LT5196B - Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms - Google Patents

Abstract

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

Description

FIELD OF INVENTION

This invention relates to crystalline polymorphic forms of atorvastatin semi-calcium, to novel crystalline forms of atorvastatin semi-calcium, and to crystalline atorvastatin semi-calcium with fine particle size distribution.

ORIGIN OF THE INVENTION

Atorvastatin ([R- (R *, R *)] - 2- (4-fluorophenyl) -?,? 5 -dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H pyrrol-1-heptanoic acid) represented by the lactone in formula (I) and its calcium salt trihydrate of formula (II) are well known in the art and are described, inter alia, in U.S. Pat. 4681893, 5273995, and pending USSN 60/166153, filed Nov. 17, 2000, all of which are incorporated herein by reference.

^Cl (II)

Atorvastatin is a member of a class of drugs called statins. Currently, statin drugs are the most therapeutically effective drugs for lowering circulating levels of low-density lipotrotein (LDL) particles in patients at risk for cardiovascular disease. High levels of LDL in the bloodstream are associated with coronary artery lesions, which cause blood flow to stop and can cause and promote thrombosis. Goodman and Gilman, The Pharmacological Basis of

Therapeutics 879 (9th ed. 1996). Reduction in plasma LDL levels has been shown to reduce the risk of clinical events in patients with cardiovascular disease and in patients without cardiovascular disease but with hypercholesterolemia. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.

The mechanism of action of statin-class drugs is detailed. During synthesis of cholesterol and other sterols, they are penetrated into the liver, competitively inhibiting the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase ”). HMG-CoA reductase catalyzes the conversion of HMG to mevalonate, a rate-limiting step in cholesterol biosynthesis and therefore inhibits its reduction in liver cholesterol. Very Low Density Lipoprotein (LMTL) is a biological carrier for the transport of cholesterol and triglycerides from the liver to peripheral cells. LMTL is catabolized in peripheral cells, which release fatty acids that can be accumulated in adoptees or oxidized in muscle. LMTL is converted to intermediate density lipoprotein (VTL), which is either removed by the LDL receptor or converted into LDL. Decreased cholesterol production promotes an increase in LDL receptor number and a corresponding decrease in LDL particle production by VTL metabolism.

Atorvastatin Semi-Calcium Salt Trihydrate is designated by LIPITOR as Varner-Lambert Co. Atorvastatin was first publicly disclosed and described in U.S. Pat. 4681893. A semi-calcium salt represented by formula (II) is disclosed in U.S. Pat. No. 5,273,995. '995 states that the semi-calcium salt is obtained by crystallization of a brine solution obtained by transposition of the sodium salt with CaCL and further purified by recrystallization of a 5: 3 mixture of ethyl acetate and hexane.

The present invention provides novel semi-calcium crystalline forms of atorvastatin in both solvated and hydrated states. The prevalence (polymorphism) of different crystalline forms is a property of some molecules and molecular complexes. A single molecule, such as atorvastatin of formula (I) or salt complex of formula (II), can enhance the diversity of solid bodies with different physical properties such as melting point, X-ray diffraction pattern, infrared absorption fingerprint, and nuclear magnetic resonance (NMR) spectrum. . Differences in the physical properties of polymorphs are derived from orientation of intermolecular molecules (complexes) and intermolecular interactions in a volumetric solid. Accordingly, polymorphs are distinct solid bodies of the same molecular formula but having individual beneficial and / or useless physical properties relative to other forms of the polymorph family. One of the most important physical properties of pharmaceutical polymorphs is their solubility in aqueous solution, more particularly their solubility in the patient's gastric juice. For example, when gastrointestinal absorption is slow, it is often desirable for a drug that is unstable in a patient's gastrointestinal tract to dissolve so slowly that it does not accumulate in the harmful medium. On the other hand, when drug efficacy correlates with drug peak blood flow levels, the property is conferred by a statin drug and the drug administered is rapidly absorbed in the gastrointestinal (GI) system, then the more rapidly dissolving form is suitable to reveal enhanced efficacy over the comparative amount.

Semi-calcium crystalline forms I, II, III and IV of atorvastatin are disclosed in U.S. Pat. 5959156 and 6121461 belonging to Varner-Lambert, and the semicalcium V crystalline form of atorvastatin is disclosed in commonly accepted PCT application no. PCT / US00 / 31555. Patent '156 states that Form I has better filtration and drying characteristics than the known semi-calcium amorphous form of atorvastatin. Although Form I eliminates some of the drawbacks of the amorphous material in terms of manufacturing capability, there is still a need for further improvement of these properties as well as other properties such as fluidity, vapor impermeability and solubility. In addition, the discovery of new crystalline forms of a drug expands the range of materials that a formulator must use to formulate a pharmaceutical dosage form of a drug, providing a release form or other desired characteristic.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representative X-ray diffraction pattern of a semi-calcium VI-form powder of atorvastatin obtained with a conventional copper anode X-ray generator.

FIG. 2 is a representative X-ray diffraction pattern of a semi-calcium Form VII powder of atorvastatin obtained using a conventional copper anode X-ray generator.

FIG. 3 is a representative X-ray diffraction pattern of a semi-calcium Form VIII powder of atorvastatin obtained using a conventional copper anode X-ray generator.

FIG. 4 is a representative X-ray diffraction pattern of a semi-calcium Form VIII powder of atorvastatin obtained using a synchrotron X-ray source.

FIG. 5 is a characteristic solid state ¹³ C NMR spectrum of atorvastatin Form VIII.

FIG. 6 is a representative X-ray diffraction pattern of a semi-calcium Form IX powder of atorvastatin obtained using a conventional copper anode X-ray generator.

FIG. 7 is a representative X-ray diffraction pattern of a semi-calcium Form IX powder of atorvastatin obtained using a synchrotron X-ray source.

FIG. 8 is the characteristic solid state ¹³ C NMR spectrum of atorvastatin Form IX.

FIG. 9 is a representative X-ray powder diffraction pattern of a semi-calcium X-shaped powder of atorvastatin obtained using a conventional copper anode X-ray generator.

FIG. 10 is a representative X-ray diffraction pattern of a semi-calcium X-shape powder of atorvastatin obtained using a synchrotron X-ray source.

FIG. 11 is a characteristic solid state ¹³ C NMR spectrum of atorvastatin X.

FIG. 12 is a representative X-ray diffraction pattern of a semi-calcium X-ray powder diffraction pattern of atorvastatin obtained using a conventional copper anode X-ray generator.

FIG. 13 is an image of typical powder X-ray diffraction patterns of the atorvastatin semiscalcium XII obtained using a conventional copper anode X-ray generator.

SUMMARY OF THE INVENTION

The present invention provides novel semi-calcium solvates and hydrates of atorvastatin.

The present invention provides a novel crystalline form of atorvastatin semi-calcium, designated Form VI, and novel processes for its preparation.

In another aspect, the present invention provides atorvastatin semi-calcium labeled

Form VIII, a new crystalline form and new ways of obtaining it.

In another aspect, the present invention provides atorvastatin semi-calcium labeled

Form IX, a new crystalline form and new ways of obtaining it.

In another aspect, the present invention provides atorvastatin semi-calcium labeled

Form X, a new crystalline form and new ways of obtaining it.

In another aspect, the present invention provides atorvastatin semi-calcium labeled

Form XI, a new crystalline form and new ways of obtaining it.

In another aspect, the present invention provides a novel crystalline form of atorvastatin semi-calcium, designated Form XI, and novel processes for its preparation.

In another aspect, the present invention provides novel processes for preparing atorvastatin semi-calcium Form I.

In another aspect, the present invention provides novel processes for the preparation of atorvastatin semi-calcium Form II.

In another aspect, the present invention provides novel processes for the preparation of atorvastatin semi-calcium Form IV.

In another aspect, the present invention provides new ways of obtaining atorvastatin semi-calcium V-form.

In another aspect, the present invention provides novel processes for the preparation of amorphous atorvastatin semi-calcium.

In another aspect, the present invention provides compositions and dosage forms comprising atorvastatin semi-calcium forms VI, VII, VIII, IX, X, XI and mixtures thereof.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Some semi-calcium crystalline forms of atorvastatin of the present invention exist in the solvated state and the hydrated state. Hydrates were analyzed by Karl-Fisher and thermogravimetric analysis.

X-ray powder diffraction (MRSD) analysis using conventional CuK _a radiation was performed using methods known in the art using a SCINTAG powder X-ray diffractometer model X'TRA with a solid detector. Copper radiation λ = 1.5418 A. Measurement range: 2-40 degrees 20. The sample was placed using a standard round aluminum holder with a round, zero-base quartz plate at the bottom. The powdered specimens were carefully lowered and filled into the round cavity of the specimen holder by pressing against a glass plate.

MRSD analysis using a synchrotron X-ray source was performed at the Brookhaven National Loratory National Synchrotron Light Source (diffractometric station Χ3Β1). Samples were freely placed in thin-walled glass capillaries. The X-ray emission was approximately 1.15 A. Since the incident wavelength corresponds to the wavelength commonly used in conventional MRSD analysis, the X-ray peak positions in the diffraction patterns obtained from the synchrotron source are expressed in terms of d time intervals that are constant during X-ray travel. wavelength used to obtain the model. The linear width of the scatter was from 1 to 20 degrees 20. The spectrum fragmentation ranges from 0.01 to 0.03 degrees of full linear width at half max. The positions of the scattered peaks are given within 0.003 to 0.01 degrees.

CP / MAS ¹³ C NMR measurements were made at 125.76 MHz using a Bruker DMX-500 digital FT NMR spectrometer equipped with a BL-4 CP / MAS measuring head and a high resolution / high performance ¹ H solid state amplifier : rotation speed 5.0 kHz, SELTICS pulse sequence, sample holder: 4mm diameter zirconia rotor.

The semi-calcium form VI of atorvastatin is characterized by a powder X-ray diffraction pattern (Fig. 1) having 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 du-theta. The most characteristic peak is obtained at 19.5 ± 0.2 degrees two theta. The Form VI MRSD model was obtained using a Philips diffractometer similar to the SCINTAG apparatus described above.

Semi-calcium form VI of atorvastatin can be obtained by dissolving any other semi-calcium form of atorvastatin, preferably Form I in acetone and then precipitating

Form VI by adding an anti-solvent, preferably water.

The semi-calcium form VII of atorvastatin is characterized by a powder X-ray diffraction pattern (Fig. 2) having two clear peaks, one ranging from 18.5 to 21.8 degrees and the other from 21.8 to 25.0 degrees 2Θ, and other additional clear peaks at 4.7; 7.8; 9.3; 12.0; 17.1; 18.2 ± 0.2 degrees 20.

Form VII specimens may contain up to 12% water.

Form VII readily differs from known semi-calcium forms of atorvastatin at distinct peaks at 7.8 and 9.3 ± 0.2 degrees 20. For example, Form I has peaks at 9.2; 9.5; 10.3; 10.6; 11.0 and 12.2 degrees 20 according to the information in U.S. Pat. 5969156. In this area, Form II has two sharp peaks at 8.5 and 9.0 degrees 20 and Form IV has one strong peak at 8.0 degrees 20. Other clear peaks at 15-25 degrees in area 20 distinguishes Form VII from other forms. Forms I, III and IV have sharp peaks in this area.

Atorvastatin Semi-Calcium Form VII may be prepared by treating Form I or V atorvastatin calcium with ethanol, preferably pure ethanol, at room temperature to reflux for 1 hour. up to about 24 hours, preferably 2.5-16 hours. period. If the process is carried out in deflated EtOH, the conversion is complete after about 2.5 hours. If the process is carried out at room temperature, a longer period is required.

The semi-calcium form VIII of atorvastatin is characterized by a powder X-ray diffraction pattern (Fig. 3) obtained using conventional CuK _o radiation and 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 (clear), 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 20. Kari Fisher found that atorvastatin semi-calcium Form VIII specimens could contain up to 7% water. Form VIII is readily distinguished from Form I-IV by a characteristic sharp peak at 9.3 and 9.6 degrees 20. According to the information disclosed in U.S. Pat. 5969156, Form I has one mean peak at 6.9 and a sharp peak at: 9.2; 9.5; 10.3; 10.6; 11.0 and 12.2 ± 0.2 degrees 20. It is noted that Form IV may have two peaks at 8.0 and 9.7 degrees 20. It is noted that Form II may have two sharp peaks at 8.5 in this area. and Form 9.0 20. Form III in this field has one strong sharp peak at 8.7 degrees 20 according to the information disclosed in U.S. Pat. 6121461. Properties of the MRSD model of Form VIII are not marked. In addition, the Form VIII MRSD model has one sharp, moderate intensity peak at 7.0, which easily distinguishes it from other peaks in the field. Comparison of the Form VIII MRSD model with the Form I-IV models demonstrates that this feature of Form VIII is exceptional.

Other peaks of the Form VIII pattern that are specific to this form are two strong and sharp peaks at 19.2 and 20.0 degrees 20. In this area, Form I has sharp peaks at 21.6; 22.7; 23.3 and 23.7 degrees 20 according to the information disclosed in U.S. Pat. '156. Form IV is noted to have peaks at 18.4 and 19.6 degrees 20, while Form II has two major peaks at 17.0 and 20.5, and Form III 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 with Form VIII to determine its crystalline system and unit cell dimensions. Form VIII has a monoclinic unit cell with crystalline lattice dimensions: a = 18.55-18.7 A, b = 5.52-5.53 A, c = 31.0-31.2 A and β angle between a and c axes 97.5-99.5 °. Unit cell parameters were determined using the Le Bail method.

FIG. The diffractogram 4 obtained using a synchrotron X-ray source has many sharp, well-fragmented peaks. Some of the more notable peaks c / -intervalai are listed in Table 1, followed by two-theta positions in units, which have peaks, with 1,541 δΑ Cuk _ff radiation.

Table

d (A) 20th 30.81 2.87 18.46 4.79 16.96 5.21 15.39 5.74 14.90 5.93 12.78 6.92 11.05 8.00

continuation of the table

d (A) 2Θ 9.58 9.23 9.22 9.59 7.42 11.93 6.15 14.40 5.43 16.32 4.62 19.21 4.44 20.00 3.98 22.34

^{a is} calculated from the d radiation of CuK ₀

Due to the natural deviation between the independent samples and the measurements, the positions of the peaks may not deviate from the positions shown by more than 0,5% of d. There may be greater shifts if the material undergoes a granulometric reduction such as micronization.

The semi-calcium form VIII of atorvastatin resulted in the solid state ¹³ C NMR spectrum shown in Figs. 5. Form VIII is characterized by the following chemical shifts in solid state ¹³ C nuclear magnetic resonance, in millions: 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 VIII is characterized by a solid state ¹³ C nuclear magnetic resonance having the following chemical shift differences between the lowest millions. 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 recorded chemical shifts of Form VIII are averaged from the spectrum taken from the four samples of Form VIII. Characteristic parts of the model were found at 24-26 million. (aliphatic index), 119-140 million. (aroma indicator) and other areas. The displacement values are within ± 0.1 million d. with the exception of the carbonyl peak at 178.8 million d, which has a fluctuation of ± 0.4 million d.

Semi-calcium form VIII of atorvastatin may exist as an ethanol solvate containing up to about 3% by weight ethanol.

The following methods suitable for obtaining Form VIII were discovered. However, this form can also be obtained by empirical investigation and routine modification of these procedures.

Form VIII of atorvastatin semi-calcium can be obtained by dispersing atorvastatin semi-calcium in a mixture of ethanol and water at elevated temperature, preferably about 78-80 ° C. The dispersion procedure can be incorporated into the final step of the atorvastatin semi-calcium production process, which is typically the production of a semi-calcium salt from atorvastatin free acid or lactone by acting as a source of calcium ion in this combined procedure in a solvent system containing ethanol and water. Accordingly, after precipitating the atorvastatin semi-calcium salt with additional water, the salt may be dispersed in the reaction mixture for several hours, preferably about 6 to about 16 hours, to obtain atorvastatin semi-calcium Form VIII.

Form VIII may also be obtained starting from Form V, by reacting Form V with EtOH / H 2 O, preferably in a ratio of about 5: 1, at elevated temperature, below reflux temperature, preferably at 78-80 ° C. Particular preference is given to a mixture of EtOH: H2O containing 4% v / v water in ethanol. During heating, the V-form of atorvastatin gradually dissolves at 78-80 ° C to give a cloudy solution, with or without particles. At this point, the suspension is immediately cooled to room temperature.

Form VIII can be obtained by treating atorvastatin semi-calcium with EtOH, preferably pure EtOH, at a higher temperature, preferably boiling EtOH. Under these conditions, atorvastatin dissolves and re-precipitates. MeOH can be added under reflux. The addition of MeOH may adversely affect the yield but may improve the chemical purity of the product. The starting materials for the preparation of Form VIII by this method may be crystalline forms of atorvastatin semi-calcium, preferably forms I and V and mixtures thereof, or amorphous atorvastatin semi-calcium.

The amount of EtOH or its mixture with water is preferably in the range of about 10 to about 100 ml g ' ¹ , more preferably about 20 to about 80 ml g' ¹ .

We have discovered that atorvastatin semi-calcium which contains more than 0.1% des-fluoro atorvastatin semi-calcium and / or more than 1% trans atorvastatin semi-calcium can be purified by suspension in about 96% ethanol and about 4% aqueous solution. at higher temperatures, preferably at reflux. Typically, atorvastatin semi-calcium is recovered with less than 0.07% contamination with des-fluoro atorvastatin semi-calcium and with less than 0.6% trans atorvastatin semi-calcium.

Form VIII may also be prepared by suspending atorvastatin semi-calcium in certain 1-butanol / water and ethanol / water mixtures for a time sufficient to cause conversion of atorvastatin semi-calcium to Form VIII 1butanol / water mixtures may contain about 20% by volume of 1-butanol temperature, preferably reflux.

Semi-calcium form IX of atorvastatin is characterized by a powder X-ray diffraction pattern (Figure 5) having 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 can contain up to 7% water. Form IX may also exist as a butanol solvate having up to about 5% butanol.

Form IX is readily distinguished by its characteristic sharp peaks at: 18.6; 19.1; 19.9; 21.4; 22.5; 23.5 degrees 2Θ. In comparison, Form I has sharp peaks at: 21.6; 22.7; 23.3 and 23.7 degrees 2Θ, while Form IV in this area has sharp peaks at 18.4 and 19.6 degrees 2Θ and Form II has two major peaks at 17.0 and 20.0 degrees 2Θ, respectively, according to the information provided. U.S. Pat. '156. Form III in this area has peaks at: 17.7; 18.3; 18.9; 20.0 and 20.3 degrees 20. Also, the Form IX MRSD model and the Form VIII model have a sharp, easily distinguishable mid-peak at 7.0 degrees 20.

The crystalline system of Form IX and the unit cell dimension were defined using synchrotron powder X-ray diffraction analysis. Form IX has a monoclinic crystalline lattice with lattice dimensions: a =

18.75–18.85 A, b = 5.525–5.54 A, c = 30.9–31.15 A, and angle β between the a and c axes of 96.5–97.5 °.

The d-ranges of some of the most prominent peaks in the synchrotron powder X-ray diffractogram are shown in Figs. 7 are listed in Table 2 next to the units with two-theta positions that the peaks would have using naudojantυΚ _σ radiation.

Table

d (A) 2Θ 30.86 2.86 18.67 4.73 16.91 5.23 15.17 5.83 12.66 6.98 11.20 7.89 9.50 9.31 9.28 9.53 8.63 10.25 7.69 11.51 7.38 11.99 6.51 13.60 5.45 16.26 5.26 16.86 5.20 17.05 5.12 17.32 4.87 18.22 4.76 18.64 4.63 19.17 4.47 19.86 4.14 21.46 4.08 21.78 3.78 23.54 3.73 23.86 3.62 24.59

continuation of the table

d (A) 2Θ 3.58 24.87

^{a is} calculated from the irradiance of d CuK _a

Due to the natural deviation between independent samples and measurements, the peak positions may deviate from the positions shown by up to 0.5% of d values. There may be greater shifts if the material undergoes a granulometric reduction such as micronization.

The semi-calcium form IX of atorvastatin resulted in a solid state ¹³ C NMR spectrum shown in Figs. 8. Form IX is characterized by the following chemical shifts in solid state ¹³ C nuclear resonance million: 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 IX is characterized by a solid state ¹³ C nuclear resonance having differences in chemical shifts between the lowest milliond. 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 model are set at 24-26 million. (aliphatic index), 119-140 million d. (aroma indicator) and other areas. Form IX chemical shifts are averaged from the spectrum of Form IX two samples. The displacement values are within ± 0.1 million d. accuracy.

Form IX can be obtained by the following methods, but this form can also be obtained by empirical study and conventional modification of these techniques.

Form IX of atorvastatin semi-calcium can be obtained by suspending atorvastatin semi-calcium in butanol and separating Form IX, for example by filtration or decanting of butanol, preferably filtration. The solvent has better temperature variations for dispersion from 78 ° C to reflux. The recovery of the atorvastatin semi-calcium salt from the suspension mixture may be enhanced by adding an anti-solvent to the suspension mixture before separating Form IX. Anti-solvents containing isopropanol and n-hexane are preferred. The starting materials for the preparation of Form IX by this method may be crystalline or amorphous atorvastatin semi-calcium, preferably Form I and Form V, and mixtures thereof.

Form IX can be obtained by suspending Form VIII from ethanol, preferably pure ethanol, at room temperature for a period sufficient to convert Form VIII to Form IX, which may range from a few hours to 24 hours and generally requires about 16 hours. Form IX is then recovered from the suspension. Form IX can also be obtained by storing Form VIII in a humid environment.

Form IX may also be prepared by suspending the semi-calcium Form V atorvastatin in 1-butanol and either ethanol or water at reflux for a period sufficient to convert Form V to Form IX and recovering Form IX from suspension. Mixtures containing about 50% by volume of each component are preferred.

The semi-calcium X form of atorvastatin is characterized by a powder X-ray diffraction pattern (Figure 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 2Θ. The most characteristic peaks are the two peaks at: 20.0 and 20.8 ± 0.2 degrees 2Θ and the other peaks at: 19.1; 19.4; 22.8; 23.6; 25.0; 28.0; 30.0 ± 0.2 degrees 2Θ. Form X contains up to 2% ethanol and can contain up to 4% water.

Form X differs from Form IV in that it has characteristic peaks at: 7.0; 19.9; 20.7; 24.1; 25.0; 28.0 and 30.3 ± 0.2 degrees 2Θ. These features are clearly distinguished from the corresponding domains arising from the previously described MRSD forms I-IV.

The X-shaped crystalline system and unit cell dimension were defined using synchrotron powder X-ray diffraction analysis.

Form X has a monoclinic crystalline lattice with lattice dimensions: a ~ 18.55-18.65 A, b = 5.52-5.53 A, c = 30.7-30.85 A and angle β between a and c axes 95.7-96.7 °.

X-ray powder diffraction patterns of synchrotron powder FIG. 10 some of the most raised peak c / -intervalai are listed in Table 3, next to the two-theta positions of the units, which have peaks using Cuk _ff radiation.

Table

d (A) 2Θ 30.63 2.88 18.49 4.78 16.66 5.30 15.12 5.85 12.49 7.08 11.19 7.90 10.20 8.67 9.38 9.43 9.24 9.57. 9.13 9.69 8.58 10.31 7.64 11.58 7.36 12.02 7.26 12.19 6.81 13.00 6.50 13.62 6.16 14.38 5.91 14.99 5.24 16.92 5.19 17.08 5.06 17.53 4.86 18.25 4.74 18.72 4.05 19.09 4.61 19.25 4.56 19.47 4.12 21.57 4.10 21.95 4.10 21.95

continuation of the table

d (A) 20th 3.93 22.62 3.90 22.80 3.77 23.60

° calculated from d CuK ₀ radiation

Due to the natural deviation between independent samples and measurements, the positions of the peaks may not deviate by more than 0,5% from the positions given. There may be greater shifts if the material undergoes a granulometric reduction such as micronization.

The semi-calcium X-form of atorvastatin resulted in a solid state ¹³ C NMR spectrum shown in Figs. 11. Form X is characterized by the following chemical shifts in solid state ¹³ C nuclear resonance million: 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 ¹³ C nuclear magnetic resonance having the following chemical shifts between the lowest resonance and the next resonance: 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 model are set at 24-26 million. (aliphatic index), 119-140 million d. (aroma indicator) and other areas. The X-shaped chemical shifts are averaged from three spectra taken from the X-shaped three samples. The displacement values are within ± 0.1 million d. with the exception of the carbonyl peak at 179.3 milliond, which is represented by ± 0.4 milliond. accuracy.

The X-form of atorvastatin semi-calcium can be obtained by reacting crystalline atorvastatin semi-calcium, preferably Form V or Form I, or mixtures thereof, or amorphous atorvastatin semi-calcium with a mixture of ethanol and water, preferably 5: 1, at elevated temperature, preferably reflux. from about half an hour to several hours, preferably about 1 \ Ί hours. period. starting material may be added to EtOH at room temperature, followed by gradual heating of the suspension to reflux. Alternatively, atorvastatin semi-calcium in its original form may be added to the deflegmable solvent mixture. Alternatively, atorvastatin semi-calcium may be obtained by dissolving in the mixture and then re-precipitating in X form. The ratio of the atorvastatin semi-calcium to EtOH: water mixture is preferably about 1:16 to about 1:25 (g: ml), more preferably about 1:16 to about 1:21 (g: ml) and most preferably about 1:16. (g: ml). The Form X may be concentrated by brief filtration after cooling to room temperature, or the suspension may be stirred for an additional period of about 1 to about 20 hours, preferably about 3 to about 16 hours, before the Form X is concentrated.

The semi-calcium form IX of atorvastatin is characterized by a powder X-ray diffraction pattern (Fig. 9) having peaks at: 3.2; 3.7; 5.1;

6.3; 7.8; 8.6; 9.8; 11.2; 11.8; 12.4; 15.4; 18.7; 19.9; 20.5; 24.0 ± 0.2 degrees two theta.

Form XI can be obtained by suspending atorvastatin semi-calcium Form V in methyl ethyl ketone ("MEK") at room temperature for a time sufficient to induce a Form V conversion to Form XI.

Form XI can also be obtained by preparing a gel containing atorvastatin in semi-calcium isopropyl alcohol followed by drying the gel. The gel is best prepared by saturating isopropyl alcohol with atorvastatin semi-calcium at reflux and then cooling to room temperature. Extensive agitation for up to or more than 20 hours may be required to form the gel. In the gel state, the solution is more difficult to mix and heterogeneous when pouring. The gel remains flowing in the sense that it can be mixed if sufficient force is applied and does not tear when applied.

Atorvastatin Semi-Calcium Form XII 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 du-theta, and halo, which indicates amorphous material. Typical X-ray powder diffraction patterns of atorvastatin semiscalcium XII powder are shown in Figs. 10th

Form XII can be obtained directly from the following compound:

whose systemic chemical name is [R- (R *, R *)] - 2- (4-fluorophenyl) - N - dioxan-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] - 1 H-Pyrrole-1-tert-butylheptane ester and which will later be referred to as the pyrrole acetonide ester or PAE. Form XII is obtained by first introducing PAEs under conditions which cleave the acetonide and tert-butyl ester group. Aqueous hydrochloric acid, preferably about 1.5% aqueous hydrochloric acid, is used under the conditions described. Thereafter, the atorvastatin solution, in the form of any free acid or lactone, or a mixture thereof, is treated with calcium hydroxide, preferably in a slight excess, more preferably about 1.5 equivalents of PAE. After the association of atorvastatin with the dissolved calcium obtained from the added hydroxide salt, any excess calcium hydroxide can be separated by filtration. One important feature of this process is the continued operation of the filtrate. water is slowly added to the reaction mixture at a slightly elevated temperature, preferably about 65 ° C, until atorvastatin semi-calcium precipitates. At this point, the temperature is raised until a clear solution is obtained again. The mixture is then allowed to cool until a semi-calcium precipitate of atorvastatin is formed. The precipitate isolated is a Form XII semi-calcium atorvastatin.

The present invention also provides novel processes for the preparation of known semi-calcium forms of atorvastatin.

Form I may be prepared by treating any of the atorvastatin semi-calcium forms with water at room temperature up to 100 ° C for a period of from several to about 25 hours, preferably about 16 hours. The following starting materials are preferred: Semi-Calcium Forms V, VII, VIII, IX and X of Atorvastatin.

Form I can also be obtained by ultrasonically crushing a suspension of atorvastatin semi-calcium in ethanol, preferably pure ethanol or water, between room temperature and reflux for a few minutes. Preferably between 1 and 3 minutes. Atorvastatin Semi-Calcium Form VII is preferred as the starting material, although other forms may also be used.

Form II can be directly obtained from [R- (R *, R *)] - 2- (4-fluorophenyl) -0,? $ Dioxan-5- (1-methylethyl) -3-phenyl-4 - [( phenyla m ino) ka rbon ii] -1 H -pyrrolo-1-tert-butyl heptane ester (PAE) according to Example 31.

Form IV of atorvastatin semi-calcium may be obtained by suspending Form I or Form V in 1-butanol for a time sufficient to complete conversion of Form I to Form V and subsequent separation of Form IV from the mixture. Conversion may require a long period depending on temperature and other conditions. The conversion usually takes about 24 to 72 hours at room temperature.

Form IV may also be obtained by suspending Form V in EtOH / H ₂ O for 50 ° C sufficient to cause conversion of Form V to Form IV and subsequent recovery of Form IV from suspension. Mixtures of EtOH / H ₂ O containing approximately 15% H ₂ O are listed.

Form IV may also be obtained by suspending the semi-calcium form V of atorvastatin in methanol for a time sufficient to cause conversion of Form V to Form IV. The conversion rate is temperature sensitive and can take from about 1 to about 25 hours under normal laboratory conditions. Conversion requires approximately 16 hours at room temperature. The conversion can be carried out at a higher temperature of the solvent to reflux.

Form V may be obtained from PAE according to the method described in the preparation of Form XII atorvastatin semi-calcium. Form V can be obtained by drying Form XII at about 65 ° C for about 24 hours. The semi-calcium V-form of atorvastatin thus obtained is of high purity. However, it can be further purified by suspending in a mixture of about 10% water and about 90% ethanol.

Amorphous atorvastatin semi-calcium can be obtained by treating any other form of atorvastatin semi-calcium with acetone at room temperature to reflux for a few hours to 25 hours, preferably about 16 hours. The specified starting material is a Form V.

Amorphous atorvastatin semi-calcium can also be obtained by sonication of any atorvastatin semi-calcium form in acetonitrile at any temperature between room temperature and acetonitrile reflux. Ultrasound for a few minutes, preferably up to 3 minutes, is sufficient to convert the starting material into amorphous atorvastatin semi-calcium. Initial forms of atosvastatin semi-calcium are of the forms VII and I.

Amorphous atorvastatin semi-calcium can also be obtained by ball milling any crystalline form of atorvastatin semi-calcium.

Another aspect of the present invention is a pharmaceutical composition and a dosage form containing novel forms of atorvastatin semi-calcium.

Compositions of the invention include powders, granules, aggregates and other solid compositions containing atorvastatin semi-calcium novel VI, VII, VIII, IX, X,

Forms XI and XII. In addition, the solid compositions of Form VI, VII, VIII, IX, X, XI and XII of the present invention may additionally contain diluents such as cellulose-derived materials such as powdered cellulose, microcrystalline cellulose, micro-fine cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose salts and other substituted or unsubstituted celluloses; starch; gelatinized starch; inorganic diluents such as calcium carbonate and calcium diphosphate; and other diluents known in the pharmaceutical industry. Still other suitable diluents include waxes, sugars, sugar alcohols such as mannitol and sorbitol, polymers and copolymers of acrylates, as well as pectins, dextrins and gelatin.

Other excipients contemplated by the present invention include binders such as acacia gum, gelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression techniques. The excipients, which may also be in the solid formulation of atorvastatin semi-calcium forms VI, VII, VIII, IX, X, XI and XII, further include disintegrating agents such as sodium starch glycollate, crospovidone, low-substituted hydroxypropyl cellulose and the like. Additionally, the excipients may include tableting fats such as magnesium and calcium stearate and sodium stearyl fumarate; flavorings and flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and lubricants such as silica.

Doses include oral, buccal, rectal, parenteral (including subcutaneous, intravenous, and intravenous), inhalation, and ocular administration. Although the preferred route of administration in any given case would depend upon the nature and specificity of the operating conditions, the preferred route of administration of the present invention is the oral dose. The doses may conveniently be presented in unit dosage form and may be prepared by any of the methods well known to those skilled in the art.

Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, suckable tablets, lozenges, as well as suspensions and elixirs. Since the description is not intended to be limiting, the invention is not intended to be related to authentic atorvastatin semi-calcium solutions, which results in the loss of properties that give atorvastatin semi-calcium solid forms. Thus, the present invention contemplates the use of novel forms for the preparation of such solutions (e.g., in addition to atorvastatin, the said solution is administered in a certain ratio to the solvate).

The capsule dosages will, of course, contain a solid composition within the capsule, which may be made from gelatin and other common ingredients contained in the capsule. The tablets and powder may be coated. The tablets and powder may be coated with a enteric coating. The enteric-coated coated powder may have coatings containing phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethyl ethyl cellulose, styrene-maleic acid copolymer, methacrylic acid and methyl methacrylate, if desired, use with suitable plasticizers and / or fillers. The coated tablet may have a coating on the tablet surface, or it may be a capsule containing a powder or granules with an enteric coating.

Unit dosage forms of the pharmaceutical compositions of this invention typically contain from 0.5 to 100 mg of novel atorvastatin semi-calcium forms VI, VII, VIII, IX, X, XI and XII or mixtures thereof with one another or with other atorvastatin semi-calcium forms. More often, the unit dose of atorvastatin semi-calcium forms is 2.5 mg to 80 mg.

In the various aspects of the present invention described below, the following examples are provided to illustrate specific embodiments of the present invention. In any case, they are not intended to be a restriction.

EXAMPLES

General

Pure ethanol with less than 0.2% water was purchased from Biolab®. Other reagents were of analytical purity and were used as received.

Ball milling was performed using a Retsch centrifugal ball mill S-100 equipped with a 250 ml stainless steel mill chamber and twenty-seven 10 mm diameter stainless steel balls as a milling medium.

(Preparation of Atorvastatin Semi-Calcium Form VI)

An example

Atorvastatin Semi-Calcium Form 1 (1 g) was dissolved in acetone (9 mL) at room temperature and stirred for 2.5 h. Water (8.5 mL) was then added to obtain a precipitate and the mixture was stirred for a further 2.5 hours. The white solid was then filtered off and dried at 50 ° C for 5 hours to give atorvastatin semi-calcium Form VI (0.88 g, 88%).

(Preparation of Atorvastatin Semi-Calcium Form VII)

An example

Semi-calcium form V atorvastatin (1.00 g) was stirred in pure EtOH (400 mL) at room temperature for 16 h. The solid was isolated by filtration and dried at 65 ° C for 24 h to give atorvastatin semi-calcium Form VII (40 mg, 40%).

An example

Semi-calcium Form I atorvastatin (75 mg) was stirred in pure EtOH (30 mL) at room temperature for 16 h. The solid was isolated by filtration and dried at 65 ° C for 24 hours to give atorvastatin semi-calcium Form VII (0.60 g, 80%).

(Preparation of Atorvastatin Semi-Calcium Form VIII) Example 4 [Magnetic stirrer flask 1.0 g (1.59 x ^{10 3} mol) [R - (R *, R *)] - 2- (4-fluorophenyl) -?, J-dioxane -5- (1-Methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrolo-1-tert-butylheptane ester was added to a suspension in 90% aqueous acetic acid (10 mL). The reaction mixture was heated to 50 ° C for three hours and then stirred at room temperature until the reaction was complete as determined by HPLC (high performance liquid chromatography). The solvent was evaporated and traces of acetic acid were removed by azeotropic distillation with toluene (3x100 mL) to give an oil with slight toluene. This oil was dissolved in EtOH (10 mL) and water (2 mL). 5.5 equivalents (8.4x10 ³ mol, 622 mg) of Ca (OH) 2 and tetrabutyl ammonium bromide (5% 0.05 g) were then added. The reaction mixture was heated to 50 ° C for 5 hours before completion of the reaction by HPLC. The hot filtrate was then placed in a vacuum to remove excess Ca (OH) ₂ . The reaction mixture was then cooled to room temperature. Water (50 mL) was added to this solution during stirring. The white precipitate was stirred at room temperature at RT (reflux) overnight, filtered under vacuum and dried at 65 ° C for 18 hours to give 145 mg (16%) of atorvastatin semi-calcium Form VIII.

An example

Semi-calcium Form I atorvastatin (1 g) was dispersed in pure EtOH (80 mL) at reflux for 24 h. The white solid was then filtered off and dried at 65 ° C for 20 hours to give atorvastatin semi-calcium Form VIII (0.85 g, 85%).

An example

Semi-calcium Form I atorvastatin (1 g) was added to boiling pure EtOH (40 mL). The compound first dissolved and then precipitated again. MeOH (20 mL) was added to this mixture. The white solid was then filtered off and dried at 50 ° C for 20 h. in a vacuum oven to obtain atorvastatin semi-calcium form VIII (188 mg, 19%).

An example

A suspension of 1.0 g of atorvastatin semi-calcium salt in 1-butanol (4 mL) and H2O (16 mL) was heated to reflux for 1 h. The mixture was then cooled to room temperature and stirred at this temperature for an additional 16 h. The solid was filtered off and dried in a 50 ° C vacuum oven for 16 hours to give 0.9 g (91%) of the atorvastatin semi-calcium salt of Form VIII.

An example

5.0 g of atorvastatin semi-calcium salt V-form was added to a boiling solution of ethanol 96% (150 ml). The mixture was kept at reflux for 2.5 hours. It was then cooled to 20 ° C for 1.5 hours. and stir at this temperature for an additional 16 hours. The solid was filtered off, washed with ethanol 96% (2 x 25 mL) and dried at 65 ° C for 20 h to give 4.4 g (88%) of the atorvastatin semi-calcium salt form VIII. This process involves chemical purification, so this method is also suitable for purification.

An example

5.0 g of atorvastatin semi-calcium salt V-form containing 0.12% desfluoro atorvastatin was added to a boiling solution of ethanol 96% (150 ml). The mixture was kept at reflux for 2.5 hours. It was then cooled to 20 ° C for 1.5 hours. and stir at this temperature for an additional 16 hours. The solid was filtered off, washed with ethanol 96% (2 x 25 mL) and dried at 65 ° C for 20 h to give 4.4 g (88%) of atorvastatin semi-calcium salt containing 0.06% des-fluoro atorvastatin. Atorvastatin is thus obtained in Form VIII.

An example

Semi-calcium form V atorvastatin (5 g) in pure ethanol was refluxed for 2.5 hours. The reaction mixture was then cooled to room temperature and stirred for an additional 16 h. Pure ethanol (15 mL) was then added and the suspension was filtered and the solids were dried at 65 ° C for 20 h to give atorvastatin semi-calcium form VIII (4.7 g, 94%).

(Obtaining Atorvastatin Semi-Calcium Form IX)

An example

Atorvastatin semi-calcium Form 1 (1 g) was dispersed in 1-butanol (20 mL) at reflux for 30 minutes. The mixture was then cooled to room temperature. The white solid was then filtered and dried at 50 ° C in vacuo for 20 hours to give atorvastatin semi-calcium Form IX (0.94 g, 94%). KF = 0.9.

An example

Semi-calcium Form I (1 g) of atorvastatin was dispersed in 1-butanol (20 mL) at reflux for 30 minutes. Then, n-hexane (40 mL) was added for further precipitation and the reaction mixture was stirred at room temperature for 2 hours. The white solid was then filtered off and dried in a 50 ° C vacuum oven for 20 hours to give atorvastatin Form IX (0.96 g, 96%).

An example

Semi-calcium Form I (1 g) of atorvastatin was dispersed in 1-butanol (20 mL) at reflux for 30 minutes. IPA (40 mL) was then added for further precipitation and the reaction mixture was stirred at room temperature for 2 hours. The white solid was filtered off and dried at 50 ° C for 20 h. in a vacuum oven to obtain atorvastatin semi-calcium

Form IX (0.94 g, 94%) containing 0.9% moisture was determined by the Karl Fisher method.

An example

Semi-calcium form VIII (800 mg) of atorvastatin was stirred in pure EtOH (320 mL) at room temperature for 16 h. The solid was isolated by filtration and dried at 65 ° C for 24 hours to give atorvastatin semi-calcium Form IX (630 mg, 79%).

An example

A mixture of half-calcium V-form (2.00 g) of attovastatin and 1-butanol (40 ml) was kept at reflux at 118 ° C for half an hour. The mixture was then cooled to room temperature and stirred an additional 3 hours. The solid was then isolated by filtration and dried at 65 ° C for 24 hours to give atorvastatin semi-calcium Form IX (1.83 g, 92%).

An example

Semi-calcium form VIII of atorvastatin was stored at 100% relative humidity at room temperature for nine days. The resulting solid was identified as Form IX by powder X-ray diffraction analysis.

Example g Atorvastatin Semi-Calcium Salt V-Form 1-BuOH (10 mL) and H ₂ O (10 mL) was heated to reflux for 1 h. The mixture was then cooled to room temperature and stirred at this temperature for an additional 16 h. Filtration and drying at 65 ° C for 24 hours. 0.79 g (79%) of the atorvastatin semi-calcium salt of Form IX was obtained.

Example g Atorvastatin Semi-Calcium Salt V-Formated 1-BuOH (10 mL) and EtOH (10 mL) was heated to reflux for 1 h. The mixture was then cooled to room temperature and stirred at this temperature for an additional 16 hours. Filtration and drying at 65 ° C for 24 hours. 0.98 g (98%) of atorvastatin semi-calcium salt of Form IX was obtained.

(Preparation of Atorvastatin Semi-Calcium X)

An example

Semi-calcium Form V atorvastatin (10.00 g) was suspended in a mixture of EtOH (135 mL) and water (24 mL) and heated to reflux for 1 h. The mixture was then cooled to room temperature and stirred for an additional 16 h. The solid was isolated by filtration and dried at 65 ° C for 24 h to afford the atorvastatin semi-calcium X (8.26 g, 83%).

An example

Semi-calcium form V atorvastatin (1.00 g) in a mixture of EtOH (9 mL) and water (1.6 mL) was refluxed for 1 h. The mixture was then cooled to room temperature and stirred for an additional 3 hours. The solid was isolated by filtration and dried at 65 ° C for 24 hours to give atorvastatin semi-calcium X (0.80 g, 80%).

(Preparation of Atorvastatin Semi-Calcium Form XI)

An example

1.0 g of atorvastatin semi-calcium salt V-form was stirred in methylethyl ketone ("MEK") (5 ml) at room temperature for 24 hours. The solid was then filtered off, washed with MEK (2ml) and dried at 65 ° C for 20 hours to give 0.5 g (50%) of the atorvastatin semi-calcium salt of Form XI.

An example

A suspension of 1.0 g of atorvastatin semi-calcium salt in V-isopropyl alcohol ("IPA") (7 mL) was heated to reflux for 1 h. The mixture was then cooled to room temperature and stirred at this temperature for an additional 20 hours. A gelatin product was obtained. After addition of IPA (3 mL), the gel was filtered off and dried at 65 ° C for 20 hours to give 0.8 g (80%) of the atorvastatin semi-calcium salt of Form XI.

(Preparation of Atorvastatin Semi-Calcium Form XII)

Example of a cylindrical reactor with a distillation apparatus and a mechanical stirrer 20 g (30.6 mol) [R- (R *, R *)] - 2- (4-fluorophenyl) -?, D-dioxane-5- (1- methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrolo-1-tert-butylheptane ester (= pyrrole acetonide ester = PAE) was added to a suspension of 250 mL of pure ethanol and 50 mL of aqueous 1.5% hydrochloric acid. The reaction mixture was heated to 40 ° C for 9-11 hours while continuous distillation of the ethanol / acetone / water mixture under reduced pressure (500-600 mbar). Pure ethanol supplementation was performed every hour (35-40 mL). After 9-11 hours, the PAE was reduced to below 0.1% (by HPLC). Ca (OH) 2 (1.5 eq, 3.4 g) was added without further treatment. The reaction mixture was heated to 70 ° C for 4-5 hours. The excess Ca (OH) 2 was then isolated by filtration. into hot filtrate (65 ° C) was slowly added 350 ml of water (using a dosing pump) over a period of -1% at 65 ° C. Atorvastatin's semi-calcium salt precipitated during the addition of water. After the addition of water, the reaction mixture was heated to reflux (84 ° C) until the solution became clear. The mixture was then cooled to 20 ° C for 3 hours. and was stirred at this temperature for an additional 12-16 hours. The solids were then filtered to give a 45.0 crystalline form of the atorvastatin semi-calcium salt XII crystalline form.

(Obtaining a known Form I of atorvastatin semi-calcium)

An example

Atorvastatin Semi-Calcium Form V (1.00 g) was stirred in water (400 mL) at room temperature for 16 h. The solid was isolated by filtration and dried at 65 ° C for 24 hours to give atorvastatin semi-calcium Form I (0.7 g, 70%).

An example

The mixture of atorvastatin semi-calcium Form VII (10.00 g) in water (100 mL) was refluxed for 2 hours. The mixture was cooled to room temperature and stirred for an additional hour. The solid was isolated by filtration and dried at 65 ° C for 24 h to give atorvastatin semi-calcium Form I (9.64 g, 96%).

An example

Semi-calcium form VIII (800 mg) of atorvastatin was stirred in water (320 mL) at room temperature for 16 h. The solid was isolated by filtration and dried at 65 ° C for 24 h to give atorvastatin semi-calcium Form I (350 mg, 44%).

An example

Atorvastatin Semi-Calcium Form X (1.0 g) was stirred in water (400 mL) at room temperature for 24 h. The solid was isolated by filtration and dried at 65 ° C for 24 hours to give atorvastatin semi-calcium Form I (720 mg, 72%).

An example

Atorvastatin Semi-Calcium Form IX (750 mL) was stirred in water (300 mL) at room temperature for 24 h. The solid was isolated and dried at 65 ° C for 20 hours to give atorvastatin semi-calcium Form I (420 mg, 56%).

An example

Semi-calcium form VII of Atorvastatin (1.00 g) was stirred in pure EtOH (20 mL) at room temperature. The suspension was then placed in an ultrasonic wave generator for 1.5 min. (energy = 235 kJ, amp = 50%) to obtain a clear solution. After the addition of water (14 ml), a precipitate formed and the suspension was placed in an ultrasonic wave generator for 2 min. (energy = 3.16 kJ, amp = 50%) which resulted in the suspension becoming a gel. The gel was dried at 65 ° C for 20 hours to give atorvastatin semi-calcium Form I (0.50 g, 50%).

An example

Atorvastatin Semi-Calcium Form VII (1.00 g) was stirred in water (200 mL) at room temperature. The suspension was then placed in an ultrasonic wave generator for 2 min. (energy = 3.0 kJ, Amp. = 50%) which resulted in the suspension becoming a gel. The gel was dried at 65 ° C for 20 hours to give atorvastatin semi-calcium Form I (0.92 g, 92%).

(Obtaining a known Form II of atorvastatin semi-calcium)

An example

20g (30.6 mmol) of [R - (R 1 R *)] - 2- (4-fluorophenyl) -?,? 5-dioxan-5- (1-) was charged to a cylindrical reactor with a distillation apparatus and a mechanical stirrer. methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptane ester (= pyrrole acetonide ester = PAE) in a suspension of 135 ml of methanol and 7.6 ml of aqueous 10% hydrochloric acid. The reaction mixture was heated to 35 ° C for 3 hours while continuous distillation under reduced pressure (820 mbar) of a mixture of methanol, acetone and water. Methanol addition was performed every / 2 hours (35 mL). After 3 or. PAE levels dropped below 0.1% (by HPLC). Ca (OH) 2 (1.5 eq, 3.4 g), water (5 mL) and methanol (45 mL) were added without further treatment. The reaction mixture was heated to 70 ° C for 2 h. The excess Ca (OH) ₂ was then isolated by filtration and the Ca (OH) 2 plate was washed with methanol (2 x 10 mL). 300 ml of water (using a dosing pump) was slowly added to the filtrate over an hour at 65 ° C. When water was added, the atorvastatin semi-calcium salt precipitated. After the addition of water, the reaction mixture was heated to reflux (78 ° C) for 2 hours. The mixture was then cooled to 20 ° C for 3 hours. and was stirred at this temperature for an additional 20 hours.

The solid was then filtered off and dried at 65 ° C for 48 hours to give 1 µg, 9 (96%) of the atorvastatin semi-calcium salt II crystalline form. KF =

3.2%.

; Obtaining Known Form IV of Atorvastatin Semi-Calcium)

An example

Semi-calcium Form I atorvastatin (1.0 g) was stirred in 9 mL of 1-butanol at room temperature for 24 hours. The white solid was then filtered off and dried at 50 ° C in a vacuum oven for 16 hours to give 0.33 g (83%) of the atorvastatin semi-calcium salt form IV.

An example

Semi-calcium salt of atorvastatin Form V (1.0 g) was stirred in 20 mL of 1-butanol at room temperature for 72 hours. The white solid was then titrated and dried at 65 ° C in an oven for 20 hours to give 0.82 g (32%) of the atorvastatin semi-calcium salt form IV.

An example

Atcr-Statine Semi-Calcium Salt Form V (2.0 g) was stirred in EtOH (18 mL): water (3.2 mL) at 50 ° C for 1 h. The precipitate was then filtered off and dried at 65 ° C for 20 hours to give 1.60 g (80%) of atorvastatin semi-calcium salt Form IV.

An example

A mixture of semi-calcium V-form (2.0 g) and methanol (20 ml) was added at room temperature for 1 hour. The mixture was cooled to room temperature and stirred for an additional 16 hours. The solid was filtered off and dried at 65 ° C for 24 h to give a crude. : Form IV of tin calcium (1.37 g, 56%).

An example

A mixture of semi-calcium atheostatin V (1.00 g) in methanol (10 mL) was stirred at room temperature for 20 hours. The solid was isolated by filtration and dried at 65 ° C for 24 hours to give atorvastatin semi-calcium Form IV (0.25 g, 25%).

(Obtaining atorvastatin semi-calcium V-form)

An example

L c '' ^. 'Rini reactor to the distillation apparatus and a mechanical agitator was inserted M _J (30.6 mmol) of [R- (R *, R *)] - 2- (4-fluorophenyl) - / ?, <5 -dioxan-5- (1-methylethyl) -3-phenyl-4-ynylamino) carbonyl] -1H-pyrrole-1-tert-butylheptane ester (= pyrrole acetor ester = PAE) in a suspension of 250 ml of pure ethanol and 50 ml water. 1.5% hydrochloric acid. The reaction mixture was heated to 40 ° C for 9-11 h, until a total of ethanol, acetone and water was added: continuous distillation under pressure (500-600 mbar). Ethanol supplementation was performed hourly (35-40 mL). After 9-11 or. PAE level sum: below 0.1% (by HPLC). Without further treatment, j (OH) 2 (1.5 eq, 3.4 g) was added. The reaction mixture was heated to 70 ° C for 4-5 v. The excess Ca (OH) ₂ was then isolated by filtration. 350 ml of water (using a dosing pump) was slowly added to the hot filtrate (65 ° C) at 65 ° C over a period of -1 h. When water was added, atorvastatin semi-calcium salt was precipitated. After the addition of water, the reaction mixture was heated to reflux (84 ° C) until a clear solution was obtained. The mixture was then cooled to 20 ° C for 3 hours. and stir at this temperature for an additional 20 hours. The solid was then filtered to give 45.0 g of a wet scaffold of crystalline form XII crystalline form of atorvastatin semi-calcium salt. The solid was dried at 65 ° C for 24 hours to give 16.7 g (95%) of the semiscalcium salt of atorvastatin V in crystalline form. KF = 2.8% -6.6%.

(Method of purification of atorvastatin semi-calcium V)

An example

5.0 g of atorvastatin semi-calcium salt V-form (boiling aqueous solution of ethanol 90% (150 ml) was added. The mixture was refluxed for 2.5 h and then cooled to 20 ° C for 1.5 h and stirred at this temperature for an additional 16 h. The solid was then filtered off, washed with 90% (2 x 25 mL) ethanol and dried at 65 ° C for 20 h to give 3.4 g (68%) of the atorvastatin semi-calcium salt form V.

(Preparation of known amorphous atorvastatin semi-calcium)

An example

Semi-calcium form V atorvastatin (2.00 g) was stirred in acetone (14 mL) at room temperature in a sealed flask for 16 h. After 2 hours the mixture became clear. While stirring at room temperature, the solid precipitated out. The acetone was decanted and the solid was removed with a spatula and placed in a drying oven and dried at 65 ° C for 20 hours to give amorphous atorvastatin semi-calcium (1.85 g, 93%).

An example

Semi-calcium form VII of atorvastatin (1.00 g) was stirred in acetonitrile (20 mL) at room temperature. The suspension was then exposed to an ultrasonic wave generator for 2 min. (energy = 2.5 kJ, amp = 50%). After decanting the acetonitrile, the solid was dried at 65 ° C for 20 hours to give amorphous atorvastatin semi-calcium (0.71 g, 71%).

An example

Semi-calcium form I atorvastatin (1.00 g) was stirred in acetonitrile (20 mL) at room temperature. The suspension was then placed in an ultrasonic wave generator for 2 min. (energy = 2.5 kJ, amp = 50%). After decanting the acetonitrile, the solid was dried at 65 ° C for 20 hours to afford amorphous atorvastatin semi-calcium (0.71 g, 71%).

An example

Atorvastatin semi-calcium (108 g) and twenty-seven 10 mm diameter stainless steel mill balls were placed in a ball mill mill chamber. The chamber was weighed and the mill was balanced by weight. The mill was set to operate at 500 rpm with a mill reversing system for 0.5 hours. The resulting material was scraped from the chamber walls into the main mass and the mill restarted for 4 hours every 15 minutes. in the final cleaning of the formed material, the material was finally separated from the balls by sieving through a 300 µm sieve. The resulting material was analyzed by MRSD and found to be amorphous. The procedure was repeated using forms I, V and VIII of atorvastatin and in each case amorphous atorvastatin semi-calcium was obtained.

Claims (37)

DEFINITION OF INVENTION 1. Crystalline atorvastatin semi-calcium (form VIII) and its hydrates and solvates, characterized by the results of physical and spectroscopic analysis, selected from the group consisting of: (a) powder X-ray diffraction pattern produced using CuK _a -peak with a peak: 4.8; 5.2; 8.0; 9.2; 9.6; 19.0; 20.0; 24.0; and 29.0 ± 0.2 degrees two-theta; b) the powder X-ray diffraction pattern obtained using Cuk _ff radiation with peaks: 9.3; 9.6; 16.3; 19.2; 20.0; 21.6; 22.4; 23.9 ± 0.2 degrees two-theta; c) d -values of about 30.81; 18.46; 16.96; 15.39; 14.90; 12.78; 11.05; 9.58; 9.22; 7.42; 6.15; 5.43; 4.62; 4.44 and 3.98 angstroms; d) monocyclic unit cells with cell parameters: a = 18.5518.7 A, b = 5.52-5.53 A, c = 31.0-31.2 A and ap = 97.5-99.5 ° ; (e) Solid state cross-polarization / magic angle spin ¹³ C nuclear magnetic resonance spectrum with resonance: 24.8; 25.2; 26.1; 119.5; 120.1; 1Ž1.8; 122.8; 126.6; 128.8; 129.2; 134.2; 135.1; 137.0; 138.3 and 139.8 ± 0.1 ppm; and (f) solid state cross-polarization / magic angle spin ¹³ C nuclear magnetic resonance spectrum, where the chemical shifts between the lowest resonance and the other resonance are: 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; 93.2; 101.7; 102.3; 104.0; 105.0; 108.8; 111.0; 111.4; 116.4; 117.3; 119.2; 120.5; 122.0; 142.0; 148.6; 161.0 and 168.7 parts per million. 2. Atorvastatin semi-calcium and its hydrates and solvates according to claim 1, characterized by a powder X-ray diffraction pattern produced using CuK _o peak with 17.1 (bright), 24.7; 25.6; 26.5 ± 0.2 degrees two-theta in its powder X-ray diffraction pattern. Atorvastatin semi-calcium and its hydrates and solvates according to claim 1, characterized by solid state ¹³ C nuclear magnetic resonances: 17.8; 20.0; 40.3; 40.8; 41.5; 43.4; 44.1; 46.1; 70.8; 73.3; 114.1; 116.0; 159.8; 166.4; 178.8 and 186.5 ± 0.1 ppm. Atorvastatin semi-calcium and its hydrates and solvates according to any one of the preceding claims, wherein all particles are 100 microns or less in diameter, preferably all particles are 50 microns or less in diameter. Atorvastatin semi-calcium and its hydrates and solvates according to any one of claims 1 to 3, containing up to 7% water. Atorvastatin semi-calcium according to any one of claims 1 to 3, which is a trihydrate. Atorvastatin semi-calcium and its hydrates and solvates according to any one of claims 1 to 3 having up to about four moles of water. Atorvastatin semi-calcium and its hydrates and solvates according to any one of claims 1 to 3, containing up to 3% ethanol. Atorvastatin semi-calcium according to any one of claims 1 to 3, which is ethanclate. A process for preparing atorvastatin semi-calcium and its hydrates and solvates according to any one of claims 1 to 3, comprising the steps of: (a) suspending the atorvastatin semi-calcium in a mixture of ethanol and water for a time sufficient to convert Form V to Form VIII; and b) isolating the Form VIII from the suspension. ^{11 *} The process of claim 10, wherein the mixture is at least about 19 volumes of ethanol with about 1 volume of water. A process for preparing atorvastatin semi-calcium and its hydrates and solvates according to any one of claims 1 to 3, comprising the steps of: (a) suspending the atorvastatin semi-calcium in a mixture of ethanol and water for a time sufficient to convert atorvastatin semi-calcium to form VIII; and b) isolating the Form VIII from the suspension. The process of claim 12, wherein the mixture is a mixture of ethanol to water by volume of about 5: 1. The process of claim 12 or claim 13, wherein prior to isolation of Form VIII into the atorvastatin semi-calcium suspension, additional water is added to improve the isolation of Form VIII from the suspension. A process for preparing atorvastatin semi-calcium and its hydrates and solvates according to any one of claims 1 to 3, comprising the steps of: (a) suspending the semi-calcium V-form of atorvastatin in a mixture of water and a lower alcohol selected from the group consisting of 1-butanol and ethanol for a time sufficient to induce a Form V conversion, and b) isolating the atorvastatin semi-calcium form VIII from the suspension. The process of claim 15, wherein the mixture contains about 20% by volume of 1-butanol. The process of claim 15, wherein the lower alcohol is ethanol and the mixture contains about 4% water. A process for preparing atorvastatin semi-calcium and its hydrates and solvates according to any one of claims 1 to 3, comprising the steps of: (a) suspending atorvastatin semi-calcium in ethanol for a period sufficient to convert it to Form VIII; and b) isolating the Form VIII from the suspension. The method of claim 18, wherein the atorvastatin semi-calcium is selected from Form V, Form XII, and Form I. The process of claim 19, wherein the ethanol contains about 0.5% or less water, preferably about 0.2% or less water. A process according to any one of claims 18 to 20, comprising adding methanol to the suspension prior to isolation of Form VIII to improve the chemical purity of Form VIII isolated from the suspension. A process according to any one of claims 10 to 14 and 18 to 21, wherein the temperature of the suspension is raised before isolating Form VIII from the suspension. The method of claim 22, wherein the elevated temperature is about 78 to 80 ° C. A process for preparing atorvastatin semi-calcium having less than 0.1% des-fluorine atorvastatin semi-calcium, comprising suspending atorvastatin semi-calcium having more than 0.1% des-fluoro atorvastatin semi-calcium in about 96% ethanol and and about 4% water in the mixture, and isolating atorvastatin semi-calcium with less than 0.1% desfluoro atorvastatin semi-calcium. A process for preparing atorvastatin semi-calcium having less than 1% trans atorvastatin semi-calcium, comprising suspending atorvastatin semi-calcium having more than 1% trans atorvastatin semi-calcium in a mixture of about 96% ethanol and about 4% water and atorvastatin. release of semi-calcium with less than 1% trans atorvastatin semi-calcium. 26. Semi-Calcium Form VI of Atorvastatin and its solvates, characterized by its powdery X-ray diffraction pattern having peaks at: 8.7; 10.0; 12.5; 17.9; 19.5; 20.9; 22.4 ± 0.2 degrees 20. 27. Atorvastatin Semi-Calcium Form IX and its Hydrates characterized by its powder X-ray diffraction pattern having peaks: 19.1; 19.9; 21.4; 22.5; 23.5 ± 0.2 degrees 20. 28. Semi-Calcium Form X of Atorvastatin and its solvates having a powder X-ray diffraction pattern with sharp peaks: about 19.1 and 19.4 ± 0.2 degrees 20 and other peaks: 20.0 and 20.8 ± 0, Grade 2 20. 29. Semi-calcium form XI of atorvastatin and solvates thereof having a powder X-ray diffraction pattern having peaks: 3.2; 3.7; 5.1; 6.2; 7.8; 8.6; 9.8; 11.2; 11.8; 12.4; 15.4; 18.7; 19.9; 24.0 ± 0.2 degrees' 20. 30. Atorvastatin Semi-Calcium Form XII and its Solvates, characterized by its powder X-ray diffraction pattern having peaks at 8.0; 8.4; 11.2; 18.2; 19.0 ± 0.2 degrees 20. A process for the preparation of atorvastatin semi-calcium Form I comprising the steps of: (a) suspending any other semi-calcium form of atorvastatin in water for a period sufficient to convert the other form to Form I; and b) isolating farm I from the suspension. A process for the preparation of atorva'atine semi-calcium Form II comprising the steps of: a) [R- (R *, R *) - 2- (4-Fluorophenyl) -N, N-dioxan-5- (1-methylethyl) -3-phenyl-4'-phenylamino) carbonyl] -1H-pyrrole-1 suspension of the tert-butylheptane ester in methanol, b) [R- (R *, R *)] - 2- (4-Fluorophenyl) - N, N -dioxan-5- (1-methylethyl) -3-phenyl-4'-phenylamino) carbonyl] -1 H blocking the pyrrole-1-tert-butylheptane ester by adding hydrochloric acid to the suspension to form a solution of the arorvastatin ester derivatives in methanol, c) adding calcium hydroxide to the solution to form a solution of atorvastatin in semi-calcium methanol, (d) optionally removing any excess calcium hydroxide; and e) precipitating atorvastatin semi-calcium as form II from solution. 33. Method for the preparation of Atomastatin Semi-Calcium Form IV selected from: (I) comprising the steps of: a) atorvastatin calcium form I of a semi-suspension of 1-butanol is emitting ^r time sufficient to convert Form I and Form IV b) isolating farm IV from the suspension; (II) a process comprising the steps of: (a) suspending the semi-calcium V-form of atorvastatin in a mixture of ethanol and water for a time sufficient to convert the V-form into IV; and b)! isolating the form from the suspension; (III} method, which comprises the following steps: (a) suspending the semi-calcium V-form of atorvastatin in methanol for a time sufficient to convert the V-form to IV; and b) isolating the Form IV from the suspension. 34. Ato: A process for the preparation of orthatin semi-calcium V-form comprising the following beams: 3) r - (R *, R *)] - 2- (4-fluorophenyl) -N, 5-dioxan-5- (1-methylethyl) -3-phenyl-4 - [ ⁽ phenylamino) carbonyl] - Suspending the 1H-pyrrole-1-tert-butylheptanoic acid ester in ethanol, b) [R- (R *, R *)] -2- (4-Fluorophenyl) -phenyl, N-dioxan-5- (1-methylethyl) -3-phenyl-4'-3-ylamino) carbonyl] -1H- deprotecting the pyrrole-1-tert-butylheptane ester by adding hydrochloric acid to the suspension to form u'orvastatin lactone and R- (R *, R *)] - 2- (4-fluorophenyl) -? a solution of dihydroxy-5- (1-methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-tert-butylheptane in the ester in ethanol, c) adding a solution of k '' s hydroxide to form a solution of atorvastatin in cold calcium ethanol, d) precipitating atorvastatin semi-calcium from the solution; and e) drying the precipitated atorvastatin semi-calcium to obtain the atorvastatin semi-calcium form V. A process for purifying a semi-calcium V-form of atorvastatin comprising suspending the atorvastatin semi-calcium V-form in a mixture of ethanol and water and recovering the higher purity V-form from the mixture. 36. A process for the preparation of AmoCnio atorvastatin semi-calcium selected from: (I) A method comprising the steps of: (a) suspending atorvastatin semi-calcium crystalline in acetonitrile, (b) exposure of the suspension to ultrasonic waves for a time sufficient to convert the crystalline form into amorphous atorvastatin semi-calcium; and c) isolating the semiscalcium ε .crfic atorvastatin from the suspension; (II) a process comprising the steps of: a) contacting any crystalline form of atorvastatin semi-calcium with acetone for a time sufficient to convert the crystalline form of amorphous a'o'vastatin into amorphous semi-calcium; and b) separating the semi-calcium solid amorphous atorvastatin from acetone; A process (III) comprising the step of routinely grinding any semi-calcium crystalline form of atorvastatin. A pharmaceutical composition comprising atorvastatin semi-calcium VI, VIII, IX, X, XI X ^r oorią or mixtures thereof.