MXPA06011892A - Salt forms of [r-(r*, r*)]-2-(4-flourophenyl) -beta, delta-dihydroxy-5 -(1-methylethyl)-3 -phenyl-4- [(phenylamino) carbonyl]-1h- pyrrole-1-heptanoic acid - Google Patents

Abstract

Novel salt forms of [R-(R*, R*)]-2-(4-fluorophenyl) -ss, S-dihydroxy-5- (1-methylethyl) -3-phenyl- 4[(phenylamino) carbonyl]-1H -pyrrole-1 -heptanoic acid characterized by their X-ray powder diffraction pattern and solid-state NMR spectra are described, as well as methods for the preparation and pharmaceutical composition of the same, which are useful as agents for treating hyperlipidemia, hypercholesterolemia, osteoporosis, benign prostatic hyperplasia, and Alzheimer's Disease.

Description

FORM OF SALT OF THE ACID rR- (R * .R *) 1-2- (4-FLUOROFENlU-ß.d- DlHIDROXl-5- (1-MET> LETlL) -3-FENIL-4-r (FENILA INO ) CARBONlL1-1H- PIRROL-1 -HEPTANOICO FIELD OF THE INVENTION The present invention relates to new salt forms of atorvastatin which is known by the chemical name of acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d- dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrol-1-heptanoic, useful as pharmaceutical agents, to methods for their production and isolation, to pharmaceutical compositions including these compounds and a pharmaceutically acceptable carrier, as well as methods for using said compositions to treat subjects, including human subjects, suffering from hyperlipidemia, hypercholesterolemia, benign prosthetic hyperplasia, osteoporosis, and Alzheimer's Disease.

BACKGROUND OF THE INVENTION The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) into mevalonate is an early and limiting step of the cholesterol biosynthetic pathway. This stage is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase to catalyze this conversion.

As such, statins are, collectively, potent lipid lowering agents. Caloric atorvastatin is currently sold as Lipitor® under the chemical name trichhydrate of the [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1) calcium salt. -methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrol-1-heptanoic (2: 1) and has the formula: The unpatented name designated by USAN (United States Adopted Yams) is atorvastatin calcica and by INN (International Nonproprietary Yam) is atorvastatin. According to USAN's established guidelines, salt is included in the name while according to the guidelines of INN, a description of the salt is not included in the name. Calcium atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. As such, atorvastatin calcium is a compound that decreases lipids in a potent way and, therefore, is useful as a hypolipidemic and / or hypocholesterolemic agent, as well as in the treatment of osteoporosis, benign prostatic hyperplasia and disease. of Alzheimer's Numerous patents have been issued describing atorvastatin calcium, formulations of atorvastatin calcium, as well as processes and key intermediates for the preparation of atorvastatin calcica. These include U.S. Patent Nos. 4,681,893; 5,273,995; 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952; 5,298,627; . 446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,686,104; 5,998,633; 6,087,511; 6,126,971; 6,433,213; and 6,476,235, which are incorporated herein by reference. Calcium atorvastatin may exist in crystalline, crystalline, noncrystalline and amorphous form. Crystalline forms of the calcium atorvastatin are described in U.S. Patent Nos. 5,969,156, 6,121,461 and 6,605,729 which are incorporated herein by reference. In addition, several published International Patent Applications have described crystalline forms of atorvastatin calcium, as well as processes to prepare amorphous calcitic atorvastatin. These include: WO 00/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO 02/41834; WO 02/43667; WO 02/43732; WO 02/051804; WO 02/057228; WO 02/057229; WO 02/057274; WO 02/059087; WO 02/072073; WO 02/083637; WO 02/083638; and WO 02/089788. Atorvastatin is prepared as its calcium salt, ie, [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methylethyl) -calcic acid salt - 3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid (2: 1). The calcium salt is desirable since it allows to formulate the atorvastatin conveniently in, for example, tablets, capsules, pills, powders and the like for oral administration. U.S. Patent 5,273,995 describes mono-sodium salts, mono-potassium, hemi-calcium, N-methylglucamine, hemi-magnesium, hemi-zinc and 1-deoxy-1- (methylamino) -D-glucitol (N-methylglucamine) of atorvastatin. The free acid of atorvastatin, described in US Pat. No. 5,273,995, can also be used to prepare these salts of atorvastatin. In addition, US Patent 6,583,295 B1 discloses a series of amine salts of HMG-CoA reductase inhibitors that are used in a process for the isolation and / or purification of this HMG-CoA reductase.

The salts of tertiary butylamine and dicyclohexylamine of atorvastatin are described. Surprisingly and unexpectedly, we have found new salt forms of atorvastatin that include salts with ammonium, benetamine, benzathine, dibenzylamine, diethylamine, L-lysine, morpholine, olamine, piperazine and 2-amino-2-methylpropan-1-ol that have desirable properties. In addition, surprisingly and unexpectedly, we have found new crystalline forms of atorvastatin that include salts with erbumine and sodium that have desirable properties. As such, these salt forms are pharmaceutically acceptable and can be used to prepare pharmaceutical formulations. Therefore, the present invention provides basic salts of atorvastatin that are pure, have good stability, and have advantageous formulation properties compared to previous salt forms of atorvastatin.

SUMMARY OF THE INVENTION Accordingly, a first aspect of the invention is directed to atorvastatin ammonium and its hydrates characterized by the following powder x-ray diffraction pattern expressed in terms of 2T and relative intensities with an intensity relative of > 30% determined on a Bruker D5000 diffractometer with CuKa radiation: In a second aspect, the invention is directed to Form A of atorvastatin benetamine and its hydrates characterized by the following powder x-ray diffraction pattern expressed in terms of 2T and relative intensities with a relative intensity of > 8% determined on a Bruker D5000 diffractometer with CurV radiation.

In a third aspect, the invention is directed to Form A of atorvastatin benetamine and its hydrates characterized by the following solid-state 13C nuclear magnetic resonance spectrum (SSNMR) in which the chemical shift is expressed in parts per million. (ppm): 15 20"Values in ppm with respect to trimethylsilane (TMS) at 0 ppm, calibrated using an external sample of adamantane, setting its resonance to higher field at 29.5 ppm In a fourth aspect, the present invention is directed to Form A of atorvastatin benetamine and its hydrates characterized by the nuclear magnetic resonance spectrum of 19F in the solid state, following which the chemical shift is expressed in parts per million: * Value in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V V in water) at -76.54 ppm. In a fifth aspect, the invention is directed to Form B of atorvastatin benetamine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 2T and relative intensities with a relative intensity of > 6% determined on a Bruker D5000 diffractometer with CuKa radiation: In a sixth aspect, the invention is directed to Form B of atorvastatin benetamine and its hydrates characterized by the 13C nuclear magnetic resonance spectrum in the following solid state in which the chemical shift is expressed in parts per million: "Values in ppm with respect to trimethylsilane (TMS) at 0 ppm, calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm In a seventh aspect, the invention is directed to Form B of atorvastatin benetamine and hydrates thereof characterized by the nuclear magnetic resonance spectrum of 19F in the following solid state in which the chemical shift is expressed in parts per million: * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V V in water) at -76.54 ppm. In an eighth aspect, the invention is directed to Form A of atorvastatin benzathine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 2T and relative intensities with a relative intensity of > 12% determined on a Bruker D5000 diffractometer with CuKa radiation: In a ninth aspect, the invention is directed to Form B of atorvastatin benzathine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 2T and relative intensities with a relative intensity of > 9% determined on a Bruker D5000 diffractometer with CurV radiation.

In a tenth aspect, the invention is directed to Form C of atorvastatin benzathine and its hydrates characterized by the following powder x-ray diffraction pattern expressed in terms of 2T and relative intensities with a relative intensity of > 13% determined on a Bruker D5000 diffractometer with CuKa radiation: In a eleventh aspect, the invention is directed to atorvastatin dibenzylamine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 29 and relative intensities with a relative intensity of > 8% determined on a Bruker D5000 diffractometer with CuKa radiation: In a twelfth aspect, the invention is directed to atorvastatin dibenzylamine and hydrates thereof characterized by the nuclear magnetic resonance spectrum of 13C in the following solid state in which the chemical shift is expressed in parts per million: * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. In a thirteenth aspect, the invention is directed to atorvastatin dibenzylamine and hydrates thereof characterized by the nuclear magnetic resonance spectrum of 19F in the following solid state in which the chemical shift is expressed in parts per million: * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. In a fourteenth aspect, the invention is directed to Form A of atorvastatin diethylamine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 29 and relative intensities with a relative intensity of > 20% determined on a Bruker D5000 diffractometer with CuKa radiation: In a fifteenth aspect, the invention is directed to Form B of atorvastatin diethylamine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 29 and relative intensities with a relative intensity of > 8% determined in a Bruker D5000 diffractometer with CuKa radiation: 10 15 20 In a sixteenth aspect, the invention is directed to atorvastatin erbumine and its hydrates characterized by the following powder x-ray diffraction pattern expressed in terms of and of relative intensities with a relative intensity of > 6% determined on a Bruker D5000 diffractometer with CuKa radiation: In a seventeenth aspect, the invention is directed to atorvastatin erbumine and its hydrates characterized by the 13C nuclear magnetic resonance spectrum in the following solid state in which the chemical shift is expressed in parts per million: * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. In an eighteenth aspect, the invention is directed to atorvastatin erbumine and its hydrates characterized by the nuclear magnetic resonance spectrum of 19F in the following solid state in which the chemical shift is expressed in parts per million: * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. In a nineteenth aspect, the invention is directed to atorvastatin L-lysine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 29 and relative intensities with a relative intensity of > 40% determined on a Bruker D5000 diffractometer with CuKa radiation: In a twentieth aspect, the invention is directed to atorvastatin morpholine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 29 and relative intensities with a relative intensity of > 9% determined on a Bruker D5000 diffractometer with CuKa radiation: In a twenty-first aspect, the invention is directed to atorvastatin morpholine and its hydrates characterized by the 13C nuclear magnetic resonance spectrum in the following solid state in which the chemical shift is expressed in parts per million: * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. In a twenty-second aspect, the invention is directed to atorvastatin morpholine and its hydrates characterized by the nuclear magnetic resonance spectrum of 19F in the following solid state in which the chemical shift is expressed in parts per million: * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. In a twenty-third aspect, the invention is directed to atorvastatin olamine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 29 and relative intensities with a relative intensity of > 15% determined on a Bruker D5000 diffractometer with CuKa radiation: In a twenty-fourth aspect, the invention is directed to atorvastatin olamine and hydrates thereof characterized by the following 13C nuclear magnetic resonance spectrum in which the chemical shift is expressed in parts per million: 15 20 * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. In a twenty-fifth aspect, the invention is directed to atorvastatin olamine and hydrates thereof characterized by the following 19F nuclear magnetic resonance spectrum in which the chemical shift is expressed in parts per million: * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. In a . Twenty-sixth aspect, the invention is directed to atorvastatin piperazine and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 29 and relative intensities with a relative intensity of > 20% determined on a Bruker D5000 diffractometer with CuKa radiation: In a twenty-seventh aspect, the invention is directed to sodium atorvastatin and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 29 and relative intensities with a relative intensity of > 25% determined on a Bruker D5000 diffractometer with CuKa radiation: In a twenty-eighth aspect, the invention is directed to atorvastatin 2-amino-2-methylpropan-1-ol and hydrates thereof characterized by the following powder x-ray diffraction pattern expressed in terms of 29 and of relative intensities with a relative intensity of > 20% determined on a Bruker D5000 diffractometer with CuKa radiation: In a twenty-ninth aspect, the invention is directed to atorvastatin 2-amino-2-methylpropan-1-ol and its hydrates characterized by the following 13C nuclear magnetic resonance spectrum in which the chemical shift is expressed in parts per million: * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. In a threescore aspect, the invention is directed to atorvastatin 2-amino-2-methylpropan-1-ol and hydrates thereof characterized by the following 19F nuclear magnetic resonance spectrum in which the chemical shift is expressed in parts per million : * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. As inhibitors of HMG-CoA reductase, the new salt forms of atorvastatin are useful as hypolipidemic and hypocholesterolemic agents, as well as agents in the treatment of osteoporosis, benign prostatic hyperplasia and Alzheimer's disease. A further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of a salt of atorvastatin in unit dosage form in the aforementioned treatment methods. Finally, the present invention is directed to methods for the production of salt forms of atorvastatin.

BRIEF DESCRIPTION OF THE DRAWINGS The invention is further described by the following non-limiting examples which refer to the accompanying Figures 1 to 30, of which a short description is provided below. Figure 1 Diffractogram of atorvastatin ammonium performed on a Bruker D5000 diffractometer. Figure 2 Diffractogram of Form A of atorvastatin benetamine performed on a Bruker D5000 diffractometer. Figure 3 Nuclear magnetic resonance spectrum of 13C in the solid state of Form A of atorvastatin benetamine. Figure 4 Nuclear magnetic resonance spectrum of 19F solid state of Form A of atorvastatin benetamine. Figure 5 Diffractogram of Form B of. atorvastatin benetamine performed on a Bruker D5000 diffractometer. Figure 6 Nuclear magnetic resonance spectrum of 13C in solid state of Form B of atorvastatin benetamine. Figure 7 Nuclear magnetic resonance spectrum of 19F solid state of Form B of atorvastatin benetamine.

Figure 8 Diffractogram of Form A of atorvastatin benzathine performed on a Bruker D5000 diffractometer. Figure 9 Diffractogram of Form B of atorvastatin benzathine performed on a Bruker D5000 diffractometer. Figure 10 Diffractogram of Form C of atorvastatin benzathine performed on a Bruker D5000 diffractometer. Figure 11 Diffractogram of atorvastatin dibenzylamine performed on a Bruker D5000 diffractometer. Figure 12 Nuclear magnetic resonance spectrum of 13C in solid state of atorvastatin dibenzylamine. Figure 13 Nuclear magnetic resonance spectrum of 19F solid state of atorvastatin dibenzylamine. Figure 14 Diffractogram of Form A of atorvastatin diethylamine performed on a Bruker D5000 diffractometer. Figure 15 Diffractogram of Form B of atorvastatin diethylamine performed on a Bruker D5000 diffractometer. Figure 16 Diffractogram of atorvastatin erbumine performed on a Bruker D5000 diffractometer. Figure 17 Nuclear magnetic resonance spectrum of 13C in the solid state of atorvastatin erbumine. Figure 18 Nuclear magnetic resonance spectrum of solid phase 19F of atorvastatin erbumine. Figure 19 Diffractogram of atorvastatin L-lysine performed on a Bruker D5000 diffractometer. Figure 20 Diffractogram of atorvastatin morpholine performed on a Bruker D5000 diffractometer. Figure 21 Nuclear magnetic resonance spectrum of 13C in solid state of atorvastatin morpholine. Figure 22 Nuclear magnetic resonance spectrum of 19F solid state of atorvastatin morpholine. Figure 23 Diffractogram of atorvastatin olamine performed on a Bruker D5000 diffractometer. Figure 24 Spectrum of 13C nuclear magnetic resonance in solid state of atorvastatin olamine. Figure 25 Nuclear magnetic resonance spectrum of 19F solid state of atorvastatin olamine. Figure 26 Diffractogram of piperazine atorvastatin performed on a Bruker D5000 diffractometer. Figure 27 Diffractogram of sodium atorvastatin performed on a Bruker D5000 diffractometer. Figure 28 Diffractogram of atorvastatin 2-amino-2-methylpropan-1-ol carried out on a Bruker D5000 diffractometer. Figure 29 Nuclear magnetic resonance spectrum of 13C in solid state of atorvastatin 2-amino-2-methylpropan-1-ol. Figure 30 Nuclear magnetic resonance spectrum of 19F solid state of atorvastatin 2-amino-2-methylpropan-1-ol.

DETAILED DESCRIPTION OF THE INVENTION The new salt forms of atorvastatin can be characterized by their powder x-ray diffraction patterns and / or their spectra are nuclear magnetic resonance in the solid state. Powder X-ray Diffraction The salts of atorvastatin were characterized by their powder x-ray diffraction patterns. Thus, the X-ray diffraction pattern was performed on a Bruker D5000 diffractometer using copper radiation (wavelength 1: 1.54056). The voltage and current of the tube were adjusted to 40 kV and 50 mA, respectively. The divergence and dispersion slits were adjusted to 1 mm and the receiving slit was adjusted to 0.6 mm. Diffracted radiation was detected by a Kevex PSl detector. A theta-two theta continuous scan at 2.47min (1 sec / 0.04 ° stage) from 3.0 to 40 ° 29 was used. An alumina standard was analyzed to check the alignment of the instrument. The data was collected and analyzed using the Bruker axis Version 7.0 software. The samples were prepared by placing them on a quartz support. It should be noted that Bruker Instruments acquired Siemans; thus, the Bruker D5000 instrument is essentially the same as a Siemans D5000. The following tables list the 29 and the intensities of the lines for the salts of atorvastatin and their hydrates. In addition, there are tables that list the individual peaks for salts of atorvastatin and their hydrates. In cases where there are two or more crystalline forms of a salt of atorvastatin or a hydrate thereof, each form can be identified and distinguished from the other crystal form by a single line of X-ray diffraction, a combination of lines , or a pattern that is different from the powder x-ray diffraction of the other forms. Table 1 lists the 29 and the relative intensities of all the lines that have a relative intensity > 30% in the sample for atorvastatin ammonium and its hydrates: TABLE 1: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFRACTION LINES IN THE AMMONIUM ATORVASTATIN AND HYDRATES OF THIS Table 2 lists individual peaks for atorvastatin ammonium and its hydrates: TABLE 2: AMORIOUS ATORVASTATIN AND HYDRAGES OF THIS 2T Grade 7.8 8.8 9.3 9.9 10.6 12.4 19.5 Table 3 lists the 29 and the relative intensities of all the lines that have a relative intensity > 8% in the sample of Forms A and B of the atorvastatin benetamine and hydrates of these: TABLE 3: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFFRACTION LINES OF THE FORMS A AND B OF THE ATORVASTATIN BENETAMINE AND HYDRATES OF THESE Table 4 lists the individual peaks of 29 of Form A and B of atorvastatin benetamine and their hydrates. TABLE 4: FORMS A and B OF ATORVASTAT1NA BENETAMINE AND HYDRATES OF THESE Table 5 lists the 29 and the relative intensities of all the lines that have a relative intensity > 9% in the sample of Forms A, B and C of atorvastatin benzathine and hydrates of these: TABLE 5: INTENSITIES AND LOCALIZATION OF THE PEAKS OF THE DIFRACTION LINES OF THE FORMS A, B AND C OF THE BENZATIN ATORVASTATIN AND THEIR HYDRATES Table 6 lists the individual peaks of 29 of Form A, B, and C of atorvastatin benzathine and their hydrates. TABLE 6: FORMS A, B AND C OF THE BENZATINE ATORVASTATIN AND THEIR HYDRATES Table 7 lists the 29 and the relative intensities of all the lines that have a relative intensity > 8% in the sample of atorvastatin dibenzylamine and hydrates of this: TABLE 7: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFRACTION LINES OF THE ATORVASTATIN DIBENCILAMINE AND HYDRATES OF THIS Table 8 lists the individual peaks of 29 of atorvastatin dibenzylamine and its hydrates. TABLE 8: ATORVASTATIN DIBENCILAMINE AND HYDRATES OF THIS Grade 2T 8.3 18.7 19.8 20.7 21.3 25.8 Table 9 lists the 29 and the relative intensities of all the lines that have a relative intensity > 8% in the sample of Forms A and B of atorvastatin diethylamine and hydrates thereof: TABLE 9: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFRACTION LINES OF FORMS A AND B OF THE ATORVASTATIN DIETILAMINE AND HYDRATES OF THESE Table 10 lists the individual peaks of 29 of Form A, B and C of atorvastatin diethylamine e. hydrates of these. TABLE 10: FORMS A and B OF THE ATORVASTATIN DIETILAMINE AND HYDRATES OF THESE Table 11 lists the 29 and the relative intensities of all the lines that have a relative intensity > 6% in the sample of atorvastatin erbumine and its hydrates: TABLE 11: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFRACTION LINES OF THE ATORVASTATIN ERBUMIN AND HYDRATES OF THIS Table 12 lists the individual peaks of 29 atorvastatin erbumipa and its hydrates. TABLE 12: ATORVASTATIN ERBUMIN AND HYDRATES OF THIS GRADE 2T 5.4 7.4 9.3 17.8 19.2 20.0 22.2 24.2 Table 13 lists the 29 and the relative intensities of all the lines that have a relative intensity > 40% in the sample of atorvastatin L-lysine and its hydrates: TABLE 13: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFRACTION LINES OF THE ATORVASTATIN L-LYSINE AND THEIR HYDRATES Table 14 lists the individual peaks of 29 atorvastatin L-lysine and its hydrates. TABLE 14: ATORVASTATIN L-LYSINE AND HYSTARATES OF THIS Grade 2T 6.7 9.8 17.1 24.0 Table 15 lists the 29 and the relative intensities of all the lines that have a relative intensity > 9% in the sample of atorvastatin morpholine and its hydrates: TABLE 15: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFRACTION LINES OF THE MORPHOLINE ATORVASTATIN AND THIS HYDRATES 15 20 Table 16 lists the individual peaks of 29 atorvastatin morpholine and its hydrates. TABLE 16: MORPHOLINE ATORVASTATIN AND EASTER HYDRATES Grade 2T 9.7 16.0 18.9 19.6 20.8 22.1 23.9 25.0 Table 17 lists the 29 and the relative intensities of all the lines that have a relative intensity > 15% in the sample of atorvastatin olamine and its hydrates: TABLE 17: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFRACTION LINES OF THE ATORVASTATIN OLAMINE AND HYDRATES OF THIS Table 18 lists the individual 2T peaks of atorvastatin olamine and its hydrates. TABLE 18: ATORVASTATIN OLAMINE AND HYDRATES OF THIS Grade 2T 8.5 9.8 17.4 18.6 20.9 22.5 24.1 Table 19 lists the 29 and the relative intensities of all the lines that have a relative intensity > 20% in the sample of atorvastatin piperazine and its hydrates: TABLE 19: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFRACTION LINES OF THE PITERACINE ATORVASTATIN AND HYDRATES OF THIS Table 20 lists the individual peaks of 29 of atorvastatin piperazine and hydrate thereof. TABLE 20: ATORVASTATIN PIPERACINE AND HYDRATES OF THIS Grade 2T 7.8 9.3 11.8 16.1 19.7 Table 21 lists the 29 and the relative intensities of all the lines that have a relative intensity > 25% in the sample of sodium atorvastatin and its hydrates: TABLE 21: INTENSITIES AND LOCATIONS OF THE PEAKS OF THE DIFRACTION LINES OF THE SODIUM ATORVASTATIN AND HYDRATES OF THIS Table 22 lists the individual peaks of 29 atorvastatin sodium and its hydrates. TABLE 22: SODIUM ATORVASTAT1NA AND HYDRATES OF THIS Table 23 lists the 29 and the relative intensities of all the lines that have a relative intensity > 25% in the sample of atorvastatin 2-amino-2-methylpropan-1-ol and its hydrates: TABLE 23: INTENSITIES AND LOCATIONS OF THE PICOS OF THE DIFRACTION LINES OF THE ATORVASTATIN 2-AMINO-2-METILPROPAN-1 -OL AND HYDRATES OF THIS Table 24 lists the individual peaks of atorvastatin 2-amino-2-methylpropan-1-ol and its hydrates.

TABLE 24: ATORVASTATIN 2-AM1NO-2-MET1LPROPAN-1-OL AND HYDRATES OF THIS Grade 2T 4.2 8.3 16.0 17.5 18.3 19.4 19.7 Nuclear Magnetic Resonance in Solid State The new salt forms of atorvastatin can also be characterized by their nuclear magnetic resonance spectra in the solid state. Therefore, the solid-state nuclear magnetic resonance spectra of the salt forms of atorvastatin were performed on a Bruker-Biospin Advance DSX 500 MHz NMR spectrometer. 19F SSNMR Approximately 15 mg of sample were tightly packed in a rotor. ZrO of 2.5 mm for each sample analyzed. The one-dimensional 19F spectra were collected at 30 ° C and ambient pressure in a Bruker-Biospin 2.5 mm BL magical angle rotation (CPMAS) magnetic burster placed on a Bruker-Biospin Advance DSX 500 MHz NMR spectrometer. wide opening. The samples were placed at the magical angle and turned at 35.0 kHz without cross-polarization of protons, which corresponds to the maximum rotational speed specified for the 2.5 mm rotors. The high speed of rotation minimized the intensities of the rotation bands and provided an almost complete decoupling of the 9F signals from the protons. The number of scans was adjusted individually for each sample to obtain an adequate signal-to-noise ratio (S / N). Typically, 150 scans were acquired. Before the acquisition of 19F, the 19F relaxation times were determined by an inversion recovery technique. The waiting time between pulses for each sample was adjusted to five times the relaxation time of 19F longer in the sample, which ensured the acquisition of quantitative spectra. The base signal of a fluorine probe was subtracted from each alternate scanner after presaturating the 19F signal. The spectra were calibrated using an external sample of trifluoroacetic acid (diluted to 50% V / V with H2O), adjusting its resonance to -76.54 ppm. 13C SSNMR Approximately 80 mg of sample were tightly packed in a 4 mm ZrO rotor for each sample analyzed. One-dimensional 13C spectra were obtained at ambient pressure using CPMAS 1H-13C at 30 ° C on a Bruker 4 mm BL CPMAS probe located on a Bruker-Biospin Advance DSX 500 MHZ wide-aperture NMR spectrometer. The samples were rotated at 15.0 kHz which corresponds to the maximum rotational speed specified for the 7 mm rotors. The high speed of rotation minimized the intensities of the rotation bands. To optimize the sensitivity of the signal, the cross polarization contact time was adjusted to 1.5 ms, and the proton decoupling power was set to 100 kHz. The number of scans was adjusted individually for each sample to obtain an adequate S / N ratio. Typically, 1,900 scans were obtained with a waiting time between pulses of 5 seconds. The spectra were calibrated using an external sample of adamantane, adjusting their resonance to higher field at 29.5 ppm. Table 25 and Table 25a list the chemical shifts in 13 C NMR for Form A and B of atorvastatin benetamine and their hydrates: TABLE 25: BENETAMINE FORM A AND HYDRATES THIS 15 20 * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. TABLE 25a: FORM B OF BENETAMINE AND HYDRATES OF THIS * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 26 lists individual chemical shifts in 13 C NMR for Form A of atorvastatin benetamine: TABLE 26: FORM OF ATORVASTATIN BENETAMINE AND HYDRATES OF THIS * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 27 lists individual chemical shifts in 13 C NMR for Form B of atorvastatin benetamine: TABLE 27: B SHAPE OF BENZERAMINE ATORVASTATIN AND ETHYL HYDRATES * Values in ppm with respect to trimethylsilane (TMS) a.O ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 28 and Table 28a list the chemical shifts in NMR of 19F for Forms A and B of atorvastatin benetamine and hydrates thereof: TABLE 28: FORM OF ATORVASTATIN BENETAMINE AND HYDRATES OF THIS * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. TABLE 28a: FORM B OF THE ATORVASTATIN BENETAMINE AND HYDRATES OF THIS * Values in ppm with respect to CC13F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. Table 29 lists the chemical shifts in 13 C NMR for atorvastatin dibenzylamine and hydrates thereof: TABLE 29: ATORVASTATIN DIBENCILAMINE AND HYDRATES OF THIS * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 30 lists the individual chemical shifts in 13 C NMR for atorvastatin dibenzylamine and its hydrates: TABLE 30: ATORVASTATIN DIBENCILAMINE AND HYDRATES OF THIS * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 31 lists the chemical shifts in NMR of 19F for atorvastatin dibenzylamine and hydrates thereof: TABLE 31: ATORVASTATIN DIBENCILAMINE AND HYDRATES OF THIS * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. Table 32 lists the chemical shifts in 13 C NMR for atorvastatin erbumine and its hydrates: TABLE 32: ATORVASTATIN ERBUMIN AND ETHYL HYDRATES * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 33 lists the individual chemical shifts in 13 C NMR for atorvastatin erbumine and its hydrates: TABLE 33: ATORVASTATIN ERBUMIN AND HYDRATES THIS * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 34 lists the chemical shifts in NMR of 19F for atorvastatin erbumine and its hydrates: TABLE 34: ATORVASTATIN ERBUMIN AND HYDRATES THIS * Values in ppm with respect to C.CI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. Table 35 lists the chemical shifts in 13 C NMR for atorvastatin morpholine and its hydrates: TABLE 35: ATORVASTATIN MORPHOLINE AND ETHYL HYDRATES * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm.

Table 36 lists the individual chemical shifts in NMR of 13, C for atorvastatin morpholine and hydrates thereof: TABLE 36: ATORVASTATIN MORPHOLINE AND HYDRATES THIS * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 37 lists the individual chemical shifts in 19F NMR for atorvastatin morpholine and hydrates thereof: TABLE 37: ATORVASTATIN MORPHOLINE AND HYDRATES THIS * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. Table 38 lists the chemical shifts in 13 C NMR for atorvastatin olamine and hydrates thereof: TABLE 38: ATORVASTATIN OLAMINE AND HYDRATES OF THIS * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 39 lists the individual chemical shifts in 13 C NMR for atorvastatin olamine and hydrates thereof: TABLE 39: ATORVASTATIN OLAMINE E HYDRATES OF THIS * Value in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 40 lists the chemical shifts in NMR of 19F for atorvastatin olamine and hydrates thereof: TABLE 40: ATORVASTATIN OLAMINE AND HYDRATES OF THIS * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. Table 41 lists the chemical shifts in 13 C NMR for atorvastatin 2-amino-2-methyl-propan-1-ol and hydrates thereof: TABLE 41: ATORVASTATIN 2-AMINO-2-METHYL-PROPAN-1-OL E HYDRATES OF THIS 15 20 * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 42 lists the individual chemical shifts in 13 C NMR for atorvastatin 2-amino-2-methyl-propan-1-ol and hydrates thereof: TABLE 42: ATORVASTATIN 2-AMINO-2-METHYL-PROPAN-1-OL AND HYDRATES OF THIS * Values in ppm with respect to trimethylsilane (TMS) at 0 ppm; calibrated using an external sample of adamantane, adjusting its resonance to higher field at 29.5 ppm. Table 43 lists the chemical shifts in NMR of 19F for atorvastatin 2-amino-2-methyl-propan-1-ol and hydrates thereof: TABLE 43: ATORVASTATIN 2-AMINO-2-METHYL-PROPAN-1- OL E HYDRATES OF THIS * Values in ppm with respect to CCI3F at 0 ppm, calibrated using an external standard of trifluoroacetic acid (50% V / V in water) at -76.54 ppm. In addition, Forms A and B of atorvastatin benetamine, atorvastatin dibenzylamine, atorvastatin erbumine, atorvastatin morpholine, atorvastatin olamine and atorvastatin 2-amino-2-methyl-propan-1-ol or a hydrate of the aforementioned salts can be characterized by a X-ray powder diffraction pattern or a 19F nuclear magnetic resonance spectrum in the solid state. For example: An atorvastatin ammonium or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using Cul ^ radiation: 7.8, 8.8, 9.3, 9.9 , 10.6, 12.4 and 19.5. A Form A of atorvastatin benetamine or a hydrate thereof having a powder x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 4.7, 5.3, 9.5, 12.0 , 15.6, 18.1 and 19.9, or a nuclear magnetic resonance of 19F in solid state having the following chemical shifts expressed in parts per million: -113.2 and -114.2.

A Form B of atorvastatin benetamine or a hydrate thereof having a powder x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 5.0, 7.1, 8.4, 10.0 , 11.6, 12.6, 14.8 and 20.2 or a nuclear magnetic resonance of 19F in solid state having the following chemical shifts expressed in parts per million: -113.7 and -114.4. A Form A of atorvastatin benzathine or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 14.0 and 15.1. A Form B of atorvastatin benzathine or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 8.3, 10.2, 14.4, 15.8 , 18.6, 21.8 and 23.3. A Form C of atorvastatin benzathine or a hydrate thereof that has a powder x-ray diffraction pattern containing the peaks 29 following determined using CuKa radiation: 3, 9, 6.9, 7.9, 9.7 and 12.8. An atorvastatin dibenzylamine or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuK radiation ": 8.3, 18.7, 19.8, 20.7, 21, 3 and 25.8, or a 19F nuclear magnetic resonance in the solid state having the following chemical shifts expressed in parts per million: -107.8. A compound selected from the group consisting of: (a) Form A of atorvastatin diethylamine or hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 determined using CuKa radiation. 17,0, 18,2, 20,0, 21,7 and 23,0; and (b) Form B of atorvastatin diethylamine or hydrate thereof having a dust x-ray diffraction pattern containing the peaks 29 following determined using CuKa radiation: 6.1, 11.5, 15.3, 17.4, 20.5, 23.2 and 27.6. An atorvastatin erbumine or a hydrate thereof having a powder x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 5.4, 7.3, 9.5, 17.8, 19.2 , 20.0, 22.2 and 24.2, or a 19F nuclear magnetic resonance in the solid state that has the following chemical shifts expressed in parts per million: -110.4. An atorvastatin L-lysine or a hydrate thereof having a dust-x-ray diffraction pattern containing the following peaks 29 determined using CuKa radiation: 6.7, 9.8, 17.1 and 24.0. An atorvastatin morpholine or a hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 using Cuf ^ radiation: 9.7, 16.0, 18.9, 19.6, 20, 8, 22.1, 23.9 and 25.0, or a nuclear magnetic resonance of 19F in solid state having the following chemical shifts expressed in parts per million: -117.6. An atorvastatin olamine or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 8.5, 9.8, 17.4, 18.6, 20.9 , 22.5 and 24.1, or a nuclear magnetic resonance of 19F in solid state having the following chemical shifts determined in parts per million: - 118.7. An atorvastatin piperazine or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 7.8, 9.3, 11.8, 16.1, and 19.7 . A sodium atorvastatin or a hydrate thereof having a powder x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 3.4, 4.9, 7.6, 8.0, 9.9 , 18.9 and 19.7. An atorvastatin 2-amino-2-methylpropan-1-ol or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 4.2, 8.3, 16 , 0, 17.5, 18.3, 19.4 and 19.7, or a nuclear magnetic resonance of 19F in solid state that has the following chemical shifts determined in parts per million: -113.6 and -116.5 . The salt forms of the atorvastatin of the present invention, regardless of the magnitude of the hydration and / or solvation, having powder X-ray diffractograms, or SSRMN, equivalents are within the scope of the present invention. The new salt forms of atorvastatin described herein have advantageous properties. For example, it was determined that the salts benetamine, benzathine, dibenzylamine, diethylamine, erbumine and morpholine were anhydrous compounds, with a high melting point as well as non-hygroscopic compounds. It was determined that the olamine and 2-amino-2-methylpropan-1-ol salts were also anhydrous and with a high melting point. The diethylamine, erbumine, morpholine, olamine and 2-amino-2-methylpropan-1-yl salts of atorvastatin also exhibit a high aqueous solubility compared to that of Form I of the calcium atorvastatin (described in U.S. Pat. 5,969,156). The present invention provides a process for the preparation of salt forms of atorvastatin comprising preparing a solution of free acid from atorvastatin (US Patent 5,213,995) in one of the following solvents: acetone, acetonitrile, THF, : 1 acetone / water (v / v), isopropanol (IPA), or chloroform. The cationic counterion solutions were prepared using 0.5 or 1.0 equivalent in the same solvent. Water was added to some counterions to increase its solubility. The solution of the free acid of atorvastatin was added to the counterion solution while stirring. The reaction was stirred for at least 48 hours at room temperature. The samples containing solids were filtered in vacuo, washed with the reaction solvent and air dried overnight under ambient conditions. If no precipitation appeared after ~ 2 weeks, the solution evaporated slowly. All samples were stored at room temperature and characterized as described hereinafter.

TABLE 44. Structure of the Counterions used in the preparation of the salts of Atorvastatin.

Structure Name Common Name NH, Ammonium Ammonium ? / - Benzyl-2-Benetamine Phenylethylamine ? /,? / '- Bis (phenylmethyl) - Benzathine 1,2-ethanediamine ? / - (Phenylethyl) Dibenzylamine benzenemethamine a H? / - Ethylethanamine Diethylamine ferc-butylamine Erbumine H2N-CH-CO2H (CH 22) .4 Acid (S) -2,6- L-diaminehexanoic NH, The compounds of the present invention can be prepared and administered in different oral and parenteral dosage forms. Therefore, the compounds of the present invention can be administered by injection, i.e., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. In addition, the compounds of the present invention can be administered by inhalation, for example, intranasally. In addition, the compounds of the present invention can be administered transdermally. To prepare pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, seals, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In the powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain from two to ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier which provides a capsule in which the active component, with or without other vehicles, is surrounded by a vehicle, which is thus in association with he. Similarly, seals and pills are included. The tablets, powders, capsules, pills, seals and pills can be used as solid dosage forms suitable for oral administration !. To prepare suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed therein homogeneously by agitation. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and thus solidifies. Liquid form preparations include solutions, suspensions, retention enemas and emulsions, for example, water or aqueous propylene glycol solutions. In the case of parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable coloring, flavoring, stabilizing and thickening agents, as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents. Also included are solid form preparations that are intended to be converted, immediately before use, in liquid form preparations for oral administration. Said liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, synthetic and natural sweeteners, dispersants, thickeners, solubilizing agents and the like. The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, and the package contains discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, seal or tablet in themselves, or it can be an appropriate number of any one of these packaged forms. The amount of active component in a unit dose preparation can be varied or adjusted from 0.5 mg to 100 mg, preferably from 2.5 mg to 80 mg depending on the particular application and the potency of the active component. The composition may also contain, if desired, other compatible therapeutic agents. In the therapeutic use as hypolipidemic and / or hypocholesterolemic agents and agents for treating osteoporosis, benign prostatic hyperplasia and Alzheimer's disease, the salt forms of atorvastatin used in the pharmaceutical method of this invention are administered at the initial dose of about 2, 5 mg to approximately 80 mg per day. A daily dosage range of about 2.5 mg to about 20 mg is preferred. However, the dosages can be varied depending on the patient's requirements, the severity of the condition being treated, and the compound being used. The determination of the appropriate dosage for a specific situation is within the technique. In general, the treatment starts with smaller dosages, which are less than the optimum dose of the compound. Then, the dose is increased with small increments until the optimal effect is reached in each circumstance. For convenience, the total daily dose can be divided and administered in portions throughout the day if desired. The following non-limiting examples illustrate the preferred methods of the inventors for preparing the compounds of the invention. EXAMPLE 1 Ammonium salt of the acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methylethyl) -3-phenyl-4- [ (phenylamino) carbonyl] -1H-pyrrole-1-heptanoic (atorvastatin ammonium). The ammonium salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (ACN) (0.634 g in 25 mL of ACN). A solution was prepared by dissolving 12.04 mg of ammonium hydroxide (1.0 equivalent) in acetonitrile (0.5 mL). The stock solution of the free acid of atorvastatin (2.24 mL) was added to the counterion solution with stirring. If a gel formed, additional acetonitrile and water were added as necessary. After 2 days of stirring at room temperature, the solids were isolated by vacuum filtration using a 0.45 μm nylon membrane filter. The solids were washed with acetonitrile and air-dried under ambient conditions to yield atorvastatin ammonium. EXAMPLE 2 N-benzyl-2-phenylethylamine of the acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methyl-ethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1 H -pyrrol-1-heptanoic (atorvastatin benetamine). Method A: The salt benetamine of atorvastatin (Form A) was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N-benzyl-2-phenylethiamine (benetamine) was prepared by dissolving 378.59 mg (1.0 equivalent) in acetonitrile (10 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. After, an additional 40 mL of acetonitrile was added to prevent the formation of a gel. After 5 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (75 mL), and placed in an oven at 25 ° C under nitrogen to dry them overnight to yield Form A of atorvastatin benetamine. Method B: The salt benetamine of atorvastatin (Form B) was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in 2-propanol (IPA) (1 g in 40 mL of IPA). A solution of N-benzyl-2-phenylethylamine (benetamine) was prepared by dissolving 388.68 mg (1.1 equivalents) in 2-propanol (100 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. Seed crystals of the benetamine salt were added. The mixture was reduced to a wet solid under a stream of nitrogen and the resulting solids were suspended in 2-propanol (40 mL). After 7 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2).

Whatman). The solids were washed with 2-propanol (25 mL), and placed in an oven at 25 ° C under nitrogen to dry them overnight to yield Form B of the atorvastatipa benetamine. EXAMPLE 3 N, N 1 -bis (phenylmethyl) -1,2-ethanediamine of the acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1- methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic acid (atorvastatin benzathine). Method A: The benzathine salt of atorvastatin (Form A) was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N, N'-bis (phenylmethyl) -1,2-ethanediamine (benzathine) was prepared by dissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water (20 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. After 2 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (75 mL), and placed in an oven at 25 ° C under nitrogen to dry them overnight to yield Form A benzathine. Method B: The benzathine salt of atorvastatin (Form B) was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of N, N'-bis (phenylmethyl) -1,2-ethanediamine (benzathine) was prepared by dissolving 220.64 mg (0.5 equivalents) in acetonitrile (80 mL) and water (20 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. After 2 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (75 mL) to yield Form B of the atorvastatin benzafine. See that this process is the same as the previous one except that the sample was not dried in an oven. Method C: The benzathine salt of atorvastatin (Form C) was synthesized by adding Form A of atorvastatin benzatine to 3 mL of deionized water above its solubility. The solids in suspension were stirred at room temperature for 2 days, isolated by vacuum filtration and dried at ambient conditions to yield Form C of the atorvastatin benzathine. EXAMPLE 4 N- (Phenylmethyl) benzenemethanamine of the acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methyl-ethyl) -3-phenyl-4- [(phenylamino) carbonyl] -1 H -pyrrol-1-heptanoic (atorvastatin dibenzylamine). The dibenzylamine salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Pat. ,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of dibenzylamine was prepared by dissolving 351.05 mg (1.0 equivalent) in acetonitrile (100 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. Then, additional acetonitrile was added to prevent the formation of a gel (100 mL), and the solid was stirred.

After 4 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (75 mL), and placed in an oven at 25 ° C under nitrogen to dry overnight to yield atorvastatin dibenzylamine. EXAMPLE 5 N-ethylethanamine of the acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methyl-ethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic (atorvastatin diethylamine). Method A: The diethylamine salt of atorvastatin (Form A) was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of diethylamine was prepared by dissolving 132.33 mg (1.0 equivalent) in acetonitrile (20 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. Then, an additional 40 mL of acetonitrile was added to prevent the formation of a gel. After 5 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (75 mL), and placed in a 25CC oven under nitrogen to dry overnight to yield Form A of atorvastatin diethylamine. Method B: The diethylamine salt of atorvastatin (Form B) was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of diethylamine was prepared by dissolving 132.33 mg (1.0 equivalent) in acetonitrile (20 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. Then, an additional 40 mL of acetonitrile was added to prevent the formation of a gel.

After 5 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (75 mL) to yield Form B of atorvastatin diethylamine. See that this process is the same as the previous one except that the sample was not dried in an oven. EXAMPLE 6 Tertiary butylamine acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methyl-ethyl) -3-phenyl-4 - [(phenylamino ) carbonyl] -1 H-pyrrole-1-heptanoic (atorvastatin erbumine). The salt erbumin of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of ferc-butylamine (erbumin) was prepared by dissolving 128.00 mg (1.0 equivalent) in acetonitrile (10 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. Then, an additional 120 mL of acetonitrile was added to prevent the formation of a gel. After 5 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (75 mL), and placed in an oven at 25 ° C under nitrogen to dry them overnight to yield atorvastatin erbumine. EXAMPLE 7 Acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] - 1H-pyrrole-1-heptanoic, L-lysine (atorvastatin L-lysine).

The L-lysine salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in isopropyl alcohol (IPA) (2.577 g in 50 mL of IPA). A solution of L-lysine was prepared by dissolving 28.0 mg (1.0 equivalent) in isopropyl alcohol (1 mL). The stock solution of the free acid of atorvastatin (2.08 mL) was added to the counterion solution with stirring. After 7 days of stirring at room temperature, the solids were isolated by vacuum filtration using a 0.45 μm nylon 66 membrane filter. The solids were washed with IPA and air-dried at room temperature to yield L-lysine. EXAMPLE 8 Acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] - 1 H-pyrrole-1-heptanoic, tetrahydro-2H-1,4-oxazine (atorvastatin morpholine). The morpholine salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A morpholine solution was prepared by dissolving 160.28 mg (1.1 equivalents) in acetonitrile (100 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. No salts were formed so the solution was evaporated under N2 until a white solid formed. Then, acetonitrile was added to the solid (50 mL), and the solid was stirred. After 3 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (25 mL), and placed in an oven at 25 ° C under nitrogen to dry them overnight to yield atorvastatin morpholine. EXAMPLE 9 Acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] - 1 H-pyrrole-1-heptanoic, 2-aminoethane I (atorvastatin olamine). Method A - The olamine salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (U.S. Patent 5,273,995) in acetonitrile (, 8 g in 25 mL of ACN). An olamine solution was prepared by dissolving 15.0 mg of olamine (~ 2.7 equivalents) in 0.5 mL of acetonitrile. The stock solution of the free acid of atorvastatin (3.0 mL) was added to the counterion solution with stirring. If a gel formed, additional acetonitrile was added as necessary. After 6 days of stirring at room temperature, the solids were isolated by vacuum filtration using a 0.45 μm nylon 66 membrane filter. The solids were washed with acetonitrile and air-dried under ambient conditions to yield atorvastatin olamine. Method B - The olamine salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (1 g in 40 mL of ACN). A solution of 2-aminoethanol (olamine) was prepared by dissolving 139.77 mg (1.1 equivalents) in acetonitrile (100 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. Seed crystals of the olamine salt were added. Then, additional acetonitrile was added to improve stirring (300 mL), and the solid was stirred. After 4 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (75 mL), and placed in an oven at 25 ° C under nitrogen to dry them for two days to yield atorvastatin olamine. EXAMPLE 10 Acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] - 1 H-pyrrole-1-heptanoic, piperazine (atorvastatin piperazine). The piperazine salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Pat. . 273,995) in isopropyl alcohol (2.577 g in 50 mL of IPA). A piperazine solution was prepared by dissolving 14.4 mg (1.0 equivalent) in isopropyl alcohol (1 mL). The stock solution of the free acid of atorvastatin (1.85 mL) was added to the counterion solution with stirring. After 7 days of stirring at room temperature, the solids were isolated by vacuum filtration using a 0.45 μm nylon 66 membrane filter. The solids were washed with isopropyl alcohol and air-dried under ambient conditions to yield piperazine atorvastatin.

EXAMPLE 11 Acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methylethyl) -3- phenyl-4 - [(phenylamino) carbonyl] - 1 H-pyrrol-1-heptanoic, sodium (atorvastatin sodium). The sodium salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Pat. . 273,995) in acetonitrile (0.634 g in 25 mL of ACN). A solution was prepared by dissolving 2.67 mg of sodium hydroxide (1.0 equivalent) in 0.5 mL of acetonitrile and 0.05 mL of water. The stock solution of the free acid of atorvastatin (1.55 mL) was added to the counterion solution with stirring.

If a gel formed, additional acetonitrile and water were added as necessary. After 6 days of stirring at room temperature, the solids were isolated by vacuum filtration using a 0.45 μm nylon 66 membrane filter. The solids were washed with acetonitrile and air-dried under ambient conditions to yield atorvastatin sodium. EXAMPLE 12 Acid [R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl ] -1H-pyrrole-1-heptanoic, 2-amino-2-methyl-propan-1-ol (atorvastatin 2-amino-2-methylpropan-1-ol). Method A - The 2-amino-2-methylpropan-1-ol salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (0.8 g in 25% strength). mL of ACN). A solution of 2-amino-2-methylpropan-1-o! dissolving 6.1 mg of 2-amino-2-methylpropan-1-ol (1 equivalent) in 0.5 mL of acetonitrile. The stock solution of the free acid of atorvastatin (1.21 mL) was added to the counterion solution with stirring. If a gel formed, additional acetonitrile was added as necessary. After 6 days of stirring at room temperature, the solids were isolated by vacuum filtration using a 0.45 μm nylon 66 membrane filter. The solids were washed with acetonitrile and air-dried under ambient conditions to yield atorvastatin 2-amino-2-methylpropan-1-ol. Method B - The 2-amino-2-methylpropan-1-ol salt of atorvastatin was synthesized by preparing a stock solution of the free acid of atorvastatin (US Patent 5,273,995) in acetonitrile (1 g in 40 mL of ACN) . A solution of 2-amino-2-methylpropan-1-ol was prepared by dissolving 173.08 mg (1.1 equivalents) in acetonitrile (100 mL). The stock solution of the free acid of atorvastatin was added to the counterion solution with stirring. Seed crystals of the salt 2-amino-2-methylpropan-1-ol were added. Then, additional acetonitrile was added to improve stirring (100 mL), and the solid was stirred. After 4 days of stirring at room temperature, the solids were isolated by vacuum filtration using a Buchner funnel equipped with a paper filter (# 2 Whatman). The solids were washed with acetonitrile (75 mL), and put in an oven at 25 ° C under nitrogen to dry them for two days to yield atorvastatin 2-amino-2-methylpropan-1-ol.

Claims (15)

1. - An atorvastatin ammonium or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 7.8, 8.8, 9.3, 9.9, 10, 6, 12.4 and 19.5. 2.- A Form A of atorvastatin benetamine or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 4.7, 5.3, 9.5, 12.0, 15.6, 18.1 and 19.9, or a 19F nuclear magnetic resonance in solid state having the following chemical shifts expressed in parts per million: -113.2 and -114.

2.

3. A Form B of atorvastatin benetamine or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 5.0, 7.1, 8.4, 10.0, 11.6, 12.6, 14.8 and 20.2, or a nuclear magnetic resonance of 19F in solid state having the following chemical shifts expressed in parts per million: -113.7 and -114.4.

4.- A Form A of atorvastatin benzatine or a hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 determined using CuKa radiation: 14.0 and 15.1.

5.- A Form B of atorvastatin benzathine or a hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 using CuKa radiation: 8.3, 10.2, 14.4, 15.8, 18.6, 21, 8 and 23.3.

6.- A Form C of atorvastatin benzathine or a hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 determined using CuKa radiation: 3.9, 6.9, 7.9, 9.7 and 12.8.

7. An atorvastatin dibenzylamine or a hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 determined using CuKa radiation: 8.3, 18.7, 19.8, 20.7, 21.3 and 25.8, or a 19F nuclear magnetic resonance in solid state having the following chemical shifts expressed in parts per million: -107.8.

8. A compound selected from the group consisting of: (a) Form A of atorvastatin diethylamine or hydrate thereof having a dust x-ray diffraction pattern containing the peaks 29 following determined using CuKa radiation: 17.0, 18.2, 20.0, 21.7 and 23.0; and (b) Form B of atorvastatin diethylamine or hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 6.1, 11.5, 15.3, 17 ,4, 20.5, 23.2 and 27.6.

9. An atorvastatin erbumine or a hydrate thereof having a powder x-ray diffraction pattern containing the following 29 peaks determined using Cu2 radiation: 5.4, 7.3, 9.5, 17.8 , 19.2,

20. 0, 22.2 and 24.2, or a nuclear magnetic resonance of 19F in solid state having the following chemical shifts expressed in parts per million: -110.4.

10. An atorvastatin L-lysine or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 6.7, 9.8, 17.1 and 24, 0

11. An atorvastatin morpholine or a hydrate thereof having a dust x-ray diffraction pattern containing the following 29 peaks determined using CuKa radiation: 9.7, 16.0, 18.9, 19.6, 20.8,

22. 1, 23.9 and 25.0, or a 19F nuclear magnetic resonance in solid state having the following chemical shifts expressed in parts per million: -117.6.

12. An atorvastatin olamine or a hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 determined using CuKa radiation: 8.5, 9.8, 17.4, 18.6, 20.9, 22.5 and 24.1, or a nuclear magnetic resonance of 19F in solid state having the following chemical shifts determined in parts per million: -118.7.

13. An atorvastatin piperazine or a hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 determined using CuKa radiation:, 8, 9.3, 11.8, 16.1 and 19.7.

14. An atorvastatin sodium or a hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 determined using CuKa radiation: 3.4, 4.9, 7.6, 8.0, 9.9, 18.9 and 19.7.

15. An atorvastatin 2-amino-2-methylpropan-1-ol or a hydrate thereof having a dust x-ray diffraction pattern containing the following peaks 29 determined using CuKa radiation: 4.2, 8, 3, 16.0, 17.5, 18.3, 19.4 and 19.7, or a nuclear magnetic resonance of 19F in solid state having the following chemical shifts determined in parts per million: -113.6 and - 116.5.