WO2008059372A2

WO2008059372A2 - Crystal form of (3r,5r)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-metyl-benzylcarbamoyl)-2h-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt

Info

Publication number: WO2008059372A2
Application number: PCT/IB2007/003636
Authority: WO
Inventors: Jonathan M. Miller
Original assignee: Pfizer Products Inc.
Priority date: 2006-11-17
Filing date: 2007-11-16
Publication date: 2008-05-22
Also published as: WO2008059372A3

Abstract

A crystal form A of sodium; (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl- benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dιhydroxy-heptanoic acid is provided.

Description

CRYSTAL FORM OF (3R, 5R)-7-[2-(4-FLUORO-PHENYL)-4-ISOPROPYL-5-(4-METHYL- BENZYLCARBAMOYL)^H-PYRAZOL-S-YL]-S₁S-DIHYDROXY-HEPTANOIC ACID SODIUM SALT

BACKGROUND OF THE INVENTION

The present invention relates to a novel crystalline form of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4- isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt useful as a pharmaceutical agent, to a method for its production and isolation, to a pharmaceutical composition which includes this compound and a pharmaceutically acceptable carrier, as well as methods of using such compositions to treat subjects, including human subjects, suffering from hyperlipidemia, hypercholesterolemia, osteoporosis, and Alzheimer's disease.

High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis. The conversion of HMG-CoA to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. It is known that inhibitors of HMG-CoA reductase are effective in lowering the blood plasma level of low density lipoprotein cholesterol (LDL-C), in man. (cf. M.S. Brown and J. L. Goldstein, New England Journal of Medicine, 305, No. 9, 515-517 (1981)). It has been established that lowering LDL-C levels affords protection from coronary heart disease (cf. Journal of the American Medical Association, 251 , No. 3, 351- 374 (1984)).

Statins are collectively lipid lowering agents. Representative statins include atorvastatin, lovastatin, pravastatin, simvastatin and rosuvastatin. Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase. A number of patents have issued disclosing atorvastatin. These include: United States Patent Numbers 4,681 ,893; 5,273,995 and 5,969,156, which are incorporated herein by reference.

All statins interfere, to varying degrees, with the conversion of HMG-CoA to the cholesterol precursor mevalonate by HMG-CoA reductase. These drugs share many features, but also exhibit differences in pharmacologic attributes that may contribute to differences in clinical utility and effectiveness in modifying lipid risk factors for coronary heart disease. (Clin. Cardiol. BoI. 26 (Suppl. Ill), III-32-III-38 (2003)). Some of the desirable pharmacologic features with statin therapy include potent reversible inhibition of HMG-CoA reductase, the ability to produce large reductions in LDL-C and non- high-density lipoprotein cholesterol (non-HDL-C), the ability to increase HDL cholesterol (HDL-C), tissue selectivity, optimal pharmacokinetics, availability of once a day dosing and a low potential for drug-drug interactions. Also desirable is the ability to lower circulating very-low-density- lipoproteiπ(VLDL) as well as the ability to lower triglyceride levels.

At the present time, the most potent statins display in vitro IC₅₀ values, using purified human HMG-CoA reductase catalytic domain preparations, of between about 5.4 and about 8.0 nM. (Am. J. Cardiol. 2001; 87(suppl): 28B-32B; Atheroscer Suppl. 2002;2:33-37). Generally, the most potent LDL-C- lowering statins are also the most potent non-HDL-C-lowering statins. Thus, maximum inhibitory activity is desirable. With respect to HDL-C, the known statins generally produce only modest increases in HDL- C. Therefore, the ability to effect greater increases in HDL-C would be advantageous as well.

With respect to tissue selectivity, differences among statins in relative lipophilicity or hydrophilicity may influence drug kinetics and tissue selectivity. Relatively hydrophilic drugs may exhibit reduced access to nonhepatic cells as a result of low passive diffusion and increased relative hepatic cell uptake through selective organic ion transport. In addition, the relative water solubility of a drug may reduce the need for extensive cytochrome P450 (CYP) enzyme metabolism. Many drugs, including the known statins, are metabolized by the CYP3A4 enzyme system. (Arch. Intern. Med. 2000; 160:2273-2280; J. Am. Pharm. Assoc. 2000; 40:637-644). Thus, relative hydrophilicity is desirable with statin therapy. Two important pharmacokinetic variables for statins are bioavailability and elimination half-life. It would be advantageous to have a statin with limited systemic availability so as to minimize any potential risk of systemic adverse effects, while at the same time having enough systemic availability so that any pleiotropic effects can be observed in the vasculature with statin treatment. These pleiotropic effects include improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, reduction in blood plasma levels of certain markers of inflammation such as C-reactive protein, decreasing oxidative stress and reducing vascular inflammation. (Arterioscler. Thromb. Vase. Biol. 2001; 21 :1712-1719; Heart Dis. 5(1 ):2-7, 2003). Further, it would be advantageous to have a statin with a long enough elimination half-life to maximize effectiveness for lowering LDL-C.

Finally, it would be advantageous to have a statin that is either not metabolized or minimally metabolized by the CYP 3A4 systems so as to minimize any potential risk of drug-drug interactions when statins are given in combination with other drugs.

Accordingly, it would be most beneficial to provide a statin having a combination of desirable properties including high potency in inhibiting HMG-CoA reductase, the ability to produce large reductions in LDL-C and non-high density lipoprotein cholesterol, the ability to increase HDL cholesterol, selectivity of effect or uptake in hepatic cells, optimal systemic bioavailability, prolonged elimination half-life, and absence or minimal metabolism via the CYP3A4 system.

In addition, compounds exhibiting optimal solubility and hygroscopicity properties are desirable for pharmaceutical applications. More specifically, compounds having high aqueous solubility and low hygroscopicity in combination with high physical and chemical stability would be most beneficial for use in pharmaceutical formulations.

Amorphous (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol- 3-yl]-3,5-dihydroxy-heptanoic acid sodium salt, methods of making, methods of formulating and methods of using same are disclosed in U.S. Patent Application Serial No. 11/283,264 and PCT Patent Application Publication No. WO 2006/056845 which are fully incorporated herein by reference. I have now found a novel crystalline form of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4- methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt. The new crystalline form of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5- dihydroxy-heptanoic acid sodium salt is purer, more stable, and has advantageous manufacturing properties than the amorphous product. SUMMARY OF THE INVENTION

The present invention provides a crystalline form, "Form A", of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4- isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt having an X-ray powder diffraction pattern containing at least one of the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 6.9 or 18.9. Crystalline Form A of (3R, 5R)-7-[2-(4-fluoro- phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt may be further characterized as having an X-ray powder diffraction pattern containing the following 2- theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 6.9, 17.9, and 18.9. Additionally, Crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt may be further characterized as having an X-ray powder diffraction pattern containing any of the 2-theta values contained in Table 1 (+/- 0.1 degrees 2- theta) measured using CuKa radiation in addition to the 2-theta values listed above. The present invention is further directed to crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4- isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by solid state ¹³C nuclear magnetic resonance referenced to adamantane (29.5 ppm) having the following chemical shifts expressed in parts per million (+/- 0.2 ppm): 20.8, 25.8, and 45.1. Crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt may be further characterized by solid state ¹³C nuclear magnetic resonance referenced to adamantane (29.5 ppm) having the following chemical shifts expressed in parts per million (+/- 0.2 ppm): 131.4, 134.5, and 180.1. Additionally, crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy- heptanoic acid sodium salt may be further characterized by solid state ¹³C nuclear magnetic resonance referenced to adamantane (29.5 ppm) as having any of the chemical shifts contained in Table 2 expressed in parts per million (+/- 0.2 ppm) in addition to the chemical shifts listed in this paragraph.

In a separate embodiment, the present invention is directed to crystalline Form A of (3R, 5R)-7- [2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by solid state ¹⁹F nuclear magnetic resonance referenced to trifluoroacetic acid (50% VA/ in H₂O) (-76.54 ppm) comprising the following chemical shift in parts per million (+/- 0.2 ppm): -109.7.

In a still further embodiment, the present invention relates to crystalline Form A of (3R, 5R)-7-[2- (4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by Raman spectroscopy having at least one of the following peaks expressed in cm^'1 (+/- 2 cm^"1): 824.2, 831.5, or 844.5 Crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4- isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt may be further characterized by Raman spectroscopy having the following peaks expressed in cm^"1 (+/- 2 cm^" ¹): 824.2, 831.5, or 844.5. Additionally, crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl- 5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt may be further characterized by Raman spectroscopy having any of the peaks contained in Table 4 expressed in cm^'1 (+/- 2 cm^'1) in addition to the peaks listed above in this paragraph.

Crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-

2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt exhibits high water solubility, non- hygroscopicity, non-hydration, and high physical/chemical stability. Accordingly, crystalline Form A of

(3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy- heptanoic acid sodium salt is particularly useful for pharmaceutical formulation and application.

As an inhibitor of HMG-CoA reductase, the novel crystalline Form of (3R, 5R)-7-[2-(4-fluoro- phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt described herein is a useful hypolipidemic and hypocholesterolemic agent as well as an agent in the treatment of osteoporosis and Alzheimer's disease.

A further embodiment of the present invention is a pharmaceutical composition for administering an effective amount of crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl- benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt in unit dosage form in the treatment methods mentioned above.

Finally, the present invention is directed to methods for the production of crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy- heptanoic acid sodium salt in unit dosage form in the treatment methods mentioned above.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is further described by the following non-limiting examples which refer to the accompanying FIGS. 1 to 5, short particulars of which are given below.

FIG. 1 Powder x-ray diffractogram of crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4- isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt .

FIG. 2 Solid-state ¹³C nuclear magnetic resonance spectrum of crystal Form A of (3R, 5R)-7-[2- (4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt with spinning side bands identified by an asterisk.

FIG. 3 Solid-state ¹⁹F nuclear magnetic resonance spectrum of crystal Form A of (3R, 5R)-7-[2- (4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt with spinning side bands identified by an asterisk.

FIG. 4 Raman spectrum of crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4- methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt. DETAILED DESCRIPTION OF THE INVENTION

A crystalline form of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt , "Form A", has been characterized by powder X-ray diffractometry, ¹³C solid-state nuclear magnetic resonance spectroscopy, Raman spectroscopy, and ¹⁹F solid-state nuclear magnetic resonance spectroscopy.

Powder X-ray Diffractometry

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt was characterized by x-ray powder diffractometry. The x-ray powder diffraction pattern was collected on a Scintag X₂ Advanced Diffraction System X-ray powder diffractometer using Cu Ka radiation (1.54 A). The tube voltage and amperage were set to 45 kV and 40 mA, respectively. The sample was scanned from 3° to 34° 2-theta at a rate of 1° 2-theta per minute and a step size of 0.02° 2-theta. The diffractometer was calibrated for peak positions in 2-theta using a silicon standard. The sample was analyzed in an aluminum sample holder. The analysis was conducted at room temperature, which is generally 20°C to 30°C. Data were collected and integrated using DMSNT software version 1.37. Diffractograms were evaluated using DiffracPlus software, release 2003, with Eva version 9.0.

To perform an X-ray diffraction measurement on a Scintag X₂ Advanced Diffraction System X-ray powder diffractometer used for the measurement reported herein, the sample is typically placed into a cavity in the middle of the aluminum sample holder. The sample powder is pressed by a glass slide or equivalent to ensure a random surface and proper sample height. The sample holder is then placed into the Scintag X₂ Advanced Diffraction System instrument and the powder x-ray diffraction pattern is collected using the instrumental parameters specified above. Measurement differences associated with such X-ray powder diffraction analyses result from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument 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 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 x-ray powder diffraction peak positions. A systematic study showed that a sample height difference of 1 mm could 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 differences in measurements from the various instruments by applying a systematic correction factor to bring the peak positions into agreement. In general, this correction factor will bring the measured peak positions into agreement with the expected peak positions and may be in the range of the expected 2-theta value ± 0.1 ° 2-theta. Figure 1 shows the x-ray powder diffraction pattern of crystal Form A of (3R, 5R)-7-[2-(4-fluoro- phenylH-isopropyl-S-^-methyl-benzylcarbamoyl^H-pyrazol-S-yll-S.S-dihydroxy-heptanoic acid sodium salt. Table 1 lists peak positions in degrees 2-theta and relative intensities (>6%) for the x-ray powder diffraction pattern of crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl- benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt. The error for the peak positions in Table 1 is expected to be about +/- 0.1 degrees 2-theta. The relative intensities are expected to vary from sample to sample depending on the experimental conditions and preferred orientation.

TABLE 1 Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3- yl]-3,5-dihydroxy-heptanoic acid sodium salt x-ray powder diffraction pattern expressed in terms of the degrees 2-theta and relative intensities of >6%

¹³C Solid-State Nuclear Magnetic Resonance Spectroscopy

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt was characterized by ¹³C solid-state nuclear magnetic resonance spectroscopy (SS-NMR). Approximately 80 mg of the sample were tightly packed into a 4 mm ZrO spinner. The spectra were collected at ambient conditions on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned into a wide-bore Bruker-Biospin Avance DSX 500 MHz NMR spectrometer. The samples were positioned at the magic angle and spun at 15.0 kHz, corresponding to the maximum specified spinning speed for the 4 mm spinners. The fast spinning speed minimized the intensities of the spinning side bands. The number of scans was adjusted to obtain adequate S/N. The ¹³C solid state spectrum was collected using a proton decoupled cross-polarization magic angle spinning experiment (CPMAS). The proton decoupling field of approximately 85 kHz was applied. 762 scans were collected with a recycle delay of 9 seconds. The spectrum was referenced using an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm.

Figure 2 shows the solid-state ¹³C CP/MAS NMR spectra of crystal Form A of (3R, 5R)-7-[2-(4- fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt. Table 2 lists chemical shifts in ppm ¹³C CP/MAS NMR spectrum of crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy- heptanoic acid sodium salt. The error for the chemical shifts in Table 2 is expected to be about +/- 0.2 ppm. Relative intensities can vary depending on the actual setup of the CPMAS experimental parameters and the thermal history of the sample. CPMAS intensities are not necessarily quantitative.

TABLE 2 Crystal Form A (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3- yl]-3,5-dihydroxy-heptanoic acid sodium salt solid-state ¹³C nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million (ppm).

¹⁹F Solid-State Nuclear Magnetic Resonance Spectroscopy

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt was characterized by ¹⁹F solid-state nuclear magnetic resonance spectroscopy (SS-NMR). Approximately 80 mg of the sample were tightly packed into a 4 mm ZrO spinner. The spectra were collected at ambient conditions on a Bruker-Biospin 4 mm BL HFX CPMAS probe positioned into a wide-bore Bruker-Biospin Avance DSX 500 MHz NMR spectrometer. The samples were positioned at the magic angle and spun at 15.0 kHz, corresponding to the maximum specified spinning speed for the 4 mm spinners. The fast spinning speed minimized the intensities of the spinning side bands. The number of scans was adjusted to obtain adequate S/N. The ¹⁹F solid state spectrum was collected using a proton decoupled magic angle spinning (MAS) experiment. The proton decoupling field of approximately 80 kHz was applied and 16 scans were collected. The recycle delay was set to 600 seconds to ensure acquisition of quantitative spectra. Proton longitudinal relaxation times (¹H T₁) of 5.6 seconds were calculated based on a fluorine detected proton inversion recovery relaxation experiment. Fluorine longitudinal relaxation times (¹⁹F T₁) of greater than 102 seconds were calculated based on a fluorine detected fluorine inversion recovery relaxation experiment. The spectrum was referenced using an external sample of trifluoro-acetic acid (50% VW in H2O), setting its resonance to -76.54 ppm.

Figure 3 shows the solid-state ¹⁹F MAS NMR spectra of crystal Form A of (3R, 5R)-7-[2-(4-fluoro- phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt. Resonances due to spinning sidebands are marked with asterisks (*). Table 3 lists chemical shifts in ppm for the ¹⁹F MAS NMR spectrum of crystal Form A of (3R, 5R)-7-[2-(4-fluoro-pheπyl)-4-isopropyl-5-(4- methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt. The error for the chemical shifts in Table 3 is expected to be about +/- 0.2 ppm.

TABLE 3

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-beπzylcarbamoyl)-2H-pyrazol-3- yl]-3,5-dihydroxy-heptanoic acid sodium salt solid-state ¹⁹F nuclear magnetic resonance spectrum wherein chemical shift is expressed in parts per million (ppm).

F shifts ppm -109.7 Raman Spectroscopy

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt was characterized by Raman spectroscopy. The Raman spectrum was collected on a Kaiser Optical Systems Raman microscope interfaced with a Raman spectrometer. The laser source was a 300 mW diode laser operating at 785 nm, with an average power output of about 50 to 60 mW through a 5Ox, 11 mm working distance objective. The instrument was wavelength calibrated with a neon source such that the chemical shift of a silicon standard was within 1 cm^"1 of its expected value of 520.8 cm^'1. The spectrum collected represents an exposure time of 60 seconds with 5 accumulations at 4 cm'i resolution. The sample was prepared for analysis by placing a small amount onto a microscope slide and placing it under the microscope.

Figure 4 shows the Raman spectrum of crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4- isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt. Table 4 lists Raman shifts in cm^'1 and relative intensities (>9%) for the Raman spectrum of crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy- heptanoic acid sodium salt. The error for the chemical shifts in Table 4 is expected to be about +/- 2 cm^'1. The relative intensities are expected to vary from sample to sample depending on the experimental conditions.

TABLE 4 Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3- yl]-3,5-dihydroxy-heptanoic acid sodium salt Raman spectrum expressed in terms of the Raman shift

(cm^"1) and relative intensities of >9%

Crystalline forms, in general, can have advantageous properties. A polymorph, hydrate, or solvate is defined by its crystal structure and properties. The crystal structure can be obtained from X-ray data or approximated from other data. The properties are determined by testing. The chemical formula and chemical structure does not describe or suggest the crystal structure of any particular polymorphic or crystalline hydrate form. One cannot ascertain any particular crystalline form from the chemical formula, nor does the chemical formula tell one how to identify any particular crystalline solid form or describe its properties. Whereas a chemical compound can exist in three states - solid, solution, and gas - crystalline solid forms exist only in the solid state. Once a chemical compound is dissolved or melted, the crystalline solid form is destroyed and no longer exists (Wells J. I., Aulton M. E. Pharmaceutics. The Science of Dosage Form Design, Reformulation, Aulton M. E. ed., Churchill Livingstone, 1988; 13:237). The new crystalline form of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl- benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt described herein has advantageous properties:

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt is highly water soluble. 50 mg of sodium; (3R.5R)- 7-[4-benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate form A readily dissolves in 2 mL of water.

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt is non-hygroscopic. Sodium; (3R,5R)-7-[4- benzylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate form A adsorbs less than 2 weight % water at 25 ⁰C and 90% RH as measured by dynamic water vapor sorption analysis.

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt is anhydrous. Anhydrous forms are generally preferred as they have a lower propensity to dehydrate/transform to another solid form during processing and storage.

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptaπoic acid sodium salt is thermodynamically and physically stable. Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3- yl]-3,5-dihydroxy-heptanoic acid sodium salt does not transform to any more thermodynamically stable polymorphs or hydrates when suspended in organic solvents or aqueous-organic solvent mixtures. Further, crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-behzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt does not transform to any more thermodynamically stable polymorphs or hydrates upon heating up to about 225⁰C.

Crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H- pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt is chemically stable. Crystal Form A of (3R, 5R)-7- [2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt remains chemically stable during storage at 40 ⁰C and 75% RH. Further, crystal Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5- dihydroxy-heptanoic acid sodium salt remains chemically stable during storage at 70 ⁰C. The present invention provides a process for the preparation of crystalline Form A of (3R, 5R)-7-

[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt which comprises crystallizing (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl- benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt from a solution in solvents under conditions which yield crystalline Form A (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl- benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt .

The precise conditions under which crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4- isopropyl-5-(4-methyl-beπzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt is formed may be empirically determined, and it is only possible to provide a few methods which have been found to be suitable in practice. 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 transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either compounds or a corresponding pharmaceutically acceptable salt of a compound of the present invention.

For preparing pharmaceutical compositions from 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 encapsulating material.

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

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

The powders and tablets preferably contain from two or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting 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.

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 homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. 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.

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. 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.

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.

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. The quantity of active component in a unit dose preparation may be varied or adjusted from 0.5 mg to 1000 mg, preferably 1.0 mg to 200 mg, 2.5 mg to 150 mg, 5.0 to 100 mg, and from 10 mg 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. '

In therapeutic use as hypolipidemic and/or hypocholesterolemic agents and agents to treat osteoporosis and Alzheimer's disease, the crystalline Forms A of sodium; (3R,5R)-7-[4-benzylcarbamoyl- 2-(4-fluorophenyl)-5-isopropyl-imidazol-1-yl]-3,5-dihydroxy-heptanoate utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.5 mg to about 1000 mg daily. Daily dose ranges of about 1.0 mg to about 200 mg; about 2.5 mg to about 150 mg; about 5.0 to about 100 mg, and from about 10 mg to about 80 mg are 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.

The following non-limiting examples illustrate the inventors' preferred methods for preparing the compounds of the invention.

EXAMPLE 1

(3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy- heptanoic acid sodium salt (crystalline Form A)

Amorphous (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol- 3-yl]-3,5-dihydroxy-heptanoic acid sodium salt (Example 4, WO 2006/056845 and U.S. Pat. Appln. Ser. No. 11/283,264) (5 mg) is combined with a mixture of acetonitrile/water (95:5) (125 μl_) and heated for one hour at 80⁰C. The solution is then cooled to afford crystalline Form A of (3R, 5R)-7-[2-(4-fluoro- phenyl^-isopropyl-δ^-methyl-benzylcarbamoyl^H-pyrazol-S-yll-S.S-dihydroxy-heptanoic acid sodium salt. EXAMPLE 2

Alternative Process to Prepare (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-

2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt (crystalline Form A)

A 3-necked, 2 L round-bottomed flask is equipped with a mechanical stirrer, a J-KEM temperature probe, a Dean-Stark apparatus (used as a distillation head when needed), and a condenser, and is charged with crude (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol- 3-yl]-3,5-dihydroxy-heptanoic acid sodium salt (220 g, 91.8% pure by HPLC (area %)), 2-propanol (500 mL), and deioπized water (50 mL). The resulting mixture is heated to reflux at 82 ⁰C to achieve a thin slurry, which is then charged drop-wise with water, while maintaining reflux, until a solution is achieved (water addition was 40 mL to give a total water addition of 90 mL in 2-propanol (500 mL). The Dean Stark apparatus is opened so distillates could be drained off, the round-bottomed flask is fitted with an addition funnel, and 2-propanol is added at the same rate that distillation occurred to maintain a constant pot volume of approximately 600 mL. After distillation and re-addition of approximately 1.05 L of 2-

Propanol, the clear solution begins to look turbid, and the pot temperature rises slightly from 80 ⁰C until 83 ⁰C. The Dean Stark apparatus is closed to recycle the distillates and a solution of water (30 mL) in 2- propanol (500 mL) is added over 10 minutes while maintaining a pot temperature of > 79 ⁰C. The resulting solution is stirred at 80 ⁰C for 1 h. The heating is ceased, and the mixture is cooled to 40 ⁰C over >30 minutes. The resulting thin slurry is re-heated to 80 ⁰C for 1 h and is cooled to 20 ⁰C over 3 h and a thick slurry is observed. The solid is collected on a sintered glass funnel, and the cake is washed with 2-propanol (2 x 200 mL) and is dried on the filter for 1 h and then in a vacuum oven at 30 torr at 50 °C to afford (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]- 3,5-dihydroxy-heptanoic acid sodium salt (200 g) as a white to off-white crystalline solid.

Claims

CLAIMSWhat is claimed is:

1. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-ιsopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt having an X-ray powder diffraction pattern containing at least one of the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 6.9 or 18.9.

2. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt having an X-ray powder diffraction pattern containing the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 6.9, 17.9, and 18.9.

3. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt having an x-ray powder diffraction pattern containing the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 6.9, 9.4, 16.8, 17.9, and 18.9.

4. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt having an x-ray powder diffraction pattern according to claim 2 further comprising the following 2-theta values (+/- 0.1 degrees 2- theta) measured using CuKa radiation: 19.5, 23.2 and 28.6.

5. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt having an x-ray powder diffraction pattern according to claim 3 further comprising the following 2-theta values (+/- 0.1 degrees 2- theta) measured using CuKa radiation: 19.5, 23.2 and 28.6.

6. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by solid state ¹³C nuclear magnetic resonance referenced to adamantane (29.5 ppm) having the following chemical shifts expressed in parts per million (+/- 0.2 ppm): 20.8, 25.8, and 45.1.

7. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by solid state ¹³C nuclear magnetic resonance referenced to adamantane (29.5 ppm) having the following chemical shifts in parts per million (+/- 0.2 ppm): 131.4, 134.5, and 180.1.

8. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by solid state ¹³C nuclear magnetic resonance referenced to adamantane (29.5 ppm) according to claim 6 further comprising the following chemical shifts in parts per million (+/- 0.2 ppm): 126.6, 129.6, 131.4, 134.5, 138.0, 144.1 , and 180.1.

9. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenylH-i^s°Pr°Pyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by solid state ¹⁹F nuclear magnetic resonance referenced to trifluoroacetic acid (50% V/V in H₂O) (-76.54 ppm) comprising the following chemical shift in parts per million (+/- 0.2 ppm): -109.7.

10. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by Raman spectroscopy having at least one of the following peaks expressed in cm^"1 (+/- 2 cm^'1): 824.2, 831.5, or 844.5.

11. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by Raman spectroscopy having the following peaks expressed in cm^"1 (+/- 2 cm^"1): 824.2, 831.5, or 844.5.

12. A crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt characterized by Raman spectroscopy having the following peaks expressed in cm^'1 (+/- 2 cm^"1): 642.7, 812.8, 824.2, 831.5, 844.5, or 1205.4.

13. A pharmaceutical composition comprising a compound according to any of claims 1 to 12 in unit dosage form and a pharmaceutically acceptable carrier.

14. A process for the preparation of crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl- 5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt having an X-ray powder diffraction containing the following 2-theta values (+/- 0.1 degrees 2-theta) measured using CuKa radiation: 6.9, 17.9, and 18.9 which comprises crystallizing (3R, 5R)-7-[2- (4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy- heptanoic acid sodium salt from a solution in solvents under conditions which yield said crystalline Form A of (3R, 5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)- 2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt.

15. A process according to claim 14 wherein said solvent is the following solvent or solvent mixture: 2-propanol, 2-propanol/water, ethanol, ethanol/water, acetonitrile, acetonitrile/water, acetone, acetone/water, tetrahydrofuran, or tetrahydrofuran/water.