CRYSTALLINE PITAVASTATIN CALCIUM

INTRODUCTION

Aspects of the present application relate to crystalline form of pitavastatin calcium and processes for its preparation and isolation. Aspects of the application further relate to pharmaceutical compositions comprising crystalline form of the present application as well as methods for treating hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

Pitavastatin calcium is a common chemical name for bis [(E)-3f?,5S-dihydroxy-7-[4'-(4"-fluorophenyl)-2,-cyclopropyl-quinolin-3,-hept-6-enoic acid] calcium salt, is represented by formula (1):

Pitavastatin is a cholesterol-lowering agent (HMG-Co A reductase inhibitor). The HMG-Co A reductase enzyme catalyzes the conversions of HMG-Co A to mevalonate. Inhibitors of HMG-Co A reductase are commonly referred to as "statins." Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentrations in the blood of patients at risk for cardiovascular disease. The calcium salt, having a chemical name (+)monocalcium i)/'s{(3f?,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3,5-dihydroxy-6-heptanoate}, referred to hereinafter as "pitavastatin calcium," is the active ingredient in products marketed as LIVALO®.

Pitavastatin and its pharmaceutical^ acceptable salts are described in U.S. Patent Nos. 5,753,675 and 5,856,336. International patent applications viz., WO 2005/063711 A1 describes crystalline Form A of pitavastatin calcium which contains 5 to 15% of water and WO 2004072040 A1 discloses crystalline Forms A, B, C, D, E, F, and an amorphous form of pitavastatin calcium along with processes for their
preparation. Polymorphism is very common among pharmaceutical substances. Further, Chinese Patent Application Publication 101195603A describes a crystalline form of pitavastatin calcium, wherein the water content is in the range of 0.5-3%. Korean Patent Application Publication No. 2010125124A relates to a crystal form A of pitavastatin hemicalcium salt having peaks with relative intensities above 50%, at 5.2°, 6.2°, 7.7°, 19.9°, and 23.1° 29, in an X-ray powder diffraction pattern using copper Ka radiation.
Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one polymorphic form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.

Pharmaceutical stability is believed to depend on simultaneous influence of various factors, of which some important factors are the water content, residual solvents, and impurities. One or more of these factors may be uniquely addressed by the isolation process of the polymorphic forms of pitavastatin calcium. Therefore, it would be desirable to prepare and characterize new polymorphs of pitavastatin calcium. Further, it would be desirable to have reliable processes for producing these forms.

It is desirable that pharmaceutical products are stable for commercially relevant periods of time, without the need for specialized storage conditions. In the development of pharmaceutical compositions, crystallinity can be a desirable property for an active pharmaceutical ingredient. Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification, or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. They enlarge the repertoire of materials that a formulation scientists has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics.

Although the known forms of pravastatin and their polymorphic forms may address some of the deficiencies in terms of formulated product and its manufacturability, there remains a need for yet further improvement in these properties as well as improvements in other properties such as flowability, vapor impermeability, and solubility. Therefore, a need remains to prepare and characterize new crystalline forms of pitavastatin calcium, and to develop reliable processes for producing these crystalline forms.
SUMMARY Aspects of the present application relate to novel crystalline form of pitavastatin calcium and processes for its preparation.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 is an illustration of a powder X-ray diffraction ("PXRD") pattern of novel crystalline pitavastatin calcium Form III, as prepared in Example 1.

DETAILED DESCRIPTION

In an aspect, there are provided processes for the preparation of novel crystalline form of pitavastatin calcium, embodiments including:

a) providing a mixture comprising pitavastatin calcium in N,N-dimethyl acetamide;
b) combining the mixture of step a) with a suitable anti-solvent; and
c) recovering crystalline pitavastatin calcium
d) drying the product of step c)

A mixture comprising pitavastatin calcium may be obtained by providing isolated pitavastatin calcium in any form in a suitable solvent or such a mixture may be obtained directly from a reaction in which pitavastatin calcium is formed. To obtain a clear solution of pitavastatin calcium the reaction mixture can be heated to dissolution temperature that can be any temperature as long as the stability of the pitavastatin calcium is not compromised and a substantially clear solution is obtained. For example, the dissolution temperature may range from about 20°C to about the reflux temperature of the solvent. The solution can optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite®. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be heated to avoid premature crystallization.

Step b) involves combining the solution of step a) with an anti-solvent. The solution of step a) is added to a suitable anti-solvent. Suitable anti-solvents used in this step include, but are not limited to, alcohols, such as, for example, ethanol; ethers, such as, for example, diisopropyl ether, methyl terf-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, isopropyl acetate, and iso-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; hydrocarbons, such as heptane, hexane, cyclohexane, methyl cyclohexane; aromatic hydrocarbons such as xylene and toluene; nitriles, such as acetonitrile, or the like; water; and any mixtures of two or more thereof. In embodiments, water is employed.

Suitable temperatures of an anti-solvent for combining with a solution of step a) can be any temperature below 40°C. In one embodiment, the temperature is below 20°C. In another embodiment, the temperature is below 5°C. The mixture may be stirred for solid formation at temperatures such as, for example, below about 5°C to about 25°C, for periods of time as required for complete solid formation. The exact temperatures and time required for complete solid formation can be readily determined by a person skilled in the art. Alternately, step-wise cooling can be done to ease the filtration by improving the morphology of crystalline particles. Further, the embodiment also includes the normal mode of addition wherein an anti-solvent is added to a mixture comprising pitavastatin calcium. In yet another aspect of the invention, either the solution of step a) or mixture of step b) can be kept for slow solvent evaporation at room temperature for a period suitable for crystallization of pitavastatin calcium in novel crystalline form.
Step c) involves recovery or isolation of crystalline pitavastatin calcium from the reaction mixture.
The isolation or recovery of crystalline pitavastatin calcium from the final mixture, with or without cooling below the operating temperature, can be any of techniques such as decantation, filtration by gravity or suction, centrifugation, or the like. The isolated crystals may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the isolated crystals may be washed with a solvent to wash out the mother liquor.

Step d) involves drying the product. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Drying may be carried out at temperatures less than about 60°C, less than about 40°C, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium, with or without applying vacuum. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 10 minutes to about 15 hours, or longer.

In yet another aspect, the present invention provides processes for the preparation of novel crystalline form of pitavastatin calcium, embodiments comprising:

a) slurrying pitavastatin calcium in a mixture of N,N-dimethyl acetamide and a suitable anti-solvent; and

b) recovering crystalline pitavastatin calcium from step a).

c) drying the product of step b)

In step a), suitable anti-solvent can be selected from the aforementioned list of solvents. The mixture of step a) may be stirred for formation of desired crystalline forms at temperatures such as, for example, below about 5°C to about 25°C, for periods of time as required for complete solid formation.

In step b) isolation or recovery of crystalline pitavastatin calcium from the final mixture, with or without cooling below the operating temperature, can be any of techniques such as decantation, filtration by gravity or suction, centrifugation, or the like. The isolated crystals may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the isolated crystals may be washed with a solvent to wash out the mother liquor.

Step c) involves drying the product of step b). Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Drying may be carried out at temperatures less than about 60°C, less than about 40°C, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium, with or without applying vacuum. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 10 minutes to about 15 hours, or longer.

Once obtained, crystals of pravastatin calcium may be used as the nucleating agent or "seed" crystals for subsequent crystallizations of pitavastatin calcium from solutions. The isolated novel crystalline form of pitavastatin calcium appears to be a mixed solvate of N,N-dimethyl acetamide and water.

An aspect of the present disclosure includes novel crystalline form of pitavastatin calcium, designated as "Form IN" that can be characterized by using any of various analytical techniques, such as powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), or Fourier-transform infrared (FT-IR) spectroscopy. For example, there is provided a novel crystalline Form III of pitavastatin calcium characterized by its powder X-ray diffractogram comprising peaks at 31.26 and 34.40 degrees of 20 values, a PXRD pattern with two or more peaks further selected from about 4.82, 6.16, 6.50, 8.18, 9.28, 9.73, 10.33, 12.32, 13.08, 13.95, 14.55, 18.04, 18.62, 20.89, 23.73, 24.78, and 29.67 degrees of 29 values.

In an embodiment, there is provided crystalline Form III of pitavastatin calcium, having a PXRD pattern with peaks located substantially as shown in Fig. 1. The crystalline form of the present invention is a solvated form, for example, a mixed solvate of dimethyl acetamide and water.

Also provided are pharmaceutical compositions containing a therapeutically effective amount of the crystalline form of pitavastatin calcium described herein, together with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions that include salts of pitavastatin with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir systems or combinations of matrix and reservoir systems. The compositions may be prepared using any of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated. Compositions of the present application further comprise one or more pharmaceutical acceptable excipients.

Pharmaceutically acceptable excipients that find use in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic, cationic, and neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.

The processes of the present application are simple, cost-effective, ecologically friendly, reproducible, scalable, and robust, to produce pitavastatin calcium with high purity. Pitavastatin calcium employed as a starting material for generation of pitavastatin free acid can be obtained by any processes known in the art, including processes disclosed in U.S. Patent No. 5,856,336 and International Application Publication No. WO 95/11898 A1, both of which are incorporated herein by reference for their process descriptions, as well as by any other processes.

PXRD data reported herein are obtained using copper Ka radiation, and were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer. Crystalline forms are characterized using scattering techniques, e.g., powder or single crystal X-ray diffraction patterns, spectroscopic methods, e.g., infrared absorption spectrophotometry and 13C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry and differential thermal
analysis. In general, polymorphic forms are best distinguished by X-ray diffraction patterns, determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblain, J. Pharm. Sc/'.1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sc/1969 58:911-929.

Generally, the diffraction angles (20) for peaks in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, diffraction angle values should be understood as including values within the range of about ±0.2°. Although the intensities of peaks in X-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the PXRD peaks can vary depending on the sample preparation techniques, crystal size distributions, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2°.

DEFINITIONS

The following definitions are used in connection with the present application, unless the context indicates otherwise. Polymorphs are different solids sharing the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same formula. A pseudopolymorph is a different crystal types that is the result of hydration or solvation. The acronym ATD means "Agitated Thin-film Dryer".

All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25°C and atmospheric pressure unless otherwise designated. As used herein, a "room" or "ambient" temperature includes temperature from about 15°C to about 35°C, from about 20°C to about 30°C, or about 25°C.

As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. All ranges recited herein include the endpoints, including those that recite a range "between" two values.

Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value. Where this document refers to a material, such as in this instance, crystalline forms of pitavastatin calcium by reference to patterns, spectra or other graphical data, it may do so by qualifying that they are "substantially" shown or as depicted in Figures, or by one or more data points. By "substantially" used in such a context, it will be appreciated that patterns, spectra and other graphical data can be shifted somewhat in their positions, relative intensities and/or values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X-ray diffraction arts, such shifts in peak positions or the relative intensities of one or more peaks can occur because of, without limitation: the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, or the like. However, those of ordinary skill in the art will be able to compare the figures herein with a pattern generated of an unknown form of, in this case, pitavastatin calcium, and confirm its identity as a form disclosed herein. The same holds true for other techniques which may be reported herein. In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure that uniquely define that crystalline form, salt, and/or optical isomer, within any associated and recited margin of error, for purposes of identification.

An "alcohol" is an organic liquid containing a carbon bound to a hydroxyl group, including, but not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, Ci. 6alcohols,orthe like.

An "ether" is an organic liquid containing an oxygen atom -O- bonded to two other carbon atoms, including, but not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like.

A "halogenated hydrocarbon" is an organic liquid containing a carbon bound to a halogen, including, but not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A "ketone" is an organic liquid containing a carbonyl group -(C=0)- bonded to two other carbon atoms, including, but not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3ketones, or the like.

A "hydrocarbon" is a liquid compound formed from carbon and hydrogen atoms, and may be linear, branched, cyclic, saturated, unsaturated, non-aromatic, or aromatic. Examples include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8aliphatic hydrocarbons, petroleum ethers, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10aromatic hydrocarbons, or the like.

A "nitrile" is an organic liquid containing a cyano -(C=N) bonded to another carbon atom, including, but not limited to, acetonitrile, propionitrile, C2-6nitriles, or the like.

A "polar aprotic solvent" has a dielectric constant greater than 15 and includes: amide-based organic solvents, such as hexamethyl phosphoramide (HMPA) and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; ester-based organic solvents, such as y-butyrolactone, ethylene carbonate, propylene carbonate, butylene carbonate, dimethyl carbonate, and propiolactone; pyridine-based organic solvents, such as pyridine and picoline; and sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethylsulfolane, 3-sulfolene, and sulfolane.

Any organic solvents may be used alone, or two or more of these may be combined in desired ratios.As used herein, the term "crystalline forms of pravastatin" encompasses solvates, hydrates, or the like.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES EXAMPLE 1: PREPARATION OF PRAVASTATIN CALCIUM FORM III.
Pravastatin calcium (5 g) is charged into a dry round bottom flask containing dimethyl acetamide (20 mL) at room temperature and stirred to produce a clear solution. The solution is filtered to remove particles and subsequently poured into pre-cooled water (80 mL) at 4°C and stirred for solid formation for about 15-20 minutes. The solid is collected by filtration and dried in an ATD at about 40°C for about 4 hours to afford the title compound in 86% having HPLC purity of about 99.73%. The moisture content is about 4.49% (w/w) and the dimethyl acetamide content is 92,900 ppm. The said pitavastatin calcium has the PXRD pattern of Fig. 1.

EXAMPLE 2: PREPARATION OF PITAVASTATIN CALCIUM FORM III.
Pitavastatin calcium (2 g) is charged into a dry round bottom flask containing dimethyl acetamide (8 mL) at room temperature and stirred to produce a clear solution. The solution is filtered to remove particles and subsequently poured into pre-cooled water (32 mL) at about 0-5°C and stirred for solid formation for about 15-20 minutes. The solid is collected by filtration and dried in an ATD at about 40°C for about 3 hours to afford the title compound in 75%. The moisture content is about 4.53% (w/w) and the dimethyl acetamide content is 87,163 ppm.

EXAMPLE 3: PREPARATION OF PITAVASTATIN CALCIUM FORM III.
Pitavastatin calcium (100 mg) is charged into a dry round bottom flask containing dimethyl acetamide (0.4 mL) at room temperature and stirred to produce a clear solution. The solution is taken in a clean beaker, covered with perforated aluminium foil, and kept at room temperature for slow solvent evaporation for about 1 month to afford the title compound.

EXAMPLE 4: PREPARATION OF PITAVASTATIN CALCIUM FORM III.

Pitavastatin calcium (500 mg) is charged into a dry round bottom flask containing dimethyl acetamide (2 mL) at room temperature and stirred to produce a clear solution. The solution is poured into pre-cooled methyl tert-butyl ether (8 mL) at 2°C. The solution is kept at room temperature for slow solvent evaporation for about 8 days and solid obtained is collected by filtration under vacuum and then dried in an ATD for 1 hour at 40°C to afford the title compound.

EXAMPLE 5: PREPARATION OF PITAVASTATIN CALCIUM FORM III.
Pitavastatin calcium (500 mg) is charged into a dry round bottom flask containing dimethyl acetamide (2 mL) at room temperature and stirred to produce a clear solution. The solution is poured into pre-cooled methyl iso-butyl ketone (8 mL) at 2°C. The solution is kept at room temperature for slow solvent evaporation for about 8 days and solid obtained is collected by filtration under vacuum and then dried in an ATD for 1 hour at 40°C to afford the title compound.

EXAMPLE 6: PREPARATION OF PITAVASTATIN CALCIUM FORM III.
Pitavastatin calcium (1 g) is slurried in a mixture of N,N-dimethyl acetamide (0.5 mL) and iso-butyl acetate (4.5 mL) at room temperature for 1 hour. The solid is collected by filtration under vacuum and then dried in an ATD for 1 hour at 40°C to afford the title compound.

EXAMPLE 7: PREPARATION OF PITAVASTATIN CALCIUM FORM III.
Pitavastatin calcium (1 g) is slurried in a mixture of N,N-dimethyl acetamide (0.5 mL) and methyl iso-butyl ketone (4.5 mL) at room temperature for 1 hour. The solid is collected by filtration under vacuum and then dried in an ATD for 1 hour at 40°C to afford the title compound.

CLAIMS:

1. A crystalline Form III of pitavastatin calcium characterized by powder X-ray diffractogram comprising peaks at 31.26 and 34.40 degrees of 20 values.

2. The crystalline form of claim 1 characterized by powder X-ray diffractogram with two or more peaks further selected from about 4.82, 6.16, 6.50, 8.18, 9.28, 9.73, 10.33, 12.32, 13.08, 13.95, 14.55, 18.04, 18.62, 20.89, 23.73, 24.78, and 29.67 degrees of 29 values.

3. A process for the preparation of Form III of pitavastatin calcium comprising,

a) providing a mixture comprising pitavastatin calcium in N,N-dimethyl acetamide;

b) combining the mixture of step a) with a suitable anti-solvent; and

c) recovering crystalline pitavastatin calcium.

d) drying the product of step c)

4. A process of claim 3 wherein suitable anti-solvent in step b) is selected from alcohols, ethers, esters, ketones, hydrocarbons, nitriles, water or their mixtures.

5. A process of claim 4 wherein suitable anti-solvent in step b) is selected from methyl iso-butyl ketone, methyl tert-butyl ether and water.

6. A process for the preparation of Form III of pitavastatin calcium comprising,

a) slurrying pitavastatin calcium in a mixture of N,N-dimethyl acetamide and a suitable anti-solvent; and

b) recovering crystalline pitavastatin calcium from step a).

c) drying the product of step b)

7. A process of claim 6 wherein in step a) suitable anti-solvent is selected from alcohols, ethers, esters, ketones, hydrocarbons, nitriles, water or their mixtures.

8. A process of claim 7 wherein suitable anti-solvent is selected from iso-butyl acetate and iso-butyl ketone.