Sign In to Follow Application
View All Documents & Correspondence

"Novel Crystal Forms Atorvastatin Hemi Calcium And Processes For Their Preparation As Well As Novel Processes For Preparing Other Forms"

Abstract: The present invention relates to atorvastatin hemi-calcium Form VI and solvates thereof having a powder X-ray diffraction pattern substantially as depicted in figure 1.

Get Free WhatsApp Updates!
Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
19 September 2007
Publication Number
41/2007
Publication Type
INA
Invention Field
PHARMACEUTICALS
Status
Email
Parent Application

Applicants

TEVA PHARMACEUTICALS INDUSTRIES LTD.
5 BASEL STREET P.O.BOX 3190, PETAH TIQVA 49131 ISRAEL.

Inventors

1. JUDITH ARONHIME
REHOV HARAV MAOR IOSEF 5A, 76217 REHOVOT, ISRAEL.
2. RAMI LIDOR-HADAS
19 MOR STREET 44242 KFAR-SABA ISRAEL.
3. VALERIE NIDDAM-HILDESHEIM
9 KEREN HAYESSOD, PO 1343 EVEN-YEOUDA 40500 ISRAEL.
4. REVITAL LIFSHITZ-LIRON
12A KIBBUSH HA'AVODA STREET APT.#8,HERZLIA 46322 ISRAEL
5. ETI KOVALESVSKI-ISHAI
SOKOLOV STREET, NO.68 NETANYA 4225 ISRAEL
6. GUY SAMBURSKI
HAIRUSIM 19 GANOT-HADAR 42930 ISRAEL.

Specification

NOVEL CRYSTAL FORMS OF ATORVASTATIN HEMI-CALCIUM AND PROCESSES FOR THEIR PREPARATION AS WELL AS NOVEL PROCESSES FOR PREPARING OTHER FORMS CROSS-REFERENCE TO RELATED APPLICATIONS This application 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 and 60/326,529, filed October 1, 2001, all of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention relates to crystalline polymorphic forms of atorvastatin hemi-calcium, novel processes for preparing crystalline forms of atorvastatin hemi-calcium and crystalline atorvastatin hemi-calcium with a small particle size distribution BACKGROUND OF THE INVENTION Atorvastatin, ([R-(R*,R*)]-2-(4-fluorophenyl)-p,8-dihydroxy-5-(l -methy!ethyl)-3-phenyl^[(phenylamino)carbonyI]-lH-pyrrole-l-heptanoic acid), depicted in lactone form in formula (I) and its calcium salt trihydrate of formula (II) are well known in the art, and described, inter alia, in U.S. Patents Nos. 4,681,893,5,273,995, and in copending USSN 60/166,153, filed November 17,2000, all of which are herein incorporated by reference. (Figure Removed) 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 Oilman, The Pharmacological Basis of Therapeutics 879 (9th ed. 1996). Reducing plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and patients who are free of cardiovascular disease but who have hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b. 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-methyl-glutaryl-coenzyme A reductase enzyme ("HMG-CoA reductase")- HMG-CoA reductase catalyzes the conversion HMG to mevalonate, which is the rate determining step hi the biosynthesis of cholesterol, and so, its inhibition leads to a reduction hi 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 fatty acids which may be stored hi adopcytes or oxidized by muscle. The VLDL is converted to intermediate density lipoprotein (IDL), which is either removed by an LDL receptor, or is converted to LDL. Decreased production of cholesterol leads to an increase hi 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 UPITOR by Warner-Lambert Co. Atorvastatin was first disclosed to the public and claimed in U.S. Patent No. 4,681,893. The hemi-calcium salt depicted in formula (IT) is disclosed hi 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 recrystallization from a 5:3 mixture of ethyl acetate and hexane. The present invention provides new crystal forms of atorvastatin hemi-calcium hi both solvated and hydrated states. The occurrence of different crystal forms (polymorphism) is a property of some molecules and molecular complexes. A single molecule, like the atorvastatin in formula (I) or the salt complex of formula (II), may give rise to a variety of solids having distinct physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and NMR spectrum. The differences in the physical properties of polymorphs result from the orientation and intermolecular interactions of adjacent molecules (complexes) in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous and/or disadvantageous physical properties compared to other forms in the polymorph family. One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. On the other hand, where the effectiveness of a drug correlates with peak bloodstream levels of the drug, a property shared by statin drugs, 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 L n, HI and IV of atorvastatin hemi-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 PCT Application No. PCT/USOO/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. Although Form I remedies some of the deficiencies of the amorphous material in terms of manufacturability, there remains a need for yet further improvement in these properties as well as improvements in other properties such as flowability, 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 DESCRIPTION OF TTTF. FIGURES Fig. 1 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi-calcium Form VI obtained using a conventional X-ray generator with a copper anode. Fig. 2 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi-calcium Form VH 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 \TQ obtained using a conventional X-ray generator with a copper anode. Fig. 4 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi-calcium Form Yin obtained using a synchrotron X-ray source. Fig. 5 is a characteristic solid state 13C NMR spectrum of atorvastatin Form VHL 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 DC obtained using a synchrotron X-ray source. Fig. 8 is a characteristic solid state 13C NMR spectrum of atorvastatin Form DC Fig. 9 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi-calcium Form X obtained using a conventional X-ray generator with a copper anode. Fig. 10 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi-calcium Form X obtained using a synchrotron X-ray source. Fig. 11 is a characteristic solid state 13C NMR. spectrum of atorvastatin hemi-calcium Form X. Fig. 12 is a characteristic powder X-ray diffraction pattern of atorvastatin hemi-calcium Form XI obtained using a conventional X-ray generator with a copper anode. Fig. 13 is an overlay of typical powder X-ray diffraction patterns of atorvastatin hemi-calcium Form XH obtained using a conventional X-ray generator with a copper anode. 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 denominated Form VI and novel processes for its preparation. In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form VTH and novel processes for its preparation. In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form IX and novel processes for its preparation. In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated Form X and novel processes for its preparation. In another aspect, the present invention provides a novel crystalline form of atorvastatin hemi-calcium denominated 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 novel processes for preparing atorvastatin hemi-calcium Form I. In another aspect, the present invention provides novel processes for preparing atorvastatin hemi-calcium Form H In another aspect, the present invention provides novel processes for preparing atorvastatin hemi-calcium 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 hemi-calcium Forms VI, VII, VHI, IX, X, XI and their mixtures. DF.TATT.ED 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 thermogravimetric analysis. Powder X-ray diffraction ('TXRD") analysis employing conventional CuK, radiation was performed by methods known in the art using a SCINTAG powder X-ray diffractometer model X'TRA equipped with a solid-state detector. Copper radiation of X = 1.5418 A was used. Measurement range: 2-40 degrees 20. The sample was introduced , using a round standard aluminum 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 1.15 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 13C NMR measurements were made at 125.76 MHz and were performed on a Bruker DMX-500 digital FT NMR spectrometer equipped with a BL-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 hemi-calcium Form VI is characterized by a powder X-ray diffraction pattern (Fig. 1) with peaks at 3.5, 5.1, 7.7, 8.2, 8.7,10.0,12.5,13.8,16.2,17.2,17.9 18.3, 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 instrumentation described above. Atorvastatin hemi-calcium Form VI may be obtained by dissolving any other form of atorvastatin hemi-calcium, preferably Form I, in acetone and then precipitating Form VI by addition of an anti-solvent, preferably water. Atorvastatin hemi-calcium Form Vn 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 29, and other additional broad peaks at 4.7,7.8, 9.3,12.0,17.1,18.2±0.2 degrees 20. Samples of Form VII may contain up to 12% water. Form VII is readily distinguished from known forms of atorvastatin hemi-calcium by the broad peaks at 7.8 and 9.3±0.2 degrees 20. For instance, Form I has peaks at 9.2, 9.5,10.3,10.6,11.0 and 12.2 degrees 20 according to the information provided in U.S. Patent No. 5,969,156. In this region, Form n has two sharp peaks at 8.5 and 9.0 degrees 29 and Form IV has one strong peak at 8.0 degrees 20. The other broad peaks in the region of 15-25 degrees 26 distinguish Form VII from all other forms. Forms I, in and IV all have sharp peaks in this region. Atorvastatin hemi-calcium Form Vn 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 hemi-calcium Form VIE is characterized by a powder X-ray diffraction pattern (Fig. 3) obtained using conventional CuK,, radiation having peaks at 4.8,5:2,5.9,7.0, 8.0, 9.3, 9.6,10.4,11.9,16.3,17.1(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± 0.2 degrees two-theta. The most characteristic peaks are at 6.9,9.3,9.6,16.3,17.1,19.2, 20.0,21.6,22.4,23,9,24.7,25.6, and 26.5±0.2 degrees 29. Samples of atorvastatin hemi-calcium Form VHI were found to contain up to 7% water by Karl Fisher. Form VHI is readily distinguished from Forms I-IV by its characteristic sharp peaks at 9.3 and 9.6 degrees 29. According to the information provided in U.S. Patent No. 5,969,156, Form I has one medium peak at 6.9 and sharp peaks at 9.2, 9.5,10.3,10.6,11.0 and 12.2±0.2 degrees 29. Form IV is said to have two peaks at 8.0 and 9.7 degrees 29. Form E is said to have in this region two sharp peaks at 8.5 and 9.0 degrees 20. Form HI 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 VHIPXRD pattern. Further, there is in the PXRD pattern of Form VHI 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 Vm with the patterns of Forms I-IV reveals that this feature of the Form VET pattern is distinctive. Other peaks in the Form VIE pattern that are unique to this form are the two strong and sharp peaks at 19.2 and 20.0 degrees 29. In this region, Form I has sharp peaks at 21.6,22.7, 23.3 and 23.7 degrees 29 according to the information provided in the '156 patent. Form IV is said to have peaks at 18.4 and 19.6 degrees 26, while Form n has two main peaks at 17.0 and 20.5 and Form HI has peaks at 17.7,18.2,18.9,20.0 and 20.3±0.2 degrees 20. Synchrotron X-ray powder diffraction analysis was performed on Form VHI to determine its crystal system and unit cell dimensions. Form VIII has a monoclinic unit cell with lattice dimensions: a = 18.55-18.7 A, b = 5.52-5.53 A, c = 31.0-31.2 A and angle P between the a and c axes of 97.5-99.5 °. The unit cell parameters were determined using the Le Bail method. The dim-actogram of Fig. 4 obtained using a synchrotron X-ray source has many sharp well resolved peaks. The rf-spacings of some of the more prominent peaks are listed in Table 1, along with the positions hi units of two-theta that the peaks would have using CuK,, radiation of 1.5418A. Table 1 (Table 1 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 may be larger shifts if the material undergoes size reduction as micronization. Atorvastatin hemi-calcium Form VIII produced the solid-state "C NMR spectrum shown in Fig. 5. Form VHI is characterized by the following solid-state "C nuclear magnetic resonance chemical shifts in ppm: 17.8, 20.0,24.8,25.2,26.1,40.3, 40.8,41.5, 43.4, 44.1, 46.1, 70.8, 73.3,114.1,116.0, 119.5,120.1, 121.8, 122.8,126.6,128.8, 129.2, 134.2 ,135.1,137.0,138.3, 139.8,159.8, 166.4,178.8,186.5. Form Vm is characterized by a solid-state I3C nuclear magnetic resonance having the following chemical shifts differences between the lowest ppm resonance and other resonances: 2.2,7.0, 7.4, 8.3, 22.5,23.0,23.7,25.6,26.3, 28.3, 53.0,55.5,96.3, 98.2,101.7,102.3, 104.0,105.0, 108.8,111.0, 111.4, 116.4,117.3,119.2,120.5,122.0,142.0, 148.6,161.0 and 168.7. The chemical shifts reported for Form VIH are averaged from spectra taken of four samples of Form VEH. 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 carbonyl peak at 178.8 ppm which has a fluctuation of ±0.4 ppm. Atorvastatin hemi-calcium Form VHI can exist as an ethanol solvate containing up to about 3 % ethanol by weight. The following methods have been found suitable for generating Form VIII. This form may, however, also be accessible by empirical development and by routine modification of these procedures. Atorvastatin hemi-calcium Form VHI may be obtained by slurrying atorvastatin hemi-calcium in a mixture of ethanol and water at elevated temperature, preferably about 78-80°C. The slurrying procedure may be incorporated into the last step of a process for preparing atorvastatin hemi-calcium, which typically is generation of the hemi-calcium salt from the atorvastatin free acid or lactone by treatment with a source of calcium ion. In such a combined procedure the salt is generated in a solvent system comprising ethanol and water. Conveniently, after precipitation of the atorvastatin hemi-calcium 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 VIH. Form Vm also may be obtained starting from Form V by treating Form V with a mixture of EtOH:H2O, preferably in the ratio of about 5:1 at an elevated temperature below reflux, preferably 78-80 °C. An especially preferred EtOH:H2O mixture contains about 4 % by volume water in ethanol. During the heating, atorvastatin Form V gradually dissolves and at the point of 78-80°C turbidity, with or without seeding, is observed. At this point the suspension is immediately cooled to room temperature. Form Vin may be obtained by treating atorvastatin hemi-calcium in EtOH, preferably absolute EtOH, at elevated temperature, preferably boiling EtOH. Under these conditions, the atorvastatin dissolves and reprecipitates. MeOH may be added at reflux. • Added MeOH may adversely affect the yield, but may improve the chemical purity of the product. Starting materials for preparing Form Vm 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 80 ml g'1. We have discovered that atorvastatin hemi-calcium that contains greater than 0.1% des-fmoro atorvastatin hemi-calcium and/or greater than 1% trans atorvastatin hemi-calcium may be purified by suspending in a solution of about 96% ethanol and about 4% water at elevated temperature, preferably at reflux temperature. 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 atorvastatin hemi-calcium. Form VEH also may be prepared by suspending atorvastatin hemi-calcium in certain 1-butanol/water and ethanol/water mixtures for a period of time sufficient to cause the conversion of the atorvastatin hemi-calcium to Form VIE. 1-ButanolAvater mixtures should contain about 20% 1-butanol by volume at elevated temperature, preferably at reflux temperature. Atorvastatin hemi-calcium Form IX is characterized by a powder X-ray diffraction pattern (Fig. 5) 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, 19.9,21.4,22.5 and 23.5±0.2 degrees two-theta. Form IX may contain up to 7% water. Form DC also can exist as a butanol solvate containing up to about 5 % butanol. Form DC is readily distinguished by its characteristic sharp peaks at 18.6,19.1, 19.9, 21.4,22.5,23.5 degrees 26. For comparison, Form I has sharp peaks at 21.6,22.7, 23.3 and 23.7 degrees 29, while Form IV has in this region sharp peaks at 18.4 and 19.6 degrees 29 and Form n has two mam peaks at 17.0 and 20.5 degrees 20, according to information in the "156 patent. Form HI has in this region peaks at 17.7,18.3,18.9,20.0 and 20.3 degrees 20. Also, there is in the PXKD pattern of Form IX, as there is in the pattern of Form VEI, a sharp, well distinguished medium intensity peak at 7.0 degrees 29. The crystal system and unit cell dimension of Form DC were determined using synchrotron X-ray powder diffraction analysis. Form DC 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 P between the a and c axes of 96.5-97.5°. The cf-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 2 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 may be larger shifts if the material undergoes size reduction as micronization. Atorvastatin hemi-calcium Form IX produced the solid-state I3C NMR spectrum shown in Fig. 8. Form IX is characterized by the following solid-state 13C nuclear resonance chemical shifts in ppm: 18.0,20.4,24.9,26.1,40.4,46.4, 71.0,73.4,114.3, 116.0,119.5,120.2, 121.7,122.8,126.7,128.6,129.4,134.3,135.1,136.8,138.3,139.4, 159.9,166.3,178.4,186.6. Form DC is characterized by a solid-state "C nuclear resonance having the following chemical shifts differences between the lowest ppm resonance and other resonances: 2.4, 6.9, 8.1,22.4,28.4, 53.0, 55.4, 96.3, 98.0, 101.5, 102.2, 103.7,104.8,108.7,110.6,111.4,116.3,117.1,118.8,120.3,121.4,141.9, 148.3, 160.4, 168.6. Characteristic parts of the pattern are found at 24-26 ppm (aliphatic range), 119-140 ppm (aromatic range) and other regions. The chemical shifts of Form IX are an average taken from spectra on two samples of Form IX. The shift values are accurate to within ±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-calcium Form IX may be prepared by slurrying atorvastatin hemi-calcium in butanol and isolating Form DC by, for example, filtration or decantation of the butanol, preferably by filtration. Preferred temperature ranges for the slurrying are from 78°C to the reflux temperature of the solvent. Recovery of atorvastatin hemi-calcium salt from the slurry can be enhanced by addition of an anti-solvent to the slurry before isolating Form DC. Preferred anti-solvents include isopropanol and «-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 VIE in ethanol, preferably absolute ethanol, at room temperature for a period of time sufficient to convert form VHI 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 VIE under a humid atmosphere. Form DC also may be prepared by suspending atorvastatin hemi-calcium Form V in mixtures of 1-butanol and either ethanol or water at reflux temperature for a period of time sufficient to convert Form V into Form DC and recovering Form DC from the suspension. Preferably the mixtures contain about 50 volume percent of each component. Atorvastatin hemi-calcium Form X is characterized by a powder X-ray diffraction pattern (Fig. 7) having peaks at 4.8,5.3, 5.9,9.6,10.3,11.5,12.0, a double peak at 16.1 and 16.3,16.9,17.4,18.2,19.2,19.4,20.0,20.8,21.6,22.0,22.8,23.6,24.6,25.0,25.5, 26.2,26.8,27.4,28.0,30.3±0.2 degrees 20. The most characteristic peaks are two peaks at 20.0 and 20.8±0.2 degrees 26 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. 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 20. These features are 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 monoclinic 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 0 between the a and c axes of 95.7-96.7°. The rf-spacings of some of the more prominent peaks in the synchrotron X-ray powder diffractogram of Fig. 10 are listed in Table 3, along with the positions in units of two-theta that the peaks would have using CuK,, radiation. Table3 (Table 3 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 as micronization. Atorvastatin hemi-calcium Form X produced the solid-state 13C NMR spectrum shown in Fig. 11. Form X is characterized by the following solid-state 13C nuclear resonance chemical shifts in ppm: 17.7,18.7,19.6,20.6,24.9,43.4, 63.1, 66.2, 67.5, 71.1,115.9,119.5,122.4,126.7,128.9,134.5,138.0,159.4,166.2,179.3, 181.1,184.3, 186.1. Form X is characterized by a solid-state I3C nuclear magnetic resonance having the following chemical shifts differences between the lowest ppm resonance and other resonances: 1.0,1.9, 2.9,7.2,25.7,45.4,48.5, 49.8, 53.4, 98.2,101.8,104.7,109.0, 111.2,116.8, 120.3,141.7,148.5,161.6,163.4,166.6,168.4. Characteristic parts of the pattern are found at 24-26 ppm (aliphatic range), 119-140 ppm (aromatic range) and other regions. The chemical shifts of Form X are averaged from three spectra taken of three samples of Form X. The values reported are within ±0.1 ppm, except for the carbonyl . peak at 179. 3 ppm that is accurate within ±0.4 ppm. Atorvastatin hemi-calcium Form X may be prepared by treating crystalline atorvastatin hemi-calcium, preferably Form 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 EtOH:water mixture at room temperature, followed by gradual heating of the suspension to reflux. Alternatively, the starting form of atorvastatin hemi-calcium may be added to the refluxing solvent mixture. In either case, the atorvastatin hemi-calcium should be observed to dissolve in the mixture and then reprecipitate in Form X. The ratio of atorvastatin hemi-calcium to the EtOH:water mixture preferably ranges from about 1:16 to about 1:25 (g:ml), more preferably from about 1:16 to about 1:21 (g:ml) and most preferably about 1:16 (g:ml). Form X may be collected by filtration shortly after cooling to room temperature or the suspension may be stirred for an addition period of from about 1 to about 20 hours, more preferably from about 3 to about 16 hours, before collecting the Form X. Atorvastatin hemi-calcium Form XI is characterized by a powder X-ray diffraction pattern (Fig. 9) having peaks at 32,3.7, 5.1,6.3,7.8, 8.6,9.8,11.2,11.8,12.4,15.4, 18.7,19.9,20.5,24.0 ±0.2 degrees two-theta. Form XI may be obtained by suspending atorvastatin hemi-calcium Form 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 isopropyl alcohol with atorvastatin hemi-calcium at reflux temperature and then cooling to room temperature. Extensive stirring at room temperature, as long as or more than 20 h, may be required in order for the gel to form. In the gel state, the solution is detectably more resistant to stirring and does not pour smoothly. The gel remains flowable in the sense that it can be stirred if sufficient force is applied and would not tear under such force. Atorvastatin hemi-calcium Form Xlt is characterized by a powder X-ray diffraction pattern having peaks at 2.7, 8.0, 8.4,11.8,18.2, 19.0,19.8,20.7 ±0,2 degrees two-theta, and a halo that indicates the presence of amorphous material. Typical X-ray powder diffraction patterns of atorvastatin hemi-calcium Form XH are shown in Fig. 10. Form XII may be prepared directly from the following compound (Figure Removed) whose systematic chemical name is [R-(R*,R*)]-2-(4-fluorophenyl)-p, 6-dioxane-5-(l-memylemyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-p, 5-dioxane-5-(l- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-/ert- butylheptanoic ester by adding hydrochloric acid to the suspension, thereby forming a solution of atorvastatin ester derivatives in methanol, c) adding calcium hydroxide to the solution, thereby forming a solution of atorvastatin hemi-calcium in methanol, d) optionally removing any excess calcium hydroxide, and e) precipitating atorvastatin hemi-calcium from the solution as Form H 119. A process for preparing amorphous hemi-calcium comprising the steps of: a) suspending a crystalline form of atorvastatin hemi-calcium in acetonitrile, b) sonicating the suspension for a period of time sufficient to convert the crystalline form to amorphous atorvastatin hemi-calcium, and c) recovering amorphous atorvastatin hemi-calcium from the suspension. 120. The process of claim 119 wherein the crystalline form of atorvastatin hemi- calcium is Form VEL 121. The process of claim 119 wherein the crystalline form of atorvastatin hemi- calcium is Form I. 122. The process of claim 119 wherein the suspension is sonicated for a period of from about 1 to about 3 minutes. 123. The process of claim 119 wherein the suspension is sonicated at room temperature. 124. A process for preparing atorvastatin hemi-calcium Form IV comprising the steps of: a) suspending atorvastatin hemi-calcium Form I in 1-butanol for a period of time sufficient to convert Form I into Form IV and b) recovering Form IV from the suspension. 125. The process of claim 124 wherein the suspension is maintained at room temperature for the period time in which Form I is converted into Form IV. 126. The process of claim 124 wherein the time sufficient to convert Form I into Form IV is about 24 h. 127. A process for preparing atorvastatin hemi-calcium Form IV comprising the steps of: a) suspending atorvastatin hemi-calcium Form V in a mixture of ethanol and water for a period of time sufficient to convert Form V into Form IV and b) recovering Form IV from the suspension. 128. The process of claim 127 wherein the temperature of the suspension is elevated to about 50 °C before recovering Form IV from the suspension. 129. The process of claim 127 wherein the period of time sufficient to convert Form V into Form IV is about one hour. 130. The process of claim 127 wherein the mixture contains about 15% water. 131. A process of preparing atorvastatin hemi-calcium Form IV comprising the steps of: a) suspending atorvastatin hemi-calcium Form V in methanol for a period of time sufficient to convert Form V into Form IV, and b) recovering Form IV from the suspension. 132. The process of claim 131 wherein the suspension is maintained at a temperature of from about room temperature to the reflux temperature of methanol for the period of time in which Form Vis converted into Form TV. 133. The process of claim 131 wherein the period of time sufficient to convert the other form into Form IV is from about 1 hour to about 20 hours. 134. A process for preparing atorvastatin hemi-calcium Form V comprising the steps of: a) suspending |TR.-(R*,R*)]-2-(4-fluorophenyl)-p, 8-dioxane-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-rert-butylheptanoic acid ester in ethanol, b) deprotecting the [R-(R*JR*)]-2-(4-fluorophenyl)-p, 8-dioxane-5-(l- methylethyl)-3-phenyl-4-[{phenylamiiio)carbonyl]-lH-pyrrole-l-ter/- butylheptanoic ester by adding hydrochloric acid to the suspension, thereby forming a solution of atorvastatin lactone and [R-(R*^.*)]-2-(4- fluorophenyl)-p,5-dihydroxy-5-(l-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-lH-pyrrole-l-;ert-butylheptanoic acid ester in ethanol, c) adding calcium hydroxide to the solution, thereby forming a solution of atorvastatin hemi-calcium in ethanol, d) precipitating atorvastatin hemi-calcium from the solution, and e) drying the precipitated atorvastatin hemi-calcium to obtain atorvastatin hemi-calcium as Form V. 135. A process for purifying atorvastatin hemi-calcium Form V comprising suspending the atorvastatin hemi-calcium Form V in a mixture of ethanol and water and recovering Form V from the mixture in greater purity. 136. The process of claim 135 wherein the mixture comprises from about 10 % water and about 90% ethanol by volume. 137. A process for preparing amorphous atorvastatin hemi-calcium comprising the steps of: a) contacting any crystalline form of atorvastatin hemi-calcium with acetone for a period of time sufficient to convert the crystalline form into amorphous atorvastatin hemi-calcium and b) separating solid amorphous atorvastatin hemi-calcium from the acetone. 138. The process for preparing amorphous atorvastatin hemi-calcium of claim 137 wherein the crystalline form of atorvastatin hemi-calcium dissolves in the ' acetone to yield a substantially clear solution and further wherein solid amorphous atorvastatin hemi-calcium is precipitated from the substantially clear solution. 139. A process of claim 137 wherein the crystalline form of atorvastatin hemi- calcium is Form V. 140. The process of claim 137 wherein the crystalline form of atorvastatin hemi- calcium and acetone are contacted at room temperature. 141. The process of claim 137 wherein the period of time sufficient to convert the crystalline form into amorphous atorvastatin hemi-calcium is about 16 hours. 142. A process for preparing amorphous atorvastatin hemi-calcium by ball milling any crystalline form of atorvastatin hemi-calcium. 143. The process of claim 142 wherein the crystalline form of atorvastatin hemi- calcium is selected from the group consisting of Form I, Form V and Form vm. 144. A pharmaceutical composition comprising atorvastatin hemi-calcium Form VI, Vm, DC X, XI, Xn or a mixture thereof. 145. Use of atorvastatin Form VI, VIE, DC, X, XT, XH or mixtures thereof, to prepare a pharmaceutical dosage form. 146. A pharmaceutical dosage form comprising atorvastatin hemi-calcium Form VI, VIE, DC X, XI, XH or mixtures thereof.

Documents

Application Documents

# Name Date
1 7239-DELNP-2007_EXAMREPORT.pdf 2016-06-30
1 abstract.jpg 2011-08-21
2 7239-delnp-2007-pct-304.pdf 2011-08-21
2 7239-delnp-2007-abstract.pdf 2011-08-21
3 7239-delnp-2007-form-5.pdf 2011-08-21
3 7239-delnp-2007-claims.pdf 2011-08-21
4 7239-delnp-2007-form-3.pdf 2011-08-21
4 7239-delnp-2007-correspondence-others.pdf 2011-08-21
5 7239-delnp-2007-description (complete).pdf 2011-08-21
5 7239-delnp-2007-form-2.pdf 2011-08-21
6 7239-delnp-2007-drawings.pdf 2011-08-21
6 7239-delnp-2007-form-1.pdf 2011-08-21
7 7239-delnp-2007-drawings.pdf 2011-08-21
7 7239-delnp-2007-form-1.pdf 2011-08-21
8 7239-delnp-2007-description (complete).pdf 2011-08-21
8 7239-delnp-2007-form-2.pdf 2011-08-21
9 7239-delnp-2007-correspondence-others.pdf 2011-08-21
9 7239-delnp-2007-form-3.pdf 2011-08-21
10 7239-delnp-2007-form-5.pdf 2011-08-21
10 7239-delnp-2007-claims.pdf 2011-08-21
11 7239-delnp-2007-pct-304.pdf 2011-08-21
11 7239-delnp-2007-abstract.pdf 2011-08-21
12 abstract.jpg 2011-08-21
12 7239-DELNP-2007_EXAMREPORT.pdf 2016-06-30