehead and a High Resolution / High Performance 'H preamplifier for solids: spin rate 5.0kHz, pulse sequence SELTICS, sample holder: Zirconia rotor 4mm diameter.
Atorvastatin herm'-calcium Form VI is characterized by a powder X-ray diffraction pattern (Fig. 1) with peaks at 3.5, 5.1,7.7, 8.2,8.7710.0,12.5,13-8,16.2,17.2,17.9 18-3, 19.5,20.4,20.9,21.7,22.4,23.2,24.3,25.5 ± 0-2 degrees two-theta. The most characteristic peak is observed at 19.5*0.2 degrees two-theta. The PXRD pattern of Form VI was taken using a Phylips diffractometer similar to the SCINTAG instrurncntation described above.
Atorvastatin hemi-calckm 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 hcmi-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 20, and other additional broad peaks at 4 J, 7.8,9.3,12.0,17.1,18.2±0.2 degrees 26. Samples of Form VII may contain up to 12% water.
Form VII is readily distinguished from known forms of atorvastatin herni-caJcium by the broad peaks at 7.8 and 93±0.2 degrees 20. For instance, Form I has peaks at 9.2,95, 10.3, 10.6, 11 .0 and 122 degrees 29 according to the information provided in U-S. Patent No. 5,969,156. Li this region, Form II has two sharp peaks at 8.5 and 9.0 degrees 20 and Form IV has one strong peak at 8.0 degrees 20. The other broad peaks in the region of 15-25 degrees 20 distinguish Forro VII from all other forms, Forms I, HI and IV all have sharp peaks in this region.
Alorvastatin hemi-calcium Form VII may be prepared by treating atorvastatin calcium Forms I or V 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 henri-calcium Form VIII is characterized by a powder X-ray diffraction pattern (Fig. 3) obtained using conventional CuKa radiation having peaks at 4.8,5.2,5.9,7.0, 8.0,9.3,9.6,10.4,11.9,163, l7.1(broad), 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* 02 degrees two-thcta. The most characteristic peaks are at 6.9,9.3,9.6,163,17.1,192,20.0,21.6,22.4,23,9,24.7,25.6, and 26.5±0,2 degrees 20. Samples of atorvastatin hemi-calcixim Form VIII were found to contain up to 7% water by Karl Fisher.
Form VIII is readily distinguished from Forms I-IV by its characteristic sharp peaks at 9.3 and 9.6 degrees 26. 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 92, 9.5,10.3,10.6, 11.0 and 12.2*0.2 degrees 20. Form JV is said to have two peaks at 8.0 and 9.7 degrees 20. Form II is said to have in this region two sharp peaks at 8.5 and 9.0 degrees 20. Form m has in this region one strong sharp peak at 8.7 degrees 29 according to the information provided in U.S. Patent No.
6,121,461. The features are not observed in the Form VIII PXRD pattern. Further, there is in the PXRD partem of Form VIII one sharp, medium intensity peak at 7.0 which is well distinguished from other peaks in the region. A comparison of the PXRD pattern of Form VIE with the patterns of Forms I-IV reveals that this feature of the Form VIE pattern is distinctive.
Other peaks in the Form Vin pattern that are unique to this form are the two strong and sharp peaks at 19.2 and 20.0 degrees 28. fa this region, Form I has sharp peaks at 21.6,22.7, 23.3 and 23.7 degrees 26 according to the information provided in the '156 patent. Form IV is said to have peaks at 18,4 and 19.6 degrees 20, while Form II has two main peaks at 17.0 and 20.5 and Form m has peaks at 17.7,1S-2,18-9,20.0 and 20.3±0.2 degrees 29.
Synchrotron X-ray powder diffraction analysis was performed on Form VIII to determine its crystal system and unit cell dimensions. Form VIII has a monoclinic unit cell with lattice dimensions: a= 1S.55-18.7 A, b = 5.52-5.53 A, c = 31.0-312 A and angle ß between the a and c axes of 97.5-99-5 ", The unit cell parameters were detennined using the Le Bail method.
The diffractogram of Fig. 4 obtained using a synchrotrorn X-ray source has many sharp well resolved peaks. The d-spadngs 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 1.5418 A.

Table 1(Table Removed)

Because of the natural variation between independent samples and measurements, the peak positions may deviate from the reported positions by as much as 0.5% of the d valnes. There may be larger shifts if the material undergoes size reduction such as micronization.
Atorvastatin hemi-calcium Form VIII produced the solid-state 13C NMR spectrum shown in Fig. 5. Form VIII is characterized by the following solid-state I3C nuclear magnetic resonance chemical shifts in ppm: 17.8,20.0,24.8,252,26.1,40.3, 40.8, 415,43.4,44.1, 46.1, 70.8, 73.3,114.1,116.0,119.5,120-1,121.8,122.8,126.6,128.8,1292,1342, 135.1,137.0,1383,139.8,159.8,166.4,178.8,186.5. Form VIII is characterized by a solid-state 13C nuclear magnetic resonance having the following chemical shifts differences between the lowest ppm resonance and other resonances: 22,7.0,7 4, 8.3, 22.5,23.0,23.7,25.6,26,3, 28.3, 53.0,55.5,963,982,101.7,1023,104.0,105.0,108.8,111.0,111.4,116.4,1173, 119.2,120.5,122.0,142.0,148.6,161.0 and 168.7. The chemical shifts reported for Form VIII are averaged from spectra taken of four samples of Form Yd. Characteristic parts of the pattern are found at 24-26 ppm (aliphatic range), 119-140 ppm (aromatic range) and other
regions. The shift values are accurate to within ±0-1 ppm, except for the carbotryi peak at 178.8 ppm which has a fluctuation of ±0.4 ppm.
Atorvastatin hemi-calcium Form VIE can exist as an ethanol solvate containing up to about 3 % ethanol by weight.
The following methods have been found suitable for generating Form VIIIThis form may, however, also be accessible by empirical development and by routine modification of these procedures-
Atorvastatin benoi-calcrain Form VIII may be obtained by slurrying atorvastatin hemi-caJcium in a mixture of ethanol and water at elevated temperature, preferably about 78-80°C. The slurrying procedure may be incorporated mto 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. In such a combined procedure the salt is generated in a solvent system comprising ethanol and water. Conveniently, after precipitation of the atorvastatin hemi-calcrum salt by an additional amount of 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 VIII
Form VIII also may be obtained starting from Form V by treating Form V with a mixture of EtOH:H20, preferably in the ratio of about 5:1 at an elevated temperature below tcRux, preferably 78-80 °C. An especially preferred EtOH:H20 mixture contains about 4 % by volume water in ethanol. During the heating, atorvastatin Form V gradually dissolves and al 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 VIC 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 repreefpitates. MeOH may be added at reflux. Added MeOH may adversely affect the yield, but may improve the chemical purity of the prodnct Starting materials for preparing Form VIII by this process can be crystalline forms of atorvastatin hemi-calcium, preferably Forms I and V 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 SO ml g'1.
We have discovered that atorvastatm hemi-calcium that contains greater than 0.1 % des-fluoro atorvastatin herru-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- Typically, 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 atorvastatm hemi-calcrura.
Form VIII also may be prepared by suspending atorvastatin hemi-calcium in certain 1-butanoVwarer and ethanol/water mixtures for a period of time sufficient to cause the conversion of the atorvastatin hemi-calcium to Form Vm. 1-Butanol/water mixtures should contain about 20% 1-butanol by volume at elevated temperature, preferably at reflux temperature.
It will be appreciated from the description of Form XVII that follows that conventional drying of Form XVII transforms it into Fotm VIII By conventional drying it is meant the methods of drying routinely used by those skilled in the art in the pharmaceutical industry. Any drying type of equipment conventionally used in the pharmaceutical industry is suitable for this purpose. A drying temperature in the range of about 40-70 °C (in temperature steps or in one temperature only) is preferred. The amount of time required to convert Form XVII to Form VIII depends on the quantity of material employed. Vacuum may be preferably used to convert Form XVII to Form Vm by drying. Preparation of Form VIII also may be achieved by drying Form XVII at temperatures lower than 40 °C, down to room temperature.
Atorvastatin hemi-calcium Form IX is characterized by a powder X-ray diffraction pattern (Fig. 6) with peaks at 4.7, 5.2,5.7,7.0,7.9,9.4,10.2,12.0,17.0,17.4,18.2,19.1, 19.9,21.4,22.5,23.5,24.8 (broad), 26.1,28.7,30.0±0.2 degrees two-theta. The most characteristic peaks of Form IX are at 6.9,17.0,17.4,18.2,18.6,19.1,19.9,21.4,225 and 23.5±0.2 degrees two-theta. 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, 19.1,19.9, 21 A, 22.5,23.5 degrees 20. For comparison, Form I has sharp peaks at 21.6,22.7,233 and
23.7 degrees 20, while Form IV has hi this region sharp peaks at 18.4 and 19.6 degrees 26 and Form II has two main peaks at 17.0 and 20 J degrees 20, according to information in the ' 15 6 patent. Form III has m this region peaks at 17.7,18.3,18 9 20.0 and 20.3 degrees 20. Also, there is in the PXRD pattern of Form K, as there is in the pattern of Form VIII, a sharp, well distinguished medium intensity peak at 7.0 degrees 20.
The crystal system and unit cell dimension of Form DC were determined using synchrotron X-ray powder diffraction analysis. Form IX has a monoclinic crystal lattice with lattice dimensions; a= 18.75-18.85 A, b = 5.525-5.54 A, c= 30.9-31.15 A and angle ß between the a and c axes of 96.5-975°.
The i-spacings of some of the more prominent peaks in the synchrotron X-ray powder diffractogram of Fig. 7 are listed in Table 2, along with the positions in units of two-theta that the peaks would have using CuK„ radiation.
Table 2

(Table Removed)
Because of the natural variation between independent samples and measurements, the peak positions may deviate from the reported positions by as much as 0.5% of the d values. There maybe larger shifts if the material undergoes size reduction such as micronization.
Atorvastatin hemi-calcium Form IX produced the solid-state l3C NMR spectrum shown in Fig. S. Form IX is characterized by the following solid-state 13C nuclear magnetic resonance chemical shifts inppm: 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. Foroi PC is characterized by a solid-state ' 3C 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, 111.4,116.3,117.1,118.8,1203,121.4,141.9,1483,160.4,168.6. 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 DC are an average taken from spectra on two samples of Form DC The shift values arc accurate to within ±0.1 ppm.
Form DC 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-calcram Form DC may be prepared by slurrying atorvastatin hemi-calcium in 1-bntanol and isolating Form DC by, for example, filtration or dceantation of the butanol, preferably by filtration. Preferred temperature ranges for the slurrying arc from 78 * C to the reflux temperarore 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 DC Preferred anti-solvents include isopropanol and n-hexane. Starting materials for preparing Form DC by this process can be crystalline or amorphous atorvastatin hemi-calcium, preferably Forms I and V and mixtures thereof.
Form DC may be prepared by suspending Form VIII in ethanol, preferably absolute ethanol, at room temperature for a period of time sufficient to convert Form VIII to Form DC, which may range from a few hours to 24 hours and typically requires about 16 hours. Thereafter Form DC is recovered from the suspension. Form DC also may be prepared by maintaining Form VIII under a humid atmosphere.
Form DC also can be prepared by suspending Form V in a mixture of 50% 1-butanol and 50% of another organic solvent(s) like acetone, 2-propanol, teterahydrofuran, 1-propanol and methyl r-butyl ether. The mixture is used in an amount of about 20 milliliters per gram of Form V. The suspension is heated to reflux temperature for about 16 hours, after which time Form V is transformed into Form DC, which can then be recovered from the suspension by conventional means.
It has also been found that suspending atorvastatin hemi-calcium Form V in mixtures of 1-butanol and water, wherein one or the other diluent is predominant in the mixture, will yield a more highly pure and crystalline atorvastatm hemi-calcium product This product has been
denominated Form IXa. Atoxvastatm hemi-calcium Form IXa is characterized by its PXRD pattern (Fig. 9), which is similar in some respects to that of Form DC. However, there are differences between the two patterns. The most predominant difference is at 9,5 degrees two-theta. There, a single strong peak is observed in the PXRD pattern of Form DC whereas two strong peaks are observed at 93 and 9-5 degrees two-theta in the Form IXa pattern. In addition, there are small peaks at 15.7,20.5,21.1,22.8,23.8,24.0,25.3,26.4,26.8,272, 29.2 and 31.6±0.2 degrees two-theta in the PXRD pattern of Form IXa.
Atorvastatin hemi-calciim Form DCa is considered to be an especially crystalline, filterable and pure material having similar internal structure to Form DC, hence the designation Form DCa. Form DCa can be prepared by suspending atorvastatin hemi-calcium Form V in mixtures of 1-butanol and water in which either the 1-butanol or water constitutes from about 85% to about 95%, more preferably about 90%, of the mixture. The suspension can be heated to accelerate conversion of Form V to Form IXa. Sixteen hours at about 85 °C is generally sufficient Under these conditions, yields as high as 95% can be obtained and the impurity level of the material can be significantly reduced. The impurity content of the starting atorvastatin herm-calcium can be reduced by about 50% or more. For example, Form DC can be obtained in about 0.7% chemical purity when starting with Form V of about 1.3% chemical purity. Chemical purity was measured by high performance liquid chromatography ("HPLC"). HPLC was performed on a Sphcrisorb® S5, CS column, 250x4.6 mm with gradient clution: Solvent A 0.05M KH3FO4 adjusted to pH 5 with IN KOH:acetonitiile: methanol:THF (62:26:8:4); Solvent B: methanol. The HPLC system was equipped with Waters® pumps and a UV detector set to detect at 254 nm.
Among the specific procedures that can be used there may be mentioned the following. Form V is suspended in a mixture of 90% 1-butanol and 10% water (v/v). The mixture is used in an amount of about 20 milliliters per gram of Form V The suspension is refluxed at 90°C for about 16 hours, after which time Form V is transformed into Form DC, which is then be recovered from the suspension by conventional means, like filtration.
According to another specific procedure, Form V is suspended in a mixture of 10% 1-butanol and 90% water (v/v). The mixture is used in an amount of about 20 rnilliliters per gram
of Form V The suspension is refluxed for about 16 hours, after which time Form V is transformed into Form IX, which is then recovered by conventional means.
The present invention further provides atorvastatin hcmi-calcium Form X Form X is characterized by a powder X-ray diffraction pattern (Fig. 10) having peaks at 4.8, 53,5.9,9.6, 10.3,11 5,12.0, a double peak at 16.1 and 163,16.9, 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 26 The most characteristic peaks are two peaks at 20.0 and 20.8±0.2 degrees 20 and other peaks at 19 1,19 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.
The PXRD pattern of Form X is distinguished from that of Form IV 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 arc clearly distinguished from those appearing the corresponding regions of the PXRD
patterns of Forms I-IV which have been previously described
The crystal system and unit cell dimension of Form X were determined using synchrotron
X-ray powder diffraction analysis. Form X has a monochnic crystal lattice with lattice
dimensions; a = 18.55-18.65 A, b = 5 52-5.53 A, c= 30 7-30 85 A and angle ß between the a
and c axes of 95.7-96.7".
The d-spacings of some of the more prominent peaks m the synchrotron X-ray powder
diffjractogram of Fig.11 are listed in Table 3, along with the positions m units of two-theta that the
peaks would have using CuKa radiation
Table 3
(Table Removed)
Because of the natural variation between independent samples and measurements, 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 such as micronization.
Atorvastatb hemi-caldum Form X produced the solid-state "C NMR spectrum shown m Fig. 12. Form X is characterized by the following solid-state I3C nuclear resonance chemical
shifts in ppm: 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, 138.0,159.4,1662,1793,181.1,184 3, U6.1. Form X is characterized by a solid-state UC 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 arc averaged from three spectra taken of three samples of Form X. The values reported arc within ±0.1 ppm, except for the carhonyl peak at 179- 3 ppm that is accurate within ±0.4 ppm.
Atorvastatia hcmi-calcium Form X may be prepared by treating crystalline atorvastatin hemi-calcium, preferably Form V 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 EtOHrwater mixture at room temperature, followed by gradual heatiag of the suspension to reflux. Alternatively, the starting form of atorvastatin hemi-calcium may be added to the refluing solvent mixture. In either case, the atorvastatin hemi-calcium should be observed to dissolve in uie mixture and then reprccipitate in Form X. The ratio of atorvastatin hemi-calcium to the EtOHrwater mixture preferably ranges from about 1:16 to about 1:25 (g:ml), more preferably from about 1:16 to about 1:21 (grml) and most preferably about 1:16 (gmil). 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. 13) having peaks at 3.2,3.7,5.1,63,7.8,8.6,9.8,11.2,11.8,12.4,15.4,18.7, 19.9,20.5,24.0 ±0.2 degrees two-theta.
Form XI may be obtained by suspending atorvastatin hemi-calcium Form V in methyl ethyl ketone ("MEK") at room temperature for a period of time sufficient to cause the conversion of Form V 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 isopropy] alcohol with atorvastatm hemi-calcium at reflux temperature and then cooling to room temperature. Extensive staring at room temperature, as long as or more than 20 h, may be required in order for the gel to form. hi the gel state, the solution is detecfcably more resistant to stirring and does not pour smoothly. The gel remains fiowable in the sense that it can be stirred if sufficient force is applied and would not tear under such force.
Atorvastatin hemi-calcium Form XU is characterized by a powder X-ray diffraction pattern having peaks 312.7,8-0,8.4,11.8, 18.2,19.0,19.8,20,7 ±0.2 degrees two-theta, and a balct that indicates the presence of amorphous material. Typical X-ray powder diffraction patterns of atorvastatm hcmi-calcjnm Form XII are shown in Fig, 14.
Form XII may be prepared directly from the following compound formula
(Formula Removed)
whose systematic chemical name is [R-(R*JR.*)]-2-(4-fluorophcnyl)-ß, δ-dioxane-5-(l-mefoylewyJ)-3-phenyl-4-[(phenylamino(carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester and
which will hereafter be referred to as pyrrole acetonide ester or PAE. Form XU 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. After association of the atorvastatin with dissolved calcium derived from the added hydroxide salt, 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 atorvastatm 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 XH.
The present invention further provides a novel polymorph of atorvastatin hemi-calcium that has been denominated Form XIV. Atorvastatin hemi-calcium Form XIV is characterized by a powder X-ray diffraction pattern obtained using conventional CuKα radiation (FIG. 15) having peaks at 7.6, 9.8,16.5,18.1,20.0,20.4,213,22A, 23-6, 29.4 ± 0.2 degrees two-theta. The most characteristic peaks are those at 7.6,9.8,16.5,29.4 J- 0.2 degrees two-theta.
La general terms, Form XTV can be obtained from a suspension of atorvastatin hemi-calcium in water. According to U.S. Patent No. 5,969,156, atorvastatin herni-calcium Form I precipitates when calcium acetate is added to a solution of atorvastatin sodium in water. It is also said that Form I can be prepared by suspending amorphous atorvastatin hemi-calcium in water. In the specific example provided, Example 1, a mixture formed from atorvastatin sodium and calcium acetate m water was seeded with Form I shortly after addition of the calcium acetate solution and, thereafter, Form I was obtained.
We have found that suspending atorvastatin hemi-calcium in or precipitating atorvastatin hemi-calcium from water does not invariably lead to the production of Form I as might be expected after studying the ' 156 patent On the contrary, in our hands, suspensions of atorvastatin bemi-calcium rn water yield a previously unknown polymorph that we have denominated Form XTV. Form XTV is readily distinguishable from Form I (which is also obtained by precipitation from water, but with seeding with Form I) by the peaks at 7.6,16.5, 20.0 and 19.4 degrees two-theta, which peaks are absent from the PXRD pattern of Form I. It should be noted that in Example 35, below, tho suspension is not stirred or seeded with a crystal of Form I Atorvastatin hemi-calcium Form XTV can be prepared by suspending atorvastatin hemi-calcium in water until a fine suspension forms and then allowing the suspension to stand undisturbed until the fine crystals transform substantially into white flakes. The flakes can be separated from the suspension by conventional means, like decanting or filtering (either with or without suction and they do not clog the filter) and washing the crystals. The crystals of the fine suspension are very small giving the suspension the appearance of an emulsion. The
transformation from fine suspension to flakes is readily apparent from visual inspection of the suspension. Preferred process parameters are as follows. rrhe preferred starting material is atorvastatin hemi-calcimn Form V. The fine suspension typically forms over a period of from about 2 to about 10 hours, on average about 5 hours. The fine suspension transforms into white flakes over about one to about five days, with longer time periods being preferred for more complete conversion and a more easily filterable product. Other conditions which lead to the production of Form XTV may be discovered but presently the best method known is by suspending atorvastatin heim-calciutti in water that is not agitated and has not been seeded with a different polymorph of atorvastatio. Form XTV has been obtained in our laboratory without seeding of any kind.
Form XTV crystals can be transformed into another crystal form without contact with solvent This new from has been denominated Form XVL Form XVI is characterized by a powder X-ray diffraction pattern obtained using conventional CuK, radiation (FIG. 16) having peaks at 7.7,9.9, 16.5,17.7,183,20.0,21.9,29-5 ± 02 degrees two-theta. The most characteristic peaks are at 16.5,21.9,29.5 ± 02 degrees two-theta.
Form XVI may be produced by maintaining Form XIV at from about 20 ° C to about 50°C, preferably about 22°C or room temperature, and preferably exposed to air. Preferably, Form XTV is maintained under these conditions for about three hours. Other conditions under which Form XVI is formed may be empirically determined. It is only possible to give methods which have so far been found suitable for producing it
The present invention further provides a hydrated form of atorvastatin hemi-calcium that has been denominated Form XVH. Form XVII has been isolated as the immediate product obtained by precipitation from wet ethanol. As taught by U.S. Patent Application Publication No. 2992/0183378 (alternatively, see Intematiorial Publication No. WO 01/36384 of PCT application number PCT/US00/31555), Form VIII can be prepared from a dispersion of Form V in a mixture of 96% ethanol/water at a temperature of about 70°C. By using this procedure in scales of at least I liter or more, the precipitated material, prior to being dried, is obtained in Form XVII.
Atorvastatin hemi-calcium Form XV3J is characterized by a powder X-ray diffraction pattern obtained using conventional CnK, radiation by typical X-Ray peaks at 19.1,20.6,21,4 and 23.6± 02 degrees two-theta. Additional peaks arc observed at 7.8,9.5,10.2,18.2,19.1, 25.3,26.2,30.1±02 degrees two-theta. Form XVU is also characterized by the typica powderl X-Ray diffraction pattern of FIG. 17. Form XVH is distinguishable from Form VIII (the material obtained by complete drying of material obtained by precipitation from 96% ethanol/4% water) bythepeakpatternintherangeof9-10> 18-25 degrees two-theta. In particular, Form VIII exhibits two strong peaks at 19.2 and 20.0 +0.2 degrees 26, while Form XVU has one strong peak at 19.1:1:0.2 degrees 29, but no comparably strong peak at 20±0.2 degrees 26.
Atorvastatin hemi-calcium Form XVU may be produced by suspending atorvastatin bemi-calcium Form V in a mixture of 96% ethanol and 4% water (v/v) and heating to about 78-80 °C, followed by cooling. Form XVII can be isolated immediately after the material starts to precipitate in the mixture at reflux temperature, or after all the material is precipitated, after the material is cooled down to room temperature, or after all the solid is isolated from the mother liquor (for instance by filtration). Although there may be other ways to obtain Form XVD, the best way presently known is to suspend atorvastatin hemi-calcium Form V in at least about 500 milliliters or more of a mixture of about 96% ethanol and about 4% water (v/v) and refluxmg the suspension, followed by cooling. The solids are then recovered by conventional means such as filtering or decanting as Form XVU Additional experimental details are provided in Example 38. The volume of the reactor should be at least about 1 liter.
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 V, VI, VIII, 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 VII is a preferred starting material though other forms may be used as well
Atorvastatin herni-calciam Form I may be produced by heating Form XIV to about 50° C or above, preferably about 65°C. Preferably, Form XIV is maintained at elevated temperature for about 15 hours.
Form II may be prepared directly from [R-(R* R*)]-2-(4-fluoropheny])-> -djoxano-5-(l-methylethyi)-3-phenyl^[(phenylamino)carbonyl]-H-pyrrole--tert-burylhepianoic ester (PAE) according to Example 46,
Atorvastatin hemi-calcium Form IV may be prepared by suspending Form I or Form V in 1-butanol for a period of time sufficient to complete the conversion of Form I or Form V to Form IV and then isolating Form IV 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 IV also may be obtained by suspending Form V in EtOH/HjO at 50 °C for a period of time sufficient to cause the conversion of Form V to Form IV and then recovering Form IV from the suspensions. Prefered EtOH/HO mixtures contain about 15% H20.
Form IV also may be obtained by suspending atorvastatin herai-calcium Form V in methanol for a period of time sufficient to cause the conversion of Form V to Form IV. 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 V may be prepared from PAE according to the process described with reference to the preparation of atorvastatin hcmi-calcium Form XH. Form V may be obtained by drying Form XH at about 65°C for about 24 hours- The atorvastatin hemi-calcium Form V obtained in this manner is of high purity. However, it may bo further purified by suspending in a mixture of about 10% water and about 90% ethanol and recovering Form V from the mixture in greater purity.
Amorphous atorvastatin hemi-calciam 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 starring material is Form V.
Amorphous atorvastatin hemi-calcrnm also may be prepared by sonicating any form of atorvastatm ham-calcium in acetorjitrile 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 die starting material into amorphous atorvastatin hemi-caldum. Preferred starting forms of atorvastatin hemi-calcium are Forms VII and I.
Amorphous atorvastatin henri-calcium also may be prepared by ball milling of any crystalline form of atorvastatin hemi-calciumL
Atorvastatm hemi-calcium Forms VI, VII, VII, IX, IX, X XI, XII, XIV, XVI and XVII are useful for reducing the plasma low density lipoprotein level of a patient suffering from or susceptible to hyranimolesterolenria. For this purpose, it will typically be administered to human patients in a unit dose of from about 0.5 mg to about 100 mg. For most patients, a dose of from about 2.5 to about 80 mg per day, more particularly from about 2.5 to about 20 mg per day, causes a lowering of the plasma low density lipoprotein level in human patients. Whether such lowering is sufficient or whether the dose or dose frequency should be increased is a determination that is within the skill level of appropriately trained medical personnel.
A further aspect of the present invention is a pharmaceutical composition and dosage form containing the novel forms of atorvastatin hemi-calcium.
The compositions of the invention include powders, granulates, aggregates and other solid compositions comprising novel Forms VI, VII, VEX, IX, IXa, X, XI, XII, XIV, XVI and XVII of atorvastatin hemi-calciurm In addition, Forms VI VII, VIII, IX, IXa, X, XI, XII, XIV, XVI and XVII solid compositions that are contemplated by the present invention may further include diluents, such as cellulose-derived materials like powdered cellulose, microcrystallme cellulose, nricrofine cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose
salts and other substituted and unsubstituted celluloses; starch; pregelatirrized starch; inorganic diluents like calcium carbonate and calcium diphosphate and other diluents known to the pharmaceutical industry. Yet other suitable diluents include waxes, sugars and sugar alcohols like marmitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Further excipients that are within the contemplation of the present invention include binders, such as acacia gum, pregelatrnized 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 VI, VII, VIII, IX, IXa, X, XI XII, XIV, XVI and XVII atorvastatin hemi-calciurn further include disintegrantsl like sodium starch glcolate, crospovidone, low-substituted hydroxypropyl cellulose and others. In addition, excipients may include tableting hibricants 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 (including subcutaneous, intramuscular, and intravenous), inhalant and 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 loscnges 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, of course, 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 phmalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of mcthacxyhc acid and methyl memacrylaie, and like materials, and if desired, they may be employed with suitable plastacizers 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 tins invention typically
contain from 0 3 to 100 mg of the novel atorvastatin hemi-calcium Forms VI, VII, VIII,
DC, IXa, X, XI, XII, XIV, XVI and XVII or mixtures thereof with each other or other forms
of aiorvastatin hemi-calcium. More usually, the combined weight of the atorvastatin hemi-
calcium forms of a unit dosage are from 23 mg. to 80 mg.
Having thus described the various aspects of the present invention, the following
examples are provided to illustrate specific embodiments of the present invention. They are
not intended to be limiting in any way.
EXAMPLES
General
Absolute ethanol contaning less than 0.2 % water was purchased from 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 d 250 ml stainless steal mining chamber and twenty seven 10 mm diameter stainless steal balls as milling media.
(Preparation of Atorvastatin Henri-Calcium Form VI)
Atorvastatin hemi-calcium Form 1 (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 ibr 5 brs to obtain atorvastatin hemi-calcium Form VI (0.88 g, 88%).
(Preparation of Atorvastatin Hemi-Calcium Form VII)

Example 2
Atoro»statm 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 Forxa VII (40 rag, 40%).


Example 3
Atorvastatin hcrai-calcium Form 1 (75 rog) was stirred in absolute EtOH (30 ml) at room temperature for 16 fa. The solid was collected by filtration and dried at 65 °C for 24 h to give atorvastatin hemi-caJcium Form VH (0,60 g, 80%).
(Preparation of Atorvastatin Hemi-Calcium Form VIII)
Example 4 To a flask equipped with a magnetic stirrer 1.0 g (1.59xl0-3 mole) of [R-(R*,R*)]-2-(4-fluorophenyl)-ß,δ-oxane-5-(1-methylethyl)-3-phyenyl-4-[(phenylamino)carbonyl]
lH-pyrrole-tert-butylheptanoic ester were put in suspension in a 90% aqueous solution of acetic acid (10 ml). The reaction mixture was heated to 50 °C for three hours and then stirred at room temperature until the reaction was complete as determined by HFLC. The solvent was evaporated and the traces of acetic acid were removed by azeotropic distillation with toluene (3x100 ml) to obtain an oil with some toluene This oil was dissolved in EtOH (10 ml) and water (2 ml). Then 5.5eq (8.4X10"3 mole, 622 mg) of Ca(OH)j and tetrabutyl ammonium bromide (5%, 0.05 g) were added The reaction mixture was heated at iO'C for 5 hours until the reaction was complete according to HPLC. Then a hot filtration was done under vacuum to remove the excess of Ca(OH)2- The reaction mixture was then cooled to room temperature. To this solution water (50 ml) was added while stirring. The
white precipitate was stirred at RT overnight, filtered under vacuum and dried at 65 °C for 18 hours to give 145 mg (16%) of atorvastatin hemi-calcruin salt Form VIII
Example 5 Atorvastatin hcrai-calchim Form I (1 g) was slurried in absolute EtOH (80 ral), under reflux, for 24 hrs. The white solid was thai filtered and dried at 65qC for 20 hrs to obtain atorvastatin hemi-calcrum Form VIII (0.85 g> 85%).


Example 6
Atorvastatin hcmi-calcitim Form 1(1 g) was poured in boiling absolute EtOH (40 ml). The compound began first to get soluble and then precipitate again. To this mixture was added MeOH (20 ml). The white solid was then filtered and dried at 50*C for 20 hrs in a vacuum oven to obtain atorvastatin bexm'-calcium Form VIII (188 mg, 19%).
Example 7
A suspension of 1.0g of Atorvastatin hemi-calcium salt Form V in l-butanol (4ml) and H20 (16ml) was heated to reflux temperature for 1 hr. The mixture was then cooled to room temperature and stirred at tins temperature for additional 16 hrs. The solid was filtered and dried at 50°C in a vacuum oven for 16 hrs to give 0.9g (91 %) of Atorvastatin hemi-calcium salt Form VIII
Examples 8 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 L5 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%) of Atorvastatin hemi-calcium salt Form VIII. Daring this process chemical purification occurs, HO this process is good also for purification.
Example 9. 5.0 g of Atorvastatin hemi calcium salt Form V, with a level of 0.12% of Des-iluoro Atorvastarm, Nvere added to a boiled solution of Ethanol 96% (150ml). The mixture was refluxcd 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 Eihanol 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 VTfl by this procedure.
Example 10 Atorvastatin herm-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 atorvastatrn hemi-calciurn Form VIII (4.7 g, 94%).
(Preparation of Atorvastatin Hemi-Calcium Form IX)
Example 11 Atorvastatin hemi-calcium Form I (1 g) was slurried m 1 -butanol (20 ml) under reflux for 30 minutes. The mixture was then cooled to room temperature, The white solid was then filtered and dried at 50°C under vacuum for 20 hrs to yield atorvastatin hemi-calcium Form rx (0.94 g, 94%). KF = 0.9.
Example 12 Atorvastatrn hemi-calcitun Form I (1 g) was slurried in l-butanol (20 ml) under reflux for 30 minute. Then n-hexanc (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 bis to yield atorvastatin Form fX (0.96 g, 96%)-

Example 13 Atorvastatin hemi-calcium Form I (1 g) was slurried in 1-butanol (20 ml) under Teflux 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.
Example 14 Atorvastatin herrn-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 atorvastatm hemi-calcitiin Form PC (630 mg, 79%).


Example 15
A mixture of atorvastatin hemi-calcium Form V (2.00 g) and 1-butanol (40 ml) was refluxed at 118 °C for half an hour. The mixture was then cooled to room temperature and stirred for an additional 3 hours. The solid was then collected by filtration and dried at 65 °C for 24 hours to give atorvastatin hemi-calcium Form IX (1 ,S3 g, 92%),
Example 16 Atorvastatia 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.
Example 17 Atorvastatin herm-calcium salt Form V (1 g) in 1-BuOH (10ml) and H20 (10ml) was heated to reflux for I h. The mixture was then cooled to room temperature and stirred at this temperature for additional 16 hrs. Filtration and drying at 65 PC for 24hrs gave 0.79g (79%) of Atorvastatm hemi-calcium salt form IX.
Example /ff Atorvastatin hemi-calcium salt Form V (1 g) in 1-JBuOH (l0ml) and EtOH (10ml) was heated to reflux for 1 h. The mature 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 salt Form V (5 g) was suspended in a mixture of 1-butanol (70ml) and water (30ml) at reflux temperature (87°C) for 17,5 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 0.95g (19%) of Atorvastatin hemi-calcium salt Form IX.
Example 20 Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1 -butanol (60ml) and water (40ml) at reflux temperature (905°C) for 15 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 2.1g (41%) of Atorvastatin hemi-calcium salt Form IX.
Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-butanol (50ml) and water (50ml) at reflux temperature (91°C) for 15 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65*C in a vacuum oven for 24 hours to give 2.9g (58%) of Atorvastatin heini-Calciurn salt Form DC.

Atorvastatin hemi-calcium salt Form V (3.9 g) was suspended in a mixture of 1 -butanol (20ml) and water (80ml) at reflux temperature (91 °C) for 1 6.5 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 3.4g (86%) of Atorvastatin hemisalcJum salt Form DC.
Example 23 Atorvastetia heni-cariuni salt Form V (5 g) was suspended in a mixture of 1 -butanol (50ml) and Acetone (50ml) at reflux temperature (71°C) for 17 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 4.6g (93%) of Atorvastatin hemi-calcium salt Form IX
Example 24 Atorvastatin hemj-calcium. salt Form V (5 g) was suspended in a mixture of 1-butanol (50ml) and IPA (50ml) at reflux temperature (91.5°C) for 15 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 4.7g (94%) of Atorvastatin hemi-calcium salt Form DC
Example 25
Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-butanol (50ml) and THF (50ml) at reflux temperature (806C) for 15 hours. The mixture was then cooled to room temperature and then to 0"C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 2.4g (4S%) of Atorvastatin hemi-calcium salt Form IX.
Atorvastaim hemi-calcium sait Form V (5 g) was suspended in a mixture of 1-butanol (50ml) and 1-propanol (50ml) at reflux temperature (95°C) for 16 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65"C in a vacuum oven for 24 hours to give 4.8g (96%) of Atorvastatin hemi-calcium salt Form K.
Example 27 Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1 -butanol (50ml) and MTBE (50ml) at reflux temperature (73°C) for 16 hours. The mixture was then cooled to room temperature and men to 0°C using an ice-bath. The product was isolated by filtration and dried at 65*C in a vacuum oven for 24 hours to give 4.8g (97%) of Atorvastatra hemi-calcium salt Form DC.
(Preparation of Atorvastatin Hemi-Calciium Form IXa) Example 28 Atorvastatin hemi-calcium saltForm V (5 g) was suspended in a mixture of 1-butanol (90ml) and water (10ml) at reflux temperature (85°C) for 16 hours. The mixture was then cooled to room temperature and then to 0*C using an ice-bath. The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give 4.73g (95%) of Atorvastatin hemi-calcium crystalline Form IXa.
Example 29 Atorvastatin hemi-calcium salt Form V (5 g) was suspended in a mixture of 1-butanol (10ml) and water (90ml) at reflux temperature for 16 hours. The mixture was then cooled to room temperature and then to 0°C using an ice-bath The product was isolated by filtration and dried at 65°C in a vacuum oven for 24 hours to give atorvastatin hemi-calcium crystalline Form IXa.

(Preparation of Atorvastatin Hemi-Calciun Form X)
Atorvastatin herai-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 soljd was collected by filtration and dned at 65° C for 24 h to give atorvastatin hemi-calciura Form X (8.26 & 83%)
Atorvastaira hemi-cakiurn Form V (1.00 g) in a mixture of EtOH (9 ml) and water (1.6 ml) was refhrxed for 1 h. The mixture was cooled to room temperature and then stirred an additional 3 h- The solid was collected by filtration and dned at 65 °C for 24 h to give atorvastatin heini-calcium Form X (0.80 g, $0%).
(Preparation of Atorvastatin Henri-Calcium Form XX)
l.0g of Atorvastatin herni-oalcitrm salt Form V was stirred m Methylethy] ketone ("MEK") (5ml) at room tempefature for 24 Jhrs. The solid was then filtered, washed with MEK (2ml) and dried at 65 °C for 20 hrs to give 0.5g (50%) of Atorvastatin herai-calcium salt Form XI.
Example 33 A suspension of l.0g of Atorvastatin hemi-calciiuii salt Form V in Iso-propyl alcohol ("TPA") (7 ml) was heated to reflux ternperature for 1 hr. The mixture was then cooled to room temperature and stirred at this temperature for additional 20 hrs A gelatinous product was obtained. After addition of 1PA (3ml) the gel was filtered and dried at 65 °C for 20 hrs to give 0.8g (80%) of Atorvastatin hemi-calcium salt Form XI
(Preparation of Atorvastatin Hemi-Cakium Form XII) Example 34

To a cylindrical reactor equipped with a distillation apparatus and a mechanical stirrer, 20g (30.6nnnole) of [R-(R* R*)]-2-(4-fluoropheiiyl)-ß δ-dioxane-5-(l -methylethayl)-3-phenyl-4-(phenylamino)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester
(^pyrrole acetonide ester =PAE) were put in suspension in 250 ml of absolute Ethanol and 50ml of aqueous 1,5% Hydrochloric acid. 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.r 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 fee hot filtrate (65" C), 350ml of water were added slowly (using a dosing pump) during 3/4-l hour at 65 °C. During the addition of water Atorvastatin hemi-calciurn 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 45.0g of wet cake of Atorvastatin hemi-calcium salt crystal form XIL
(Preparation of Atorvastatin Hemi-Calcinm Form XIV)
Example 35 Atorvastatin heani'-calcium Form V (1 g) was introduced into a 500 ml beaker. Water (240 ml) was added. The suspension was mixed for 5 hours. A fine suspension appeared. It was left standing undisturbed for three days. After three days white flakes formed in the suspension. The suspension was then filtered and analyzed by XRD as is. The resulting form is novel atorvastatin heroi-calcium Form XIV
(Preparation of Atorvastatin Hemi-CaJcium Form XVI)
Example 36
A small aliquot of form XIV was exposed to the air at room temperature for three hours, and then analyzed by XRD. The resulting form is Form XVI.
(Preparation of Atorvastatm Hemi-Calcium Form XVII)
Example 37 Wet Atoravstaiin hemi-calcium salt Form V (53 g) was added to a hot solution (about 70*C) of cthanol (about 485 ml). The resulting quantity of water in ethanol should be about 4%, The mixture was refluxed for about 2 hours. The mixture was cooled to 15-20 degrees. The solid was filtered, washed with ethanol 96% The material was then analysed by X-Ray powder diffraction and found to contain Form XVII. Conventional drying (40-70) degrees produced atorvastatin hemt-calciura Form VIII
Example 38 About 20 kg of Atorvastatin herni-calcdum Form V was added to a hot solution (about 70 eC) of ethanol (about 600 liters). The resulting quantity of water in cthanol should be about 4%, and it is adjusted according to the initial moisture level of Form V. The mixture was refluxed for about 2.5 hours. The mixture was cooled to 15-20°C and stirred at this temperature for at least 3 hours. The solid was filtered, washed with 96% ethanol. The material was then analyzed by powder X-Ray diffraction and found to contain form XVII. Conventional drying at 40-70°C produced atorvastatm hemi-calcium form VIII
(Preparation of Known Atorvastatin Henu-Caltium Form I)
Example 39 Atorvastatin bemi-calcium Form V (1.00 g) was stirred m water (400 ml) at room temperature for 16 h. The solid was collected by filtration and dried at 65°C for 24 hours to yield atorvastatin hemi-calcium Form I (0.7 g, 70%).
Example 40 A mixture of atorvastatin hemi-calcium Form VII (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 hexm-calcfum Form I (9.64 g, 96%).
Atorvastatin hemi-calcium Foam 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 42 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 henri-calcium Form I (720 mg, 72%).
Example 43 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 Form VII (1.00 g) was stirred in absolute BtOH (20 ml) at room temperature. The slurry was then placed into a sorricator for 1.5 mm (energy = 235 kJ? Amp. =50%) to obtain a clear solution. After addition of water (14 ml), a precipitate formed and the slurry was put in the sonicator for another 2 mm. (energy ~ 3.16 kJ, Amp. = 50%) which caused the slurry to gel The gel was dried at 65"C for 20 h to give atorvastatin hemi-calcium Form I (0.50 g, 50%),
Atorvastatin heari-calcium Form VII (1.00 g) was stirred in water (200 ml) at room temperature. The slurry was then placed into a sonicator for 2 min. (energy = 3.0 kJ, Amp, ==- 50%) which caused the slurry to gel. The gel was dned at 65 °C for 20 h to yield atorvastatin hemi-calcium Form I (032 g, 92%).
(Preparation of Known Atorvastatin Hemi-Calcium Form II)
Example 46 To a cylindrical reactor equipped with a distillation apparatus and a mechanical stirrer, 20g (3Q.6mmole) of [R-(R*,R*)]-2-(4-fluoorophenyl)-ß, δ-dioxane-5-(i-methylethyl)-3-phenyl-4-[(phenylarraro)carbonyl]-1H-pyrrole-1-tert-butylheptanoic ester
(- pyrrole acetonide ester - PAE) were put in suspension m 135ml of Methanol and 7.6ml of aqueous 10% Hydrochloric acid. The reaction mixture was heated to 35 °C for 3 hrs, while a continuous distillation of a mixture of Methanol, Acetone and water under reduced pressure (820mbar) was pcrfoimed. Make-up of Methanol was done every ½ hour (35ml). After 3 hrs the level of PAE reduced below 0.1% (according to HPLC). Without any further treatment, Cat(OH) (l-5eqv 3.4g), water (5ml) and Methanol (45ml) were added. The reaction mixture was heated to 70 °C for 2 hrs. Then the excess of Ca(OH)2 was collected by filtration and the Ca(OH)2 cake was washed with Methanol (2x10ml). To the filtrate, 300ml of water were added alowly (using a dosing pump) during % hour at 65"C. During the addition of water Atorvastatmhenn-crum salt precipitated. After the addition of water the reaction mixture was heated to reflux temperature (78 °C) for '½ hour. Then the mixture was cooled to 20PC during 3 hrs and was stirred at this temperature for additional 20 hrs. The solid was then filtered and dried at 65 °C for 48 hrs to give 16.9g (96%) Atorvastatin hemi-calcium salt crystal form U, KF-3.2%
(Preparation of Known Atorvastatin Hcmi-Calcium Form IV)
Example 47 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
rv
Example 48 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 atorvastatm hemi-calcium salt Form IV.
Example 49
Atorvastatin hemi-calcium salt form V (2.0 g) was stored 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.
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 (137 g, 56%).
Example 51 A mixture of atorvastatin hemi-calcium Form V (1.00 g) in methanol (10 ml) was stirred at room temperature for 20 hours. The solid .was collected by filtration and dried at 65 "C for 24 hours to give atorvastatin hemi-calcium Form IV (0.25 g, 25%).
(Preparation of Atorvastatin Hemi-Calcium Form V)
To a cylindrical reactor equipped with a distillation apparatus and a mechanical stirrer, 20g (30.6mmole) of -(R *R *)]-(4-fluorophenyl)-)ß, δ-dioxane-5-(l-
methylethyl)-3-phenyl-4-{(phenylamino) carboyl]-1H-pyrrole-1-tert-buyylheptanoic ester
(-pyrrole acetonide ester =PAE) were pat in suspension m 250 ml of absolute Brhanol and 50ml of aqueous 1.5% Hydrochloric acid. The reaction mixture was heated to 40°C for 9-11 hrs, while a continuous distillation of a mixture of Bthanol, Acetone and water, under reduced pressure (500-600mbar), was performed. Make-up of absolute Bthanol 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 (l.Seq, 3.4g) were added. The reaction mixture was heated to 70°C for 4-5 hrs. Then the excess of Ca(OH)j was collected by filtration. To the hot filrate (65°C), 350ml of water were added slowly (using a dosing pump) during %-l hour at 65 °C. During the addition of water 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 20 hrs. The solid was then filtered to give 45.0g of wet cake of Atorvastatin bend-calcium salt crystal form XII. This solid was dried at 65°C for 24hrs to give I6.7g (95%) Atorvastatin hemi-calcium salt crystal form V. KF-2.8%-6.6%.
(Process for Purifying Atorvastatin Hemi -calcium Form V)
Example 53 5.0g of Atorvastatin hemi-calcium salt Form V were added to a boiled aqueous solution of Ethanol 90% (150mJ). The mixture was refluxed for 2.5 hrs. Then it was cooled to 20aC during 1.5 hrs and stirred at this temperature for additional 16 hrs. The solid was then filtered, washed with Ethanol 90% (2x25rru) and dried at 65CC for 20 hrs to give 3.4g (68%) of Atorvastatin hemi-calcium salt Form V.
(Preparation of Known Amorphous Atorvastatin Hemi-caltinin)
Example 54 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 DC for 20 h to give amorphous atorvastatm hemi-calcium (1.85 g, 93%)
Atorvastatin hemi-calcium Form VII (1.00 g) was stirred in acetonitrile (20 ml) at room temperature. The shurry was then sonicated for 2 mm. (energy = 2.5 kJ Amp. =50%). After decantation the acetonitrile, the solid was dried at 65 °C for 20 h to give amorphous atorvastatm hemi-calcium (0.71 g, 71%).
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 =2.5 kj, Amp. =50%). After decanting the acetonitrile, the solid was dried at 65 °C for 20 h to give amorphous atorvastatin hemi-calcium (0.71 g, 71%).
Atorvastatin hemi-calcium (108 g) and twenty seven 10 mm diameter stainless steel milling balls were loaded into the mining 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 buildup every 15 min. finally, the material was separated from the balls by sieving with 300 fua screen. The resulting material was analyzed by PXRD and found to be amorphous. The process was repeated using atorvastatin Forms I, V and YEU and in each instance amorphous atorvastatm hemi-calcium was obtained.
Atorvastatin hemi-calcium Form V (5.0 g) was suspended in a mixture of 1 -butanol \ (30ml) and water (70ml) at reflux temperature (9l°C) for 12.5 hours. The mixture was then
cooled to room temperature and then to 0°C using an ice-bath. The product was isolated by filtration and dried at 65CC in a vacuum oven for 24 hours to give 2.5g (51 %) of amorphous Atorvastatm heroi-calciurn salt-Having thus described the invention with reference to particular preferred embodiments and illustrated it with examples, those in the art may appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as defined by the claims which follow.





WE CLAIM:
1. A process for preparing amorphous atorvastatin hemi-calcium salt
comprising:
a) suspending crystalline atorvastatin Form V in a mixture of 30% 1-butanol and 70% water at a temperature of about 91°C.
b) cooling the suspension of step a) to room temperature and then to 0°C; and
c) separating amorphous atorvastatin from the suspension of step b).

2. The process as claimed in claim 1 where the crystalline atorvastatin Form V of step a) is the hemi-calcium salt.
3. The process as claimed in claim 1 where the separating of step c) is carried out by Alteration.
4. The process as claimed in claim 3 where the product of filtration is dried in a vacuum.

Documents:

2071-delnp-2005-abstract.pdf

2071-delnp-2005-claims.pdf

2071-delnp-2005-complete specification (as,files).pdf

2071-delnp-2005-complete specification (granted).pdf

2071-delnp-2005-correspondence-others.pdf

2071-delnp-2005-correspondence-po.pdf

2071-delnp-2005-description (complete).pdf

2071-delnp-2005-drawings.pdf

2071-delnp-2005-form-1.pdf

2071-delnp-2005-form-13.pdf

2071-delnp-2005-form-18.pdf

2071-delnp-2005-form-2.pdf

2071-delnp-2005-form-3.pdf

2071-delnp-2005-form-5.pdf

2071-delnp-2005-gpa.pdf

2071-delnp-2005-pct-101.pdf

2071-delnp-2005-pct-210.pdf

2071-delnp-2005-pct-220.pdf

2071-delnp-2005-pct-304.pdf

2071-delnp-2005-pct-308.pdf

2071-delnp-2005-pct-408.pdf

2071-delnp-2005-pct-409.pdf

2071-delnp-2005-pct-416.pdf

2071-delnp-2005-petition-137.pdf

2071-delnp-2005-petition-138.pdf


Patent Number 245528
Indian Patent Application Number 2071/DELNP/2005
PG Journal Number 04/2011
Publication Date 28-Jan-2011
Grant Date 24-Jan-2011
Date of Filing 16-May-2005
Name of Patentee TEVA PHARMACEUTICAL INDUSTRIES LTD.,
Applicant Address 5BASEL STREET,P.O.BOX 3190,PETAH TIQVA 49131,ISRAEL
Inventors:
# Inventor's Name Inventor's Address
1 LIMOR TESSLER 61/11 PETACH-TIKVA STR.,NATANYA 42380,ISRAEL
2 JUDITH ARONHIME REHOV HARAV MAOR,LOSEF 5A,REHOVOT 76217,ISRAEL
3 REVITAL LIFSHITZ-LIRON, 12A KIBBUSH H'AAVODA ST. APT. #8,HERZLIA 46322,ISRAEL,
4 DALIA MAIDAN-HANOCH 50 SIGALON STR.,P.O.BOX 2556,KFAR YONA,ISRAEL
5 NIR HASSON GRAR 13, P.O.BOX 311,MEITAR 85025,ESRAEL
PCT International Classification Number C07D 207/34
PCT International Application Number PCT/US2003/036428
PCT International Filing date 2003-11-12
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/425,325 2002-11-12 U.S.A.
2 10/370,897 2003-02-19 U.S.A.