Novel Forms of [R-(R*,R*)]-2-(4-Fluorophenyl)-Beta, Gamma-Dihydroxy-5-(1-Methylethyl)-3-Phenyl-4-[(Phenylamino)carbonyl]-1H-Pyrrole-1-Heptanoic Acid Calcium Salt (2:1)

Abstract

Novel forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptatonic acid hemi calcium salt designated Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV, Form XXVI, Form XXVII, Form XXVIII, Form XXIX, and Form XXX, characterized by their X-ray powder diffraction, solid-state NMR, and/or Raman spectroscopy 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 (BPH) and Alzheimer's disease.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. A Form XXIV atorvastatin calcium having an X-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation: 2.9, 7.4, 7.8, 8.7, 9.5, 10.0, 12.2, 18.0, 18.6, 19.0, and 22.7.

5. (canceled)

6. (canceled)

7. (canceled)

8. A Form XXVIII atorvastatin calcium having an X-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation: 7.6, 9.5, 12.2, 16.5, 17.0, 18.0, 20.5, 21.5, and 22.3.

9. (canceled)

10. A Form XXX atorvastatin calcium having an X-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation: 3.1, 9.0, 9.7, 12.0, 16.5, 17.0, 20.9, 21.6, 22.5, and 24.3.

11. (canceled)

12. (canceled)

13. (canceled)

14. A Form XXVIII atorvastatin calcium having an X-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation: 7.6, 9.5, 20.5, and 22.3, and a solid state .sup.19F nuclear magnetic resonance having the following chemical shifts expressed in parts per million: −116.4, −117.1, and −119.2.

15. A Form XXX atorvastatin calcium having an X-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation: 3.1, 9.0, and 21.6, and a solid state .sup.19F nuclear magnetic resonance having the following chemical shifts expressed in parts per million: −116.7 and −118.6.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The invention is further described by the following nonlimiting examples which refer to the accompanying Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVII, XXIX, and XXX, short particulars of which are given below.

[0042] FIG. 1 Diffractogram of Form XX atorvastatin calcium carried out on a Shimadzu XRD-6000 diffractometer.

[0043] FIG. 2 Diffractogram of Form XXI atorvastatin calcium carried out on a Shimadzu XRD-6000 diffractometer.

[0044] FIG. 3 Diffractogram of Form XXII atorvastatin calcium carried out on a Shimadzu XRD-6000 diffractometer.

[0045] FIG. 4 Diffractogram of Form XXIII atorvastatin calcium carried out on a Shimadzu XRD-6000 diffractometer.

[0046] FIG. 5 Diffractogram of Form XXIV atorvastatin calcium carried out on a Shimadzu XRD-6000 diffractometer.

[0047] FIG. 6 Diffractogram of Form XXV atorvastatin calcium carried out on a Shimadzu XRD-6000 diffractometer.

[0048] FIG. 7 Diffractogram of Form XXVI atorvastatin calcium carried out on a Shimadzu XRD-6000 diffractometer.

[0049] FIG. 8 Diffractogram of Form XXVII atorvastatin calcium carried out on a Shimadzu XRD-6000 diffractometer.

[0050] FIG. 9 Diffractogram of Form XXVIII atorvastatin calcium carried out on a Bruker diffractometer.

[0051] FIG. 10 Diffractogram of Form XXIX atorvastatin calcium carried out on a Bruker diffractometer.

[0052] FIG. 11 Diffractogram of Form XXX atorvastatin calcium carried out on a Shimadzu XRD-6000 diffractometer.

[0053] FIG. 12 Small angle diffractogram of Form XX atorvastatin calcium.

[0054] FIG. 13 Small angle diffractogram of Form XXII atorvastatin calcium.

[0055] FIG. 14 Small angle diffractogram of Form XXIV atorvastatin calcium.

[0056] FIG. 15 Small angle diffractogram of Form XXV atorvastatin calcium.

[0057] FIG. 16 Small angle diffractogram of Form XXVII atorvastatin calcium.

[0058] FIG. 17 Small angle diffractogram of Form XXX atorvastatin calcium.

[0059] FIG. 18 Raman spectrum of Form XX atorvastatin calcium.

[0060] FIG. 19 Raman spectrum of Form XXII atorvastatin calcium.

[0061] FIG. 20 Raman spectrum of Form XXIV atorvastatin calcium.

[0062] FIG. 21 Raman spectrum of Form XXV atorvastatin calcium.

[0063] FIG. 22 Raman spectrum of Form XXVII atorvastatin calcium.

[0064] FIG. 23 Raman spectrum of Form XXVIII atorvastatin calcium.

[0065] FIG. 24 Solid state .sup.13C nuclear magnetic resonance spectrum of Form XX atorvastatin calcium.

[0066] FIG. 25 Solid state .sup.13C nuclear magnetic resonance spectrum of Form XXII atorvastatin calcium.

[0067] FIG. 26 Solid state .sup.13C nuclear magnetic resonance spectrum of Form XXIV atorvastatin calcium.

[0068] FIG. 27 Solid state .sup.13C nuclear magnetic resonance spectrum of Form XXV atorvastatin calcium.

[0069] FIG. 28 Solid state .sup.13C nuclear magnetic resonance spectrum of Form XXVII atorvastatin calcium.

[0070] FIG. 29 Solid state .sup.13C nuclear magnetic resonance spectrum of Form XXVIII atorvastatin calcium.

[0071] FIG. 30 Solid state .sup.13C nuclear magnetic resonance spectrum of Form XXX atorvastatin calcium.

[0072] FIG. 31 Solid state .sup.19F nuclear magnetic resonance spectrum of Form XX atorvastatin calcium.

[0073] FIG. 32 Solid state .sup.19F nuclear magnetic resonance spectrum of Form XXII atorvastatin calcium.

[0074] FIG. 33 Solid state .sup.19F nuclear magnetic resonance spectrum of Form XXIV atorvastatin calcium.

[0075] FIG. 34 Solid state .sup.19F nuclear magnetic resonance spectrum of Form XXV atorvastatin calcium.

[0076] FIG. 35 Solid state .sup.19F nuclear magnetic resonance spectrum of Form XXVII atorvastatin calcium.

[0077] FIG. 36 Solid state .sup.19F nuclear magnetic resonance spectrum of Form XXVIII atorvastatin calcium.

[0078] FIG. 37 Solid state .sup.19F nuclear magnetic resonance spectrum of Form XXX atorvastatin calcium.

DETAILED DESCRIPTION OF THE INVENTION

[0079] Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV, Form XXVI, Form XXVII, Form XXVIII, Form XXIX, or Form XXX atorvastatin calcium may be characterized by x-ray powder diffraction patterns, by itself solid stale nuclear magnetic resonance spectra (NMR), and/or their Raman spectra.

[0080] The “forms” of atorvastatin calcium disclosed in the present invention may exist as disordered crystals, liquid crystal, plastic crystals, mesophases, and the like. Forms that are related through disorder will have essentially the same major peak positions but the disordering process will cause broadening of these peaks. For many of the weaker peaks, the broadening may be so severe that they are no longer visible above the background. The peak broadening caused by disorder may in addition cause errors in the location of the exact peak position.

X-ray Powder Diffraction

[0081] Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV, Form XXVI, Form XXVII, Form XXVIII, Form XXIX, or Form XXX atorvastatin calcium may be characterized by X-ray powder diffraction patterns. Thus, the X-ray powder distraction patters of Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, and XXX were carried out on a Shimadzu XRD-6000 X-ray diffractometer using CuK.sub.a radiation. This instrument is equipped with a fine focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1°, and the receiving slit was set at 0.15 mm. Diffraction radiation was detected by a Nal scintillation detector. A theta-two theta continuous scan at 3° C./min (0.4 sec/0.0220 step) from 2.5 to 40° 2θ was used. A silicon standard was analyzed each day to check the instrument alignment. Data were collected and analyzed using XRD-6000 V. 4.1. Samples were prepared for analysis by placing them in an aluminum holder.

[0082] The X-ray powder diffraction patterns of Forms XXVIII and XXIX were carried out on a Bruker D5000 diffractometer using CuK.sub.a radiation. The instrument was equipped with a fine focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set at 1 mm, and the receiving slit was set at 0.6 mm. Diffracted radiation was detected by a Kevex PSI detector. A theta two theta continuous scan at 2.4°/min (1 sec/0.4° step) from 3.0 to 40° 2θ was used. An alumina standard was analyzed to check the instrument alignment. Data were collected and analyzed using Bruker axs software Version 7.0. Samples were prepared for analysis by placing them in a quartz holder. It should be noted that Bruker Instruments purchased Siemens; thus, a Bruker D5000 instrument is essentially the same as a Siemens D5000.

[0083] To perform an X-ray diffraction measurement on a Bragg-Brentano instrument like the Shimadzu system or the Bruker system used for measurements reported herein, the sample is typically placed into a holder which has a cavity. The sample powder is pressed by a glass slide or equivalent to ensure a random surface and a proper sample height. The sample holder is then placed into the Shimadzu instrument. The incident X-ray beam is directed at the sample, initially at a small angle relative to the plane of the holder, and then moved through an arc that continuously increases the angle between the incident beam and the plane of the holder. Measurement differences associated with such X-ray powder analyses result from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors (e.g. flat sample errors), (c) calibration errors,(d) operator errors (including those errors present when determining the peak locations), and (e) the nature of the material (e.g. preferred orientation and transparency errors. Calibration errors and sample height errors often result in a shift of all the peaks in the same direction. Small differences in sample height when using a flat holder will lead to large displacements in XRPD peak positions. A systematic study showed that, using a Shimadzu XRD-6000 in the typical Bragg-Brentano configuration, sample height difference of 1 mm lead to peak shifts as high as 1° 2θ (Chen et al.: J Pharmaceutical and Biomedical Analysis, 2001; 26,63). These shifts can be identified from the X-ray Diffractogram and can be eliminated by compensating for the shift (applying a systematic correction factor to all peak position values) or recalibrating the instrument. As mentioned above, it is possible to rectify measurements from the various machines by applying a systematic correction factor to bring the peak positions into agreement. In general, this correction factor will bring the measured peak positions from the Shimadzu or Bruker into agreement with the expected peak positions and may be in the range of 0 to 0.2°2θ.

[0084] Tables 1-11 list peak positions in degrees 2θ, relative intensities, and relative peak widths for X-ray powder diffraction patterns of each form of atorvastatin calcium disclosed in the present application. The relatively narrow peak positions were picked by the Shimadzu software using default settings. X-ray powder diffraction patterns were processed by the Shimadzu XRD-6000 version 2.6 software to automatically find peak positions The “peak position” means the maximum intensity of a peaked intensity profile. To maximize accuracy and precision, the entire intensity profile is considered when selecting peak positions. Intensity spikes from large crystals and the expected intensity fluctuations from noise were considered in picking the position of a peak.

[0085] The following processes were used with the Shimadzu XRD-6000 “Basic Process” version 2.6 algorithm:

1. Smoothing was done on all patterns. [0086] 2. The background was subtracted to find the net, relative intensity of the peaks. [0087] 3. A peak from CuK.sub.a alpha2 (1.5444 Å) wavelength was subtracted from the peak generated by CuK.sub.a alpha1 (1.5406 Å) peak at 50% intensity for all patterns.

[0088] Default values of the software were used in picking the peaks and all peak positions were rounded to 1/10.sup.th. Some of the XRPD patterns displayed very diffuse and very noisy patterns and the peak positions were determined manually, and expressed as a range of degree 2 theta (from the beginning of the broad peak to the end of the broad peak). All peak positions were rounded to 0.1° 2θ. The following abbreviations are used to describe the peak intensity (s=strong; m=medium; w=weak) and the peal width (b=broad (where broad refers to peak widths of between 0.2 and 1.0 degrees 2θ, sh=shoulder, vb=very broad (where very broad refers to peaks with >1 degrees 2θ peak width)).

TABLE-US-00012 TABLE 1 XPRD Peak List for Form XX degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 7.5-9.0 m vb 17.5-26.0 s vb .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00013 TABLE 2 XPRD Peak List for Form XXI degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 3.1 w b 4.1 w b 5.0 w b 6.3 w b 7.6 s b 8.6 m b, sh 9.2 w b, sh 10.1 w b 12.2 w b 16.7 m vb 18.2 m vb 19.2 m vb 20.1 m vb 20.5 w vb 23.1 m vb, sh 29.6 w vb .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00014 TABLE 3 XPRD Peak List for Form XXII degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 4.0 m b 4.9 w b 8.0 m b 10.0 s b 11.1 w b 11.7 w b 12.2 w b 13.1 w b, sh 13.5 m b 14.0 w b 14.8 w b, sh 16.1 m b 16.4 m b, sh 17.0 m b 17.4 m b, sh 17.7 m b, sh 19.2 w b 20.0 m b 20.3 m b 21.3 w b 22.6 w b 24.5 w vb 27.0 w b 28.1 w b 28.9 w vb 29.4 w vb .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00015 TABLE 4 XPRD Peak List for Form XXIII degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 3.2 w b 4.1 w b 5.0 w b 6.3 w b 7.2 w b, sh 7.7 s b 8.1 m b 8.5 m b 9.1 w b 10.1 w b 10.5 w b 12.1 w b 12.8 w b 13.3 w b 16.7 m vb 18.4 m vb 19.1 m b 20.2 m vb 21.0 w b 21.4 m b 23.2 m vb 24.3 w b 25.2 w b 29.3 w b .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00016 TABLE 5 XPRD Peak List for Form XXIV degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 2.9 m b 4.6 w b 5.2 w b 7.4 m b, sh 7.8 s b 8.7 m b 9.5 s b 10.0 w b 12.2 w vb 12.5 w b 13.4 w b 13.9 w b 17.3 w vb 18.0 m b 18.6 m b 19.0 m vb 20.6 w b 21.2 w vb 22.3 w vb 22.7 s b 23.2 m b, sh 24.2 w b 24.5 w vb 25.0 w vb 26.4 w vb 28.8 w vb 31.8 w b .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00017 TABLE 6 XPRD Peak List for Form XXV degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 3.1 w b 5.2 w vb 6.4 w sh, b 7.4 s vb 7.9 w sh, vb 8.7 m vb 10.4 w vb 12.0 w vb 12.7 w vb 16.6 m vb 18.1 m vb 19.2 m vb 20.0 m b 20.7 m b 22.8 m vb 23.2 m vb 24.4 m vb 25.6 w vb 26.5 w vb 29.3 w vb .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00018 TABLE 7 XPRD Peak List for Form XXVI degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 3.7 w b 7.3 w b, sh 8.4 s b 9.0 s b 12.2 w b 16.0 w vb 17.1 m vb 17.7 m vb 18.7 m b 20.1 s b 20.7 m b, sh 22.3 m vb 23.0 m vb 25.2 m vb 28.7 w vb .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00019 TABLE 8 XPRD Peak List for Form XXVII degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 3.5 w b, sh 3.9 m b 4.6 w b 7.1 w vb, sh 7.5 s b 7.9 m vb, sh 9.6 m b 9.9 m b 10.6 w b 11.8 w b 13.0 w vb 15.3 w b 16.6 w vb 17.2 w b 18.7 s b 22.6 w vb 23.8 w b 25.1 w b .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00020 TABLE 9 XPRD Peak List for Form XXVIII degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 7.6 s b 9.5 m b 12.2 w b 16.5 m b 17.0 m b 18.0 w b 19.2 w b 19.5 w b, sh 20.5 m b 20.9 w b 21.5 w b 21.8 w b, sh 22.3 m vb 23.3 w b 23.8 w b .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00021 TABLE 10 XPRD Peak List for Form XXIX degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 8.0 m b 10.2 w b 11.5 m b 14.5 w b 15.3 w b 16.2 m vb 18.0 m b 19.6 m b 20.2 m b 20.6 w b 21.4 w b 22.3 m b 23.0 m b 23.9 w b 24.2 m b 24.9 s b 25.9 w vb 26.9 w b 28.6 w b 29.1 w b 30.4 w b 30.9 w b .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

TABLE-US-00022 TABLE 11 XPRD Peak List for Form XXX degree 2θ Relative Intensity.sup.a Relative Peak Width.sup.b 3.1 s b 9.0 m b 9.7 w b 10.5 w b 12.0 w b 16.5 w b 17.0 m b 19.0 m b 19.3 w b, sh 19.9 w b 20.9 m b 21.1 w b 21.6 s b 22.5 m vb 24.3 m b 26.7 w b 27.0 w b 27.6 w b 29.6 w b 31.8 w b .sup.as = strong; m = medium; w = weak .sup.bb = broad; sh = shoulder; vb = very broad (>1 degrees 2θ peak width)

[0089] Table 12 lists combination of 2θ peaks for Forms XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium, i.e., a set of x-ray diffraction lines that are unique to each form.

TABLE-US-00023 TABLE 12 Forms XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX. Form degree 2θ XXI 3.1 4.1 5.0 7.6 16.7 18.2 19.2 20.1 20.5 23.1 XXII 4.0 8.0 10.0 13.5 16.1 16.4 17.0 17.4 19.2 20.0 20.3 XXIII 4.1 5.0 6.3 7.7 8.5 9.1 10.5 16.7 18.4 20.2 21.4 XXIV 2.9 7.4 7.8 8.7 9.5 10.0 12.2 18.0 18.6 19.0 22.7 XXV 3.1 5.2 7.4 8.7 10.4 12.7 16.6 18.1 19.2 20.0 20.7 23.2 24.4 XXVI 3.7 8.4 9.0 17.1 17.7 18.7 20.1 22.3 23.0 XXVII 3.9 4.5 7.1 7.5 9.6 10.6 11.8 13.0 15.3 18.7 XXVIII 7.6 9.5 12.2 16.5 17.0 18.0 20.5 21.5 22.3 XXIX 8.0 10.2 11.5 14.5 15.3 18.0 19.6 20.2 22.3 24.9 XXX 3.1 9.0 9.7 12.0 16.5 17.0 20.9 21.6 22.5 24.3

[0090] Further, Table 13 lists additional combinations of 2θ peaks for Forms XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium, i.e., an additional set of x-ray diffraction lines that are unique to each form.

TABLE-US-00024 TABLE 13 Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX Form Degree 2θ Form XXI 3.1 4.1 5.0 7.6 16.7 18.2 19.2 23.1 Form XXII 4.0 10.0 13.5 17.0 19.2 20.3 Form XXIII 4.1 5.0 6.3 7.7 8.5 9.1 10.5 16.7 21.4 Form XXIV 2.9 7.4 7.8 8.7 9.5 12.2 18.6 19.0 22.7 Form XXV 3.1 5.2 7.4 8.7 23.2 24.4 Form XXVI 3.7 8.4 9.0 17.1 18.7 20.1 23.0 Form XXVII 3.9 4.5 7.5 9.6 10.6 13.0 15.3 18.7 Form XXVIII 7.6 9.5 12.2 16.5 17.0 18.0 21.5 22.3 Form XXX 9.0 9.7 12.0 16.5 17.0 21.6 22.5 24.3

Small Angle Powder X-Ray Diffraction

Methodology

[0091] Powder materials of different lots of atorvastatin calcium were packed in either glass or quartz x-ray capillaries with diameter of 1 to 2 mm. Small-Angle X-Ray Diffraction (SAXD) experiments were performed at the beamline ID2. European Synchrotron Radiation Facility (ESRF) Grenoble, France. The radiation wavelength was 0.996 Å (silicon channel-cut monochromator). The 2-dimensional SAXD images were recorded using image-intensified change coupled device (CCD) detector and the data was expressed as reciprocal spacing q in nm.sup.−5 units. The exposure time was adjusted to use the maximum dynamic of the detectors for every particular sample and was less than 1s in the majority of cases. The 2-dimensional images were normalized to an absolute intensity scale after performing the standard detector corrections and azimuthally integrated to obtain the corresponding 1-dimensional x-ray diffraction curves. Peaks positions were measured using Gaussian fit using single peak analysis. The SAXD and (wide angle x-ray diffraction) WAXD q-scales were calibrated with silver behenate and silicon powders, respectively.

[0092] Table 14 shows the SAXRD peaks for Forms XX, XXII, XXIV, XXV, XXVII and XXX atorvastatin calcium.

TABLE-US-00025 TABLE 14 SAXRD Data Form Position of peaks, q, nm.sup.−1 XX 2.11 3.93 XXII 2.85 3.48 4.16 XXIV 2.09 2.24 2.84 3.33 3.54 3.69 4.50 5.23 XXV 2.22 2.86 3.62 4.46 5.28 XXVII 2.19 2.76 2.86 3.27 3.33 4.00 4.69 4.97 XXX 2.13 4.26

Raman Spectroscopy

Methodology

[0093] The Raman spectrum was obtained on a Raman accessory interfaced to a Nicolet Magna 860 Fourier transform infrared spectrometer. The accessory utilizes an excitation wavelength of 1064 nm and approximately 0.45 W of neodymium-doped yttrium aluminum garnet (Nd:YAG) laser power. The spectrum represents 6 or 128 co-added scans acquired at 4 cm.sup.−1 resolution. The sample was prepared for analysis by placing a portion into a 5-mm diameter glass tube and positioning this tube in the spectrometer. Peak tables were generated using the Nicolet software with default threshold and sensitivity settings. The spectrometer was calibrated (wavelength) with sulfur and cyclohexane at the time of use.

[0094] Table 15 shows the Raman spectra for Forms XX, XXII, XXIV, XXV, XXVII and XXVIII atorvastatin calcium.

TABLE-US-00026 TABLE 15 Raman Peak Listing Peak Positions in Wavenumbers (cm.sup.−1) Form cm.sup.−1 XX 618 818 855 892 999 1034 1158 1178 1244 1412 1480 1528 1558 1604 1649 3059 XXII 618 820 855 998 1033 1157 1243 1364 1410 1526 1603 1671 3059 XXIV 133 217 247 298 422 500 617 643 697 789 811 825 857 900 925 961 1000 1034 1056 1112 1160 1179 1240 1301 1370 1398 1413 1473 1527 1603 1651 2263 2555 2922 2972 3062 XXV 138 224 245 300 422 495 617 644 697 726 825 859 901 1001 1034 1058 1112 1159 1181 1243 1320 1368 1397 1412 1477 1528 1604 1654 2257 2933 3063 XXVII 130 288 366 512 581 618 634 736 821 858 898 998 1034 1112 1158 1240 1314 1368 1411 1481 1527 1559 1578 1604 1658 2927 3063 XXVIII 148 248 296 341 405 522 478 617 642 699 755 824 863 999 1034 1062 1090 1159 1180 1242 1298 1316 1369 1412 1468 1525 1603 1640 2882 2940 3060 3376

Solid State Nuclear Magnetic Resonance (NMR)

Methodology

[0095] Solid-state .sup.13C NMR and .sup.19F NMR spectra were obtained at 293 K on 500 MHz NMR spectrometer. Approximately 80 mg of sample were tightly packed into a 4 mm ZrO spinner for analysis. The one-dimensional solid state spectra were collected at ambient pressure and 293 K on a wide-bore Bruker-Biospin Avance DSX 500 MHz NMR spectrometer using a Bruker 4 mm HFX BL cross-polarization magic angle spinning (CPMAS) probe. To minimize the spinning side bands, spinning speed was set to 15.0 kHz, the maximum specified spinning speed for the 4 mm HFX BL probe. .sup.13C CPMAS and .sup.19F MAS peaks were peak-picked using Bruker-Biospin TOPSPIN 1.3 software, by suitably setting the spectral window and the peak picking threshold intensity to eliminate peak picking of spinning side bands. The detection sensitivity parameter (PC) was typically set to 0.5.

.SUP.13.C CPMAS

[0096] The one-dimensional .sup.13C spectra were collected using .sup.1H-.sup.13C cross-polarization magic angle spinning (CPMAS). To optimize the signal sensitivity, the cross-polarization contact time was adjusted to 2.3 ms, and the decoupling power was set to 80 kHz. The carbon spectra were acquired with approximately 1,100 scans with a recycle delay of 8 seconds. They were referenced using an external sample of adamantane, setting its upfield resonance to 29.5 ppm.

.SUP.19.F MAS

[0097] The one-dimensional .sup.19F spectra were collected using magic angle spinning (MAS) with proton decoupling. The decoupling field was set to approximately 65 kHz. .sup.19F detected .sup.1H T1 relaxation times were calculated based on inversion recovery experiments. For all samples, the probe background was reduced by subtracting signal from interleaved scans, during which a .sup.19F presaturation pulse was applied. The spectra were acquired with approximately 64 scans with a recycle delay of 10 seconds. The samples were referenced using an external sample of trifluoroacetic acid (diluted to 50% V/V by H.sub.2O), setting its resonance to −76.54 ppm.

[0098] Table 16 shows the .sup.13C solid state NMR spectrum for Forms XX, XXII, XXIV, XXV, XXVII, XXVIII, and XXX atorvastatin calcium. Table 17 shows the .sup.19F solid state NMR spectrum for Forms XX, XXII, XXIV, XXV, XXVII, XXVIII, and XXX atorvastatin calcium.

TABLE-US-00027 TABLE 16 CPMAS .sup.13C Data Form Solid State Chemical Shift.sup.a [ppm] XX 180.7 166.8 162.9 161.0 134.7 128.5 122.5 118.6 69.8 41.8 26.1 21.7 XXII 182.1 166.6 164.1 161.8 143.7 139.4 136.1 134.2 129.1 123.4 119.7 115.7 68.7 45.1 43.9 39.1 37.4 26.8 22.7 20.6 18.3 XXIV 187.5 185.2 184.2 180.5 179.0 178.4 177.4 166.8 162.7 160.9 138.7 138.2 133.7 128.7 124.4 122.4 121.2 120.5 118.0 115.7 69.8 67.4 65.7 46.4 44.3 43.5 40.6 26.7 25.5 21.8 19.6 0.0 XXV 186.3 185.0 182.5 177.0 167.0 166.2 162.8 160.9 138.6 136.1 133.4 129.2 128.5 126.0 124.0 121.5 120.7 118.0 116.8 116.0 69.9 68.0 46.4 43.3 40.9 25.7 25.2 21.3 20.0 0.6 XXVII 179.7 166.0 163.6 161.7 140.7 133.8 128.8 122.4 115.3 72.5 70.9 66.6 41.8 27.3 22.0 XXVIII 184.1 183.4 181.2 180.9 165.8 162.5 160.5 138.1 137.5 135.3 134.5 132.8 131.4 131.1 130.0 129.6 127.7 123.9 123.1 121.4 120.6 118.4 117.6 113.1 73.7 73.1 71.7 66.8 65.9 63.9 46.7 43.0 26.5 24.7 23.8 21.4 21.0 XXX 181.0 177.2 167.2 162.5 160.5 137.8 137.1 135.4 134.4 132.3 131.2 129.9 128.2 127.4 123.7 123.1 121.8 120.9 118.6 117.8 113.9 67.9 65.4 63.9 47.5 47.0 46.2 43.3 41.5 40.5 26.2 25.5 24.9 21.8 21.4 .sup.aReferenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm.

TABLE-US-00028 TABLE 17 MAS .sup.19F Data Form Fluorine chemical shift.sup.a [ppm] XX −113.9 XXII −112.0 −114.8 −118.9 XXIV −114.0 −116.8 −117.9 XXV −113.2 −116.3 −118.4 XXVII −112.2 −113.0 −117.2 XXVIII −116.4 −117.1 −119.2 XXX −116.7 −118.6 .sup.aReferenced using an external standard of trifluoroacetic acid (diluted to 50% V/V by H.sub.2O), setting its resonance to −76.54 ppm.

[0099] Additionally Forms XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium may be characterized by an x-ray powder diffraction and a solid state .sup.19F nuclear magnetic resonance spectrum. For example:

[0100] A Form XXII atorvastatin calcium having an x-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation; 10.0, 16.1, and 19.2, and a solid state .sup.19F nuclear magnetic resonance having the following chemical shifts expressed in parts per million: −112.0 −114.8, and −118.9.

[0101] A Form XXIV atorvastatin calcium having an X-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation: 7.4, 9.5 and 12.2, and a solid state .sup.19F nuclear magnetic resonance having the following chemical shifts expressed in parts per million: −114.0, −116.8, and −117.9.

[0102] A Form XXV atorvastatin calcium having an x-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation: 7.4, 8.7, 19.2, and 20.0, and a solid state .sup.19F nuclear magnetic resonance having the following chemical shifts expressed in parts per million: −133.2, −116.3, and −118.4.

[0103] A Form XXVII atorvastatin calcium having an x-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation 3.9, 7.5, and 18.7, and a solid state .sup.19F nuclear magnetic resonance having the following chemical shifts expressed in parts per million: −112.2, −113.0, and −117.2.

[0104] A Form XXVIII atorvastatin calcium having an x-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation: 7.6, 9.5, 20.5, and 22.3. and a solid state .sup.19F nuclear magnetic resonance having the following chemical shifts expressed in parts per million: −116.4, −117.1 and −119.2.

[0105] A Form XXX atorvastatin calcium having an x-ray powder diffraction containing the following 2θ values measured using CuK.sub.a radiation: 3.1, 9.0, and 21.6, and a solid state .sup.19F nuclear magnetic resonance having the following chemical shifts expressed in parts per million: −116.7 and −118.6.

[0106] The forms of atorvastatin calcium described in the present invention may exist in anhydrous forms as well as containing various amounts of water and/or solvents. In general, these forms are equivalent to the anhydrous forms and are intended to be encompassed within the scope of the present invention.

[0107] The forms of atorvastatin calcium of the present invention, regardless of the extent of water and/or solvent having equivalent x-ray powder diffractograms are within the scope of the present invention.

[0108] The new forms of atorvastatin calcium described in the present application have advantageous properties.

[0109] The ability of a material to form good tablets at commercial scale depends upon a variety of physical properties of the drug, such as, for example, the Tableting indices described in Hiestand H. and Smith D., Indices of Tableting Performance, Powder Technology, 1984, 38; 145-159. These indices may be used to identify forms of atorvastatin calcium which have superior tableting performance. One such index is the Brittle Fracture Index (BFI), which reflects brittleness, and ranges from 0 (good—low brittleness) to 1 (poor—high brittleness).

[0110] The present invention provides a process for the preparation of Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium which comprises forming atorvastatin calcium from a solution or slurry in solvents under conditions which yield Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium.

[0111] The precise conditions under which Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium are formed may be empirically determined, and it is only possible to give a number of methods which have been found to be suitable in practice.

[0112] The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered trasdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component a compound of the present invention.

[0113] For preparing pharmaceutical compositions for the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulation material.

[0114] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

[0115] In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0116] The powders and tablets preferably contain from two or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, methylcellulose, sodium carboxymethycellulose, a low melting 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 providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0117] For preparing 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 homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0118] Liquid form preparations include solutions, suspensions, retention enemas, and emulsions, for example water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0119] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.

[0120] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0121] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0122] 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, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0123] The quantity of active component in a unit dosage preparation may be varied or adjusted from 0.5 mg to 100 mg, preferably 2.5 to 80 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

[0124] In therapeutic use as hypolipidermic and/or hypocholesterolemic agents and agents to treat BPH, osteoporosis, and Alzheimer's disease, the Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 2.5 mg to about 80 mg daily. A daily dose range of about 2.5 mg to about 20 mg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

[0125] The following nonlimiting examples illustrate the inventors' preferred methods for preparing the compounds of the invention:

EXAMPLE 1

[0126] [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt (Forms XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, and XXX atorvastatin calcium).

Form XX Atorvastatin Calcium

Method A

[0127] A 12.2 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156, which is herein incorporated by reference) was suspended in 300 mL of methanol (MeOH): H.sub.2O (95:5, v:v) and sonicated. The resulting suspension was filtered into a 1 L flask. The sample was evaporated on a rotary evaporator with an unheated water bath and the vacuum provided with an aspirator. The solid obtained was dried under vacuum at ambient temperature overnight to afford Form XX atorvastatin calcium.

Method B

[0128] A 24 mg sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) was dissolved in 7 mL of ethanol (EtOH):H.sub.2O (4:1, v:v) and filtered through a 0.2 μm nylon filter. The resulting solution was evaporated in an open vial to dryness to afford Form XX atorvastatin calcium.

Form XXI Atorvastatin Calcium

[0129] A 3.6 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) was dissolved in 10 mL of tetrahydrofuran;water (9:1, v/v) at 43° C. A 1-mL aliquot was filtered into a vial and approximately 1 mL of pre-warmed acetonitrile (ACN) was added drop-wise. The clear solution was placed in a refrigerator. Solids formed within 1 day, recovered with vacuum filtration, and air-dried at ambient temperature to afford Form XXI atorvastatin calcium.

Method B

[0130] A 10.5 g sample of Form I (U.S. Pat. No. 5,969,156) was slurried in 450 mL of isopropyl alcohol (IPA)/50 mL H.sub.2O (9:1) at room temperature for 20 days. The sample was then vacuum filtered. The sample was then slurried in 450 mL of ACN/50 mL H.sub.2O (9:1) overnight. The sample was vacuum filtered for 5 hours to afford Form XXI atorvastatin calcium.

Form XXII Atorvastatin Calcium

[0131] An 11.5 g sample of Form XX atorvastatin calcium (prepared as described above) was mixed with 29 mL of MeOH and stirred on an a ambient temperature orbital shaker for 1 day. The sample was then vacuum dried at ambient temperature for 1 day. The recovered solid was mixed with 29 ml of MeOH and slurried on an ambient temperature orbital shaker for less than 1 hour. The gel that formed was then mixed with an additional 40 mL of MeOH and slurried on the ambient temperature orbital shaker for 3 days. The solids were vacuum dried at ambient temperature for 1 day to afford Form XXII atorvastatin calcium.

Form XXIII Atorvastatin Calcium

Method A

[0132] A 1.5 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) was slurried with approximately 75 mL of ACN:water (9:1,v/v) in a flask and placed on an ambient temperature orbital shaker block for 1 day. The sample was divided into four portions and centrifuged and the supernatant decanted and discarded. The recovered solids were returned to the shaker block for 1 hour. The samples were air dried for less than 1 day. The four portions were recombined and the sample was further air-dried at ambient conditions for 3 hours to afford Form XXIII atorvastatin calcium.

Method B

[0133] A 11.0 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) was slurried with approximately 430 mL of ACN:water (9:1, v/v) on an ambient temperature magnetic stir plate at 500 rpm for 2 days. The sample was vacuum filtered through a 0.22-μm nylon membrane filter and the filtered solids were air dried at ambient conditions for 1 day to afford Form XXIII atorvastatin calcium.

Form XXIV Atorvastatin Calcium

[0134] A 1.0 g sample containing a mixture of amorphous atorvastatin calcium (U.S. Pat. No. 6,087,511, which is herein incorporated by reference) and Form XX atorvastatin calcium (prepared as described above) was slurried with 195 mL of ACN:water (9:1, v/v) in a flask and placed on a magnetic stir plate set at 55% and 500 rpm for 1 day. The sample was vacuum filtered using a 0.22-μm nylon membrane filter and the solids were slurried with 195 mL of the fresh solvent at the same conditions for 1 day. Again, the sample was vacuum filtered using 0.22-μm nylon membrane filter and the solids were slurried with 195 mL of the fresh solvent at the same conditions for 1 day. The solids were isolated by vacuum filtration and were air dried in petri dish at ambient conditions for 4 days to afford Form XXIV atorvastatin calcium.

Form XXV Atorvastatin Calcium

[0135] A 58 mg sample of Form XX atorvastatin calcium (prepared as described above) was slurried in 2 mL of ACN:water (9:1) on a magnetic stir plate for 5 days and then filtered to afford Form XXV atorvastatin calcium.

Form XXVI Atorvastatin Calcium

Method A

[0136] A 2.0 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) was slurried with 0.57 mL at water in a vial, 5.1 mL of MeOH added, and the sample was placed on an orbital shaker block at 58 to 60° C. for 3 days. The resulting sample was vacuum dried between 70-75° C. for 3 days to afford Form XXVI atorvastatin calcium.

Method B

[0137] A 5.0 g sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) was dissolved in 200 mL of 80:20 (v/v) water/MeOH at 60° C. After forming a solution, a slurry resumed while stirring at 60° C. The slurry was isolated via vacuum filtration after 2.5 hours. The material was vacuum dried at 45° C. overnight to afford Form XXVI atorvastatin calcium.

Form XXVII Atorvastatin Calcium

Method A

[0138] A sample of Form VIII atorvastatin calcium (U.S. Pat. No. 6,605,729) which is herein incorporated by reference) was heatad on a sample holder in a Variable Temperature X-ray powder diffraction unit at 5° C./minute ramp rate. The temperature was held at 35°, 80°, 100°, 115°, and 140° C. for approximately 15 minutes. before reaching 165° C. to afford Form XXVII atorvastatin calcium. The Form XXVII atorvastatin calcium remained unchanged upon cooling to 40° C.

Method B

[0139] A sample of Form VIII atorvastatin calcium (U.S. Pat. No. 6,605,729) was heated using a variable temperature XRPD with humidity conditions remaining uncontrolled throughout the experiment. The sample was heated in a series of 4 steps beginning at 35° C., it continued up to 135° C. (holding for 13.5 min) and then on to 148° C. (holding for 15.5 min) before returning to 35° C. (holding for 15.5 min) to afford Form XXVII atorvastatin calcium. Form XXVII atorvastatin calcium was obtained at 148° C. and remained unchanged upon cooling to 35° C.

Form XXVIII Atorvastatin Calcium

[0140] A 0.3 g sample of amorphous atorvastatin calcium (U.S. Pat. No. 6,087,151) was slurried with 1 mL of ethylene glycol at 50° C. for 24 hours. The solids were isolates by vacuum filtration at ambient conditions to afford Form XXVIII atorvastatin calcium.

Form XXIX Atorvastatin Calcium

[0141] A 1.0 g sample of amorphous atorvastatin calcium (U.S. Pat. No. 6,087,151) was slurried with 8 mL of water tetrahydrofuran (4:1, v/v) at ambient temperature. The mixture was seeded with atorvastatin calcium Form XII (U.S. Pat. No. 6,605,729) and stirred at ambient conditions for 5 hours. The solids were isolated by vacuum filtration to afford Form XXIX atorvastatin calcium.

Form XXVIII Atorvastatin Calcium

Method A

[0142] A slurry containing 0.3 g of amorphous atorvastatin calcium (U.S. Pat. No. 6,087,151) and 24 mL of ethylene glycol was shaken on an ambient temperature orbital shaker block for about 1 day. The slurry was vacuum filtered and the solids were air dried at ambient temperature for 6 days to afford Form XXX atorvastatin calcium.

Method B

[0143] A 200 mg sample of Form I atorvastatin calcium (U.S. Pat. No. 5,969,156) was exposed to ACN vapor at ambient temperature inside a sealed chamber for two months to afford Form XXX atorvastatin calcium.